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R R " 4|"  0X'q8 R3 | 0; F   ("  " MjR ;!?MMMT T DB  CELLULAR FUNCTION Fluid Compartments Body weight: 18% protein, 7% mineral, 15% fat, 60% water Water ingested (2100ml/day), synthesized via oxidation of carbohydrates (200ml/day) 700ml/day lost through insensible losses (300-400 from resp tract, 300-400 from skin); 100ml/day lost through sweating, 100ml/day in poo 42L Decreases with age (indirectly proportion to fat), women have less water than men Extracellular FluidIntracellular Fluid14L28L20% body weight40% body weight1/3 TBW2/3 TBWHigh in Na, Cl, HCO3, CaHigh in K, Mg, proteins, PO, organic anionsLow in proteinHigh in protein (4x more) A) Extracellular fluid: Difficult to measure as few substances stay truly extracellular and takes a long time to equilibrate in jt spaces, aqueous humour, CT, cartilage, CSF Cannot be separated from lymph (returns protein back to the circulation Interstitial fluidBlood plasma10.5L3.5L75% of ECF25% of ECFOutwith vascular systemIn vascular systemLower proteinHigher proteinLower cations, higher anionsHigher cations, lower anions15% body weight5% body weight Interstitial fluid Cant be measured directly as difficult to sample fluid and drugs will spread to plasma ECF/intracellular vol ratio is higher in children, so dehydration develops more rapidly in children Interstital vol = ECF vol plasma vol Blood plasma Total blood volume (5L, 7-8% body weight) = 60% plasma + 40% cells Haematocrit (approx 0.36-0.4) = % of blood vol made up of cells Plasma and interstitial fluid are constant mixing EXCEPT proteins which has a higher concentration in plasma as they cant pass through capillary membrane, same ionic composition; because of Donnan effect conc of cations (+) is higher in plasma than interstitial fluid as protein is (-) binds cations, anions (-) higher in interstitial fluid Total blood vol = plasma vol X (100 / 100 haematocrit) Red cell volume = total blood vol plasma vol Glandular secretions, synovial, peritoneal, pericardial, eye, and CSF are separate from rest ECF so are transcellular fluids, small vol (1-2L) these are in potential spaces; have very permeable membranes with free exchange of fluid with interstitial fluid/capillaries B) Intracellular fluid: Intracellular fluid28L40% body weight2/3 TBWHigh in K, Mg, PO, organic anions, proteinDecreases with age and women (indirectly proportional to fat) Cant be measured directly: ICF vol = TBW ECF vol Measuring Volume of Fluid Compartments Measure vol of comptmt by injecting substance that will stay in that comptmt and calculating its dilution Must be amount injected / metabolized must be accurately measured non-toxic mix evenly through comptmt and not move to another comptmt have no effect on distribution of fluids in body Vol of distribution (eg. Sucrose space) = amount of drug injected amount excreted or metabolized in mixing period / conc of injected drug (remember: vol of drug x conc of drug in solution = mass of drug) To measure TBW: deuterium oxide, tritium oxide, aminopyrine/antipyrine ECF vol: inulin, mannitol, sucrose, 22Na, 125I-iothalamate, thiosulfate, radioactive Cl Interstitial fluid vol: cant be measured directly Plasma vol: Evans blue, 125I-albumin (labeled with iodine) Blood vol: RBCs labeled with 51Cr, 59Fe, 32P or antigens ICF vol: cant be measured directly Measuring Solutes Mole: molecular weight of substance in grams (eg. NaCl = 23 + 35.5g = 58.5g); 1 mole contains 6 x 1023 molecules Millimole: 1/1000 of mole Micromole: 1/1,000,000 of mole Molecular weight (in Daltons): mass of 1 molecule of substance : mass of 1/12 mass of atom of C-12 The Dalton: 1 Dalton = mass of 1/12 atom of C-12 Kilodalton: 1000th of Dalton, expressed as K, used as measure of mass of proteins Equivalent: 1 eq = 1 mol of ionized substance / its valence (eg. NaCl divides into 1 eq Na and 1 eq Cl ( 1 eq Na = 23g, 1 eq Ca = 40g/2) pH Is negative logarithm of [H]; for each unit pH drops, [H] increased x10 pH of water is 7.0 ([H] = 10-7) Need to maintain stable H; opposed by OH; should be 7.40 Maintained by buffering capacity buffer can bind/release H (eg. Carbonic acid H2CO3 = H + HCO3 if H added, equilibrium shifts to L, if OH added it will bind to H taking it out of the system and H2CO3 dissociates shifting eq to R; blood proteins) Movement Across Cell Membranes 1) Diffusion Gas/substance expands to fill all available volume - net flux from area of high concentration to low conc 2Y to continual random movement of substances Time taken to equilibrium  square of diffusion distance Magnitude of diffusing tendency  area diffusion taking place over (eg. Number of channels) conc gradient (diff in conc / thickness of boundary = Fick s law of diffusion) (ie. Amount of substance) elec gradient (Nernst potential) remember elec and conc gradients work together using Nernst equation pressure difference across membrane (the sum of all forces of molecules striking unit surface area) velocity of kinetic motion Simple diffusion: no interaction with carrier proteins; just through membrane/channel Facilitated diffusion: involves interaction with carrier protein, including binding and conformational change but needs no energy; in simple diffusion rate of diffusion is  to conc gradient, in facilitated there is a max diffusion rate (ie. It plateaus) Non-polar/lipid-soluble molecules (eg. O2, N2, CO2) can diffuse directly across lipid membranes of cells, but membranes have limited permeability to others therefore diffusion occurs through channels. Filtration: occurs in capillaries; process by which fluid forced through a membrane due to difference in pressure on 2 sides; plasma proteins/colloids cant pass through unless by vesicular transport ( osmotic pressure named oncotic pressure which opposes filtration out of capillaries 2) Osmosis The net diffusion of water across a selectively permeable membrane from a region of high water conc to low water conc High osmolality = concentrated solution = high osmotic pressure Cell membranes are relatively impermeable to solutes 3) Intercellular Connections Tight Junctions (zonula occludens): tie cells together, strength and stability (eg. In intestine, renal tubules, choroid plexus); interlocking ridges; permits passage of some ions and solute, prevent the movement of protein, maintaining different distribution of transporters in apical / basolateral membranes Gap Junctions: narrow intercellular space (3nm as opposed to 25nm) at this point; units called connexons (made up of 6 connexins surrounding a channel 2nm wide) that connects to connexon in adjacent cell ( passage of substances (eg. Molecular weight <1000 ions, sugars, aas) without entering ECF; permit rapid propogation of electrical current; Charcot-Marie-Tooth disease is 2Y to mutation of connexin 4) Exocytosis Vesicles bond to cell membrane via v-SNARE/t-SNARE arrangement ( area of fusion breaks down. Ca dependent; results in addition to cell membrane 2 pathways: non-constitutive: proteins enter secretory granules ( processing from pro-hormones to hormones ( exocytosis constitutive pathway: pro-hormones released before processed 5) Endocytosis Phagocytosis: bacteria, dead tissue etc binds with receptor ( membrane invaginates outwards to engulf bacteria ( more receptor bind to bacteria ( phagocytic vesicle formed ( actin and other fibrilar proteins contact forcing vesicle into cell and pinch it off (eg. Macrophages, WBC). If bacteria is tagged by ab this is opsonisation. Pinocytosis: same as phagocytosis, but substances ingested in soln, not visible under microscope; the only means by which macromolecules can enter cells Results in removal from cell membrane Can be constitutive: not specialized clathrin-mediated: receptor found at coated pits under which is latticework of fibrillar protein clathrin accumulated ( pit invaginates inwards ( clathrin surrounds endocytic vesiscle ( protein at neck of vesicle named dynamin involved in pinching off vesicle ( clathrin falls off ( pinocytic vesicle fuses with endosome and dumps contents into early endosome ( becomes late endosome which fuses with lysosome ( contents digested by proteases in lysosome; responsible for internalization of any receptors and ligands (eg. Nerve GF, LDL), role in synaptic function; requires intracellular ATP and extracellular Ca to aid in pinching of vesicle Lysosomes: large irregular structures surrounded by membrane formed by breaking off from GA; acidic interior helps in phagocytosis to digest food/damaged structures (lysosomes burst and digest damanged part of cell, or cause autolysis if cell badly damaged)/bacteria; will attach to vesicles that has been endocytosed ( empty hydrolases into vesicles ( digestive vesicle ( once digestion over, residual body composed of indigestible substances ( excreted by exocytosis; if lysosomal enzyme is absent ( lysosomal storage disease; contain hydrolase enzymes which split matter by adding H to one part and OH to another (eg. Glycogen ( glu, proteins ( aa) (eg. ribonuclease, deoxyribonuclease, phosphatase, glycosidases, collagenase); for killing bacteria it uses lysozyme (for bacterial membrane), lysoferrin (for Fe) and acid (to activate hydrolases and inactivate metabolism of bacteria) NB. All vesicles involved in 4) and 5) have protein coats; certain aa sequences on coats can ticket vesicle to travel to certain area NB. When a combination of 4) and 5) used to take things out of capillaries this is transcytosis/vesicular transport 6) Ion Channels Are channels; may be selectively permeable May be a) constantly open b) gated - By voltage (eg. Na channel gate opens when inner membrane loses its (-) charge; K channel gate opens when inside cell becomes (+) charged) All-or-none channel is either opened or closed rapidly at certain voltages By ligands (eg. Ach channel) binding of ligand caused conformational change External ligands (eg. Neurotransmitter, hormone) Internal ligands (eg. Ca, cAMP, G proteins) By mechanical stretch 6) Carriers Bind molecule and change its configuration when moving it Facilitated diffusion: if moving in direction of conc/elec gradient, need no energy (eg. Glu, aa) Active transport: against gradient; uses ATP therefore carriers are ATPases (eg. Na-K ATPase, H-K ATPases in gastric mucosa and renal tubules, Ca ATPase) Secondary active transport: Na transport coupled with other substances as co-transport or countertransport (eg. Na with Glu in intestine, Na with aa; Na against Ca in heart muscle, Na against H in PCT); if Na is diffusing along a conc gradient, its excess energy can take another substance with it Types are: Uniports: transport only 1 substance Symports: transport >1 substance together (eg. Na and glu from intestinal lumen into mucosal cells) Antiports: exchange one substance for another (eg. Ca out, Na in in cardiac muscles) NB. Patch clamping used to investigated transport proteins. Can be cell-attached / inside-out patch, or whole cell recording. NB. Sometimes substances must pass through  cellular sheets using combination of transport. Prinicples of Osmosis Osmotic pressure: pressure necessary to prevent solute migration ( to no. particles in certain vol of soln) higher osmotic pressure = higher solute concentration related to temp and vol dependent upon number rather than type of molecules 1mosm/L exerts 19.3mmHg of osmotic pressure so normal osmotic pressure of body fluids is 19.3 x 300 = 5790mmHg (5500 since not an ideal soln) Osmoles: express the conc of osmotically active particles 1 osmole = weight of substance / no. freely moving particles each molecule liberates in soln = 1 mole of solute particles = 1 gram molecular weight of osmotically active solute Ions will partially dissociate to become separate osmoles 1mol of NaCl ( osmolar conc of 2osm/L 1 molecule of albumin exerts same effect as 1 molecule glucose Osmole refers to NUMBER of osmotically active particles, not the molar concentration nor the weight of the particle all particles will exert roughly same amount of pressure on membrane as small molecules move fast and large slow ( same kinetic energy Ionic interactions prevent soln from being ideal soln and decrease its osmotic pressure Use the osmotic co-efficient of a substance in calculations to allow for this The more concentrated the solution the less it is an ideal soln Osmolal conc: measured by extent to which it decreases freezing point of soln 1 mol of ideal soln decreases freezing point by 1.86C expressed as osm/L of water Osmolarity: no. osmoles per litre soln affected by vol of solutes in soln and by temp Osmolality: no osmoles per kg solvent; Soln that has 1 osmole solute dissolved in kg water has osmolality of 1 osmole per kg NOT affected by vol of solute / temp Interstitial fluid and plasma: is 2Y to Na and Cl Intracellular fluid: is 2Y to K Plasma: Na, Cl, HCO3, plasma proteins, glucose, urea Plasma has slightly higher osmolarity than ISF and ICF 2Y to plasma proteins; but all approx 300mOsm/L Plasma osmolality = 2[Na] + [Glu x 0.055] + [BUN x 0.36] If plasma osmolality > than formula expects, likely foreign substance (eg. Ethanol, mannitol) Tonicity: osmolality of soln relative to plasma (eg. Isotonic, hypertonic) cells can swell/shrink when exposed to changed tonicity so long as solute cant permeate membrane Ion channels help maintain isotonicity (eg. Efflux of K + Cl if cell swells ( water follows) N saline remains isotonic (mostly Na, Cl, HCO3) ( increased ECF vol, no movement of water 5% glu is initially isotonic but glu is metabolised to becomes hypotonic 0.45% NaCl is hypotonic ( water moves into cells ( increase ICF and ECF vol Hypertonic (water moves out of cell ( increase ECF vol, decrease ICF vol, increase osmolarity both compartments Resting Membrane Potential Non-ionic diffusion: when undissociated substance diffuses across membrane then dissociates therefore cant cross membrane ( net movement in one direction (eg. In GI tract, kidneys) Donnan effect: when an ion (eg. Prot-) cant diffuse across membrane, affects diffusion of other ions The diffusible ions distribute so concn ratios are equal Gibbs-Donnan equation : (Ka/Kb = Clb/Cla) or (Ka x Cla = Kb x Clb) ( Intracellular protein concn is higher ( more osmotically active particles intracellularily than in interstitial fluid ( cells would swell and rupture if not for Na-K ATPase. Since plasma protein > interstitial fluid protein ( similar situation at capillary walls ( Concn of ions on either side of membrane is assymetrical ( electrical difference across membrane which is exactly balanced by chemical gradient eg. Chloride ions: Cl conc higher in ECF than intracellular ( Cl diffuse INTO cell along concentration gradient Intracellular charge (-) compared to extracellular ( Cl diffuse OUT along electrical gradient Equilibrium established: efflux = influx ( membrane potential here is equilibrium potential of Cl (magnitute calculated by Nernst equation the diffusion potential across membrane that is needed to prevent net diffusion of an ion, determined by ratio of conc of ion on either side of membrane) Potential dependent upon electrical charge of ions, permeability of membrane, conc of ions on either side Ion can only be involved in potential if membrane is permeable to it At equilibrium there is excess cations (+) outside, excess anions (-) inside IonConc in cellConc outside cellEquilibrium potentialConc GradElec GradNa15150+60 (+ ion coming in)ININK1505.5-90 (+ ion going out)OUTINCl9125-70 (- ion coming in)INOUT Resting membrane potential is -70mV = ECl. Neither ENa or EK is at RMP ( you expect cell to gradually gain Na and lose K ( water to enter cell due to large Na in cell ( cell to burst. Prevented by Na-K ATPase (2K in, 3Na out) working against chemical and electrical gradients to maintain RMP. NA-K ATPase MAINTAINS MEMBRANE POTENTIAL. Na-K ATPase Electrogenic pump: catalyses hydrolysis of ATP ( ADP ( 3Na out, 2K in for each molecule ATP. Hence internal of cell remains (-) compared to exterior. Extends through cell membrane Vital in controlling volume of cell Inhibited by ouabain and digitalis; separation of subunits eliminates action Accounts for 24% energy used by cells, 70% in neurons Pump is not saturated at normal conditions Activity affected by 2nd messengers (eg. cAMP, diacylglycerol); increased by thyroid, insulin and aldosterone (increase number of Na-K ATPase molecules); inhibited by dopamine (phosphorylates it) Heterodimer:  subunit  spans membrane 10x; molecular weight 100,000 Na + K transport occurs through this Binding sites: intracellular - 3 Na and 1 ATP binding sites and phosphorylation site Extracellular  2 K and ouabain Na binds intracellularily, K binds extracellularily ( ATP binds ( phosphate transferred to phosphorylation site ( change in configuration ( Na transferred out, K in Can work in reverse with phosphorylated site donating P to ADP 1  found in all cells 2  found in muscle, heart, adipose tissue, brain 3  found in heart and brain  subunit  spans membrane once; molecular weight 55,000; may act as an anchor a glycoprotein with 3 extracellular glycosylation sites 1  absent in astrocytes, vestibular cells, fast-twitch muscle 2  found in fast-twitch muscle 3 NB. There is a K-Na leak channel which allows K>Na leakage through which the initial equilibrium of ions is made to form RMP therefore K most important in determination of RMP. Specific Ion Channels 1) K channels: Tetramers (4 subunits with a charged extension which surround a pore) When closed positive extensions are near negatively charged interior of cell ( membrane potential decreased ( paddles bend towards outside ( channel opens Channel has small diameter therefore selective for small K, Na cant pass through 2) Ach channel and many other anion/cation channels: 5 subunits 3) Cl channel: many different types Dimer (2 subunits), but with a pore in each subunit Pentamers (5 subunits) (eg. GABA and glycine receptors) 4) Aquaporins: tetramers with water pore in each subunit; note, water can also travel by simple diffusion 5) Ca channel: many different types. Ca v low intracellularly as 1 pump pumps Ca into ECF, and another pumps Ca into vesicular organelles (eg. SR, mitochondria) 6) H channel: in parietal cells of gastric glands and intercalated cells of DCT and CD of kidneys 6) Na channel: many different types Can be blocked by tetrodotoxin and saxitoxin therefore can be tagged and investigated Inner surface is (-) to attract (+) Na ions Certain type = Epithelial sodium channels In kidneys, colon, lungs, brain Have 3 subunits: : transports Na (inhibited by amiloride which binds it)  and : aid transport Span membrane twice Play role in ECF vol via aldosterone Intercellular Communication Messengers: (eg. Amino acids, steroids, polypeptides, lipids, nucleotides) can be measured by making abs and using radioimmunoassay competes with endogenous ligand for receptor Neural communication: NTs released at synaptic junctions; local response Endocrine communication: hormones and GFs by circulating in body fluid; general response Paracrine communication: diffuse to neighbouring cells in interstitial fluid; locally diffuse response Autocrine communication: messengers bind to own cell Juxtacrine communication: cells express GFs (eg. Transforming GF ) extracellularily on transmembrane proteins, whereas other cells have TGF receptors ( 2 cells can bind Also: Gap junctions: direct from cell to cell; local response Receptors are active not static Down-regulation occurs if XS of hormone/NT is present (eg. Via receptor-mediated endocytosis, ligand-receptor complex is internalized; in desensitization receptors are chemically altered on binding) Up-regulation in deficiency First messengers: extracellular ligands Often work via GTP-binding proteins Can cause release of second messenger (intracellular ligands) ( Bring about short term changes in cells ( Can activate transcription factors ( induce transcription of immediate-early genes ( alter transcription of genes to produce products that cause longterm changes ( Often activate protein kinases ( catalyse phosphorylation of tyrosine/serine/threonine ( change of configuration ( alter function Intracellular part of receptor may be protein kinase (eg. Insulin) Phosphatases vital here Eg. Of Protein Kinases Phosphorylate serine and/or threonine residuesCalmodulin-dependentMyosin light-chain kinasePhosphorylase kinaseCa/calmodulin kinase I, II, IIICa-phospholipid dependentProtein kinase CCyclic nucleotide dependentcAMP-dependent kinase (protein kinase A)cGMP-dependent kinasePhosphorylate tyrosine residuesInsulin receptorEGF receptorPDGF receptorM-CSF receptor Effects of Messengers Open/close ion channels Change conductance eg. Ach on nicotinic cholingergic receptor, noradrenaline on K channel in heart Increase transcription of mRNAs via cytoplasmic/nuclear receptors Activated receptor has DNA-binding portion which is usually covered by heat shock protein (Hsp90, amount increases in times of stress) ( Hsp90 release ( receptor-ligand complex binds to untranslated 5-flanking portions of genes ( increased transcription of mRNAs ( increase proteins Ligand-binding portion of receptor is near carboxyl terminal eg. Thyroid receptor in nucleus Steroid receptor in nucleus for oestrogen, in cytoplasm for glucocorticoid; steroids also have nongenomic actions via 2nd messengers which have faster action 1,25-dihydroxycholecalciferol, retinoids Activate phospholipase C with intracellular production of DAG and IP3 Ligand binds receptor ( activation of phospholipase C on inner membrane via Gq protein or tyrosine kinase link ( catalyse hydrolysis of PIP2 (phosphatidylinositol 4,5-diphosphate) into IP3 (inositol 1,4,5-triphosphate) and DAG (diacylglycerol) ( IP3 triggers release of Ca from ER, DAG activates protein kinase C in cell membrane eg. Angiotensin II, noradrenaline via 1-adrenergic receptor, vasopressin via V1 receptor Activate/inhibit adenylyl cyclase ( inc/dec production cAMP (cyclic adenosine 3 ,5 -monophosphate) Adenyly cyclase: catalyst; transmembrane protein crossing membrane 12x Activated by Gs  subunit when stimulatory receptor bound ( cAMP formed from ATP ( activates protein kinase A ( catalyses phosphorylation of proteins including CREB (cAMP-responsive element-binding protein) ( altered activity and transcription of genes Deactivated by Gi  subunit when inhibitory receptor bound Phosphodiesterase converts cAMP to inactive 5 -AMP (inhibited by caffeine and theophylline) eg. Noradrenaline via 2 adrenergic receptor ( dec cAMP Noradrenaline via 1-adrenergic receptor ( inc cAMP Cholera toxin inhibits GTPase activity, prolonging stimulation of adenylyl cyclase Pertussis toxin inhibits function of Gi Increase cGMP (cyclic guanosine monophosphate) in cell cGMP important in vision, helps regular ion channels Guanylyl cyclase: catalyses formation of cGMP; 2 forms: Transmembrane form: has extracellular, transmembrane and cytoplasmic portion (eg. Receptor for ANP, receptor for E. coli enterotoxin) Intracellular form: soluble, containing heme (eg. Activated by NO) Increase tyrosine kinase activity of transmembrane receptors Tyrosine kinases are closed associated with phosphatases, to remove phosphate groups from proteins eg. Insulin, EGF, PDGF, M-CSF Increase serine/threonine kinase activity eg. TGF, MAPKs G Proteins Bind GDP/GTP GTPase activity encouraged by RGS (regulators of G protein signaling) proteins Many G proteins are lipidated a) Small G proteins: eg. Rab (regulate vesicle traffic) Rho/Rac (regulates interactions between cytoskeleton and cell membrane) Ras (regulates growth) b) Heterotrimeric G proteins: Couple receptors to catalysts for formation of 2nd messengers / ion channels 5 families (Gs, Gi, Gt, Gq, G13) Receptors coupled with G protein usually span cell membrane 7 times (serpentine receptors) G proteins interact with aa residues in 3rd cytoplasmic loop of receptor Small ligands bind to amino acid residues in membrane Large protein ligands bind to extracellular domains of receptor Made of ,  and  subunits  bound to GDP ( ligand binds to G-coupled receptor ( GDP exchanged to GTP (  separated from  and  ( effect via  and  complexes (eg. Ion channels, enzymes) brought about ( GTPase activity of  converts GTP to GDP ( reassociation of all units ( termination of effect Ligands for receptors coupled to heterotrimeric G proteins NeurotransmittersEpinephrine, norepinephrine, dopamine, 5-hydroytryptamine, histamine, Ach, adenosine, opioidsTachykininsSubstance P, neurokinin A, neuropeptide KOther peptidesAngiotensin II, arginine vasopressin, oytocin, VIP, GRP, TRH, PTHGlycoprotein hormonesTSH, FSH, LH, hCGArachidonic acid derivativesThrombozane A2OtherOdorants, tastants, endothelins, PAF, cannabinoids, light Intracellular Ca At rest 100nmol/L Multiple effects of Ca: changes may outlast high concentration of Ca intracellular; conc may oscillate; raised conc can spread from cell to cell in waves ( co-ordinated response Extracellular: high concentration; chemical and electrical gradient inwards Intracellular: Ca bound by ER and other organelles acting as a store Intracellular Ca activated by 2nd messengers (eg. Release from ER and mitochondria mainly caused by IP3) ( may cause store-operated Ca channels in membrane to open ( Ca influx ( free Ca activates Ca-binding proteins ( activate protein kinases; free Ca also replenishes ER stores Ca-binding proteins eg. Troponin in contraction of skeletal muscle eg. Calmodulin which activates 5 different calmodulin-dependent kinases eg. a) myosin light-chain kinase ( phosphorylates myosin ( contraction of smooth muscle b) phosphorylase kinase ( activates phosphorylase; role in synaptic function and protein synthesis c) calcineurin ( inactivates Ca channels by dephosphorylating them; activates T cells, inhibited by immunosuppressants eg. Calbindin Enters cell: through ligand gated channels stretch gated channels voltage gated channels (T transient or L longacting depending on whether deactivate during prolonged depolarisation) Exits cell: by Ca-H ATPase (2H in, 1Ca out) antiport (3Na in, 1Ca out) driven by Na gradient Ca sparks is site of high concentration of Ca where it leaves cell Growth Factors Activate transcription factors which move to nucleus and alter gene transcription 4 main groups: Agents which foster multiplication/development of various cells (eg. Nerve GF, ILGF, activins, inhibins, epidermal GF) Cytokines produced by macrophages and lymphocytes; regulate immune system Colony stimulating factors regulate proliferation and maturation of RBC and WBCs TGF and related polypeptides  receptors have serine-threonine kinase activity; effects mediated by SMAD s ( bind DNA to initiate transcription of genes In 1) receptor has membrane-spanning domain and intracellular tyrosine kinase domain Ligand binds (tyrosine kinase domain autophosphorylates ( transcription factors and altered gene expression In 2) and 3) most receptors dont have tyrosine kinase domains, but use JAK-STAT pathway Ligand binds transmembrane protein gp130 ( initiate tyrosine kinase activity in cytoplasm (eg. JAKS (Janus tyrosine kinases)) ( phosphorylation of STAT (signal transducer and activator of transcription) proteins ( act as transcription factors at nucleus. Diseases SiteType of MutationDiseaseReceptorCone opsinsLossColor blindnessRhodopsinLossCongenital night blindnessV2 vasopressinLossNephrogenic diabetes insipidisACTHLossGlucocorticoid deficiencyTSHLossHypothyroidismThromboxane A2LossCongenital bleedingEndothelin BLossHirschsprung diseaseLHGainMale precocious pubertyTSHGainNonautoimmune hyperthyroidismCaGainHypercalciuric hypocalcaemiaG proteinGs LossPseudohypothyroidismGs GainTestotoxicosisMcCune-Albright SyndromeGi GainOvarian and adrenocortical tumours Grave s disease: ab against TSH receptor Myaesthenia gravis: ab against nicotinic Ach receptors NERVES Nervous tissue made of neurons and glial cells Nerve Cells Dendrites: 5-7; extend from cell body; have knobbly projections called dendritic spines esp in brain; cell body may be at dendritic end, but may be anywhere within axon (eg. Auditory neurons) or to side of axon (eg. Cut neurons) Axon: fibrous; poor passive conductor, conduction is active originates from axon hillock on cell body 1st part is initial segment terminal branches end in synaptic knobs (terminal buttons, axon telodendria) which contain granules containing NTs myelinated (protein-lipid complex wrapped around axon, no myelin at nodes of Ranvier) produced by Schwann cells outside of brain which wrap membrane around 1 axon that it sits on ( protein 0 (P0) locks to P0 of opposing membrane to compact myelin down) produced by oligodendrogliocytes in CNS send off multiple processes that form myelin on neighbouring axons unmyelinated (surrounded by Schwann cells but no wrapping) Epineurium: peripheral nerves made of multiple axons in fibrous envelope 4 important regions: 1) Receptor/dendritic zone: changes producted by synaptic connections are integrated 2) Site where APs are created: initial segment in spinal MNs, initial node of Ranvier in cut SNs 3) Axonal process: transmits impulses to nerve endings 4) Nerve endings: APs cause release of NTs Protein synthesis: occurs in cell body ( transported to axonal ending by axoplasmic flow; in some cases mRNA strands are transported from cell body to ribosomes and protein synthesis occurs locally Anterograde transport: along microtubules (fast at 400mm/d, slow at 5-10mm/d) Retrograde transport: along microtubules (200mm/d); some used synaptic vesicles and substances taken up by endocytosis (eg. Nerve GF) may be transported back to cell body If axon cut, distal parts degenerated (Wallerian degeneration) Excitation and Conduction Measure electrical events with cathode ray oscilloscope uses cathode which shoots electrons at glass tube coated with phosphors, +ive and ive charged plate applied on either side of course of beam, when voltage applied across it beam pulled towards +ive plate, measure course of beam to work out voltage May result in: Local, nonpropogated potentials: synaptic/generator/electronic potentials Propogated potentials: action potentials Excitation Low threshold Resting membrane potential of nerve cells is -70mV (inside cell ive compared to outside)  Stimulus may be electrical, chemical, mechanical Minimal intensity of stimulating current that acting at given duration will cause AP is threshold intensity with weak stimuli this is long duration, with strong may be short ( strength-duration curve Slowly rising currents fail to cause AP due to accommodation Once threshold intensity reaches, AP will fire; increase in stimulation wont cause increased AP all-or-none law Subthreshold stimuli will still have effect on membrane potential via local response even if dont cause AP electronic potentials (if produced by cathode catelectronic, if anode anelectronic); potential is proportionate to current These will affect threshold catelectronic are depolarizing ( lower threshold Anelectronic are hyperpolarizing ( incr threshold When stimulus applied stimulus artifact recorded by CRO due to current leakage from stimulating to recording electrodes Followed by latent period ends with start of AP; = time it takes impulse to travel along axon from site of stimulation to recording electrodes; duration proportionate to distance between stimulating and recording electrodes, inversely proportionate to speed of conduction if you know distance you can work out speed of conduction In peripheral nerves with multiple axons in epineurium some axons may be conducting and others not; stimulus that produces excitation of all axons is maximal stimulus Action potentials due to changes in conduction of ions across membrane After 15mV depolarization, rate of depolarization increases this is firing level/threshold Potential overshoots isopotential to +35mV Spike potential occurs Repolarisation slows after 70% to perform after-depolarisation Overshoot slightly to form after-hyperpolarisation this is a small amplitude but long duration; it will increase if nerve has been conducting for a long time Followed by refractory period Absolute: time from firing level until repolarisation 1/3 complete; NO stimulus will excite nerve Relative: from 1/3 complete til start of after-depolarisation; stronger stimuli can excite During after-de and after-hyperpolarisation threshold is increased Peripheral nerves will produce compound AP as there will be some fast and some slow conducting axons, some cell bodies may be further away Ionic basis: remember Na diffuses in (along elec and conc grad) K diffuses out (along conc grad only) Na actively transported out K actively transported in Greater permeability to K so K determines resting membrane potential When stimulus applied voltage-activated Na channels activated ( NA INFLUX ( firing level met ( Na effect overwhelms K effect for short time ( depolarization ( membrane potential moves towards +60mV ( spike potential ( doesnt reach +60mV as Na channels only activated for short time ( Na channels close and Na influx prevented by membrane potential ( voltage-gated K channels open (longer time) ( K EFFLUX ( repolarisation followed by after-hyperpolarisation as K channels still open. Decreasing extracellular [Na] ( decr AP, no effect on MP as Na not important there Increasing extracellular [K] ( decr RMP Decreasing extracellular [Ca] ( increases excitability as decr amount of depolarization needed to start changes in Na and K conductance Accomodation: 2Y to slow opening of K channels; if Na channels stimulated over long time then K channels are still open so effect of Na channels decreased Conduction Occurs along axons; is active not passive; impulse moves at constant amplitude and velocity At rest inside nerve is +ive, outside ive (POLARISED) ( during AP polarity reversed, AP creates area of ive charge and +ive charges from alongside (ahead and behind) move to this area current sink ( decreases polarity of membrane ahead of AP ( local response until firing potential reached ( proprogated response. Saltatory conduction: myelin is effective insulator; depolarization jumps from 1 node of Ranvier to next; myelinated conduction 50x faster than unmyelinated; Na channels concentrated in node and initial segment (where AP generated) If AP initiated in middle of axon, impulse can travel either way Orthodromic: when impulses travel in 1 direction only; in mammals Antidromic: when impulses travel in opposite direction; since synapses are unidirectional, this impulse will die when it reaches one Biphasic AP: when you measure AP with 2 electrodes on inside of membrane; electrode 1 ive ( 2 electrodes same ( electrode 2 ive Volume conductor: conducting medium of body; complicates above processes somewhat Nerve Fibre Types Fibre TypeFunctionDiameterConduction VelocitySpike durationAbsolute refractory periodAProprioception (Sensory to muscle spindle (Ia) and golgi tendon organ (Ib)); somatic motor12-20 (large)70-120 (fast)0.4-0.5 (short)0.4-1 (short)Touch (II), pressure (II), motor5-12 (mod)30-70 (mod)Motor to muscle spindles3-6 (small)15-30 (mod)Pain, cold, touch (III)2-5 (small)12-30 (mod)BPreganglionic autonomic<3 (small)3-15 (mod)1.2 (long)1.2 (long)C (IV)Dorsal rootPain, temp, reflexes, mechanoreception0.4-1.2 (small)0.5  2 (slow)2 (long)2 (long)SymPostganglionic sympathetics0.3-1.3 (small)0.7 2.3 (slow)2 (long)2 (long) Susceptible toVeryIntermediateLowHypoxiaBACPressureABCLACBA I-IV used to describe sensory fibres as above Neurotrophins Produced by astrocytes/muscles 1) Bind to receptors at end of neuron ( endocytosis ( retrograde transport ( in cell body cause production of proteins for neuronal growth and survival 2) Produced in neurons ( anterograde transport to nerve ending ( support postsynaptic neuron Bind to trk receptors ( dimerise ( autophosphorylation of tyrosine kinase domains of receptors eg. NGF ( trkA; brain-derived GF ( trkB; neurotrophin 3 ( trkC; neurotrophin 4+5 ( trkB NGF: growth and maintenance of sym and sensory neurons; made up to 2  (trypsin-like activity), 2  (growth promoting activity) and 2  (serine proteases) subunits; work by process 1) described above; important in maintenance of cholinergic neurons in brain (ie. Sym nervous system) NT-3  cutaneous mechanoreceptors BDNF  peripheral senory neurons Others: CNTF (ciliary neurotrophic factor) produced by Schwann cells and astrocytes for survival of spinal cord neurons GDNF (glial cell linee-derived NTF) for midbrain and dopaminergic neurons LIF (leukemia inhibitory F), IGF I, TGF, fibroblast GF, PDGF Neuroglia Microglia: like tissue macrophages; originate in bone marrow Oligodendrogliocytes: for myelin formation Astrocytes: induce capillaries to form tight junctions for BBB; envelop synapses and surfaces of nerve cells; produces substances tropic to neurons; maintain appropriate conc of ions and NTs by taking up K, glutamate and GABA Fibrous in white matter Protoplasmic in gray matter MUSCLE Can be excited electically, chemically, mechanically Can be skeletal, cardiac, smooth SkeletalCardiacSmoothStriated?YesYesNoMitochondriaManyFewMicroscopic featuresT tubule contact at A-I bandIntercalated discs and gap junctions; T tubule contact at Z lineDense bodies in cytoplasmRMP-90-90-50Action potential2-4ms longProlonged plateau phase (200ms)Sometimes prolonged plateau phaseMetabolismSlow / fast twitchSlow-twitch, low ATP-ase activity, oxidative metabolism, high in myoglobinDependent on glycolysisStimulationExternal neededContains regular pacemaker; modified by externalContains irregular pacemakerContractionCa binds troponin C ( tropomyosin moves laterally ( myosin binds Ca binds troponin C ( tropomyosin moves laterally ( myosin bindsCa binds calmodulin ( calmodulin-dependent myosin light chain kinase activated ( catalyses phosphorylation of myosin light chain  Skeletal Muscle Each fibre is multinucleated, long, cylindrical Surrounded by membrane (sarcolemma) Each fibre made of myofibrils, made of thick and thin filaments Each fibril surrounded by sarcotubular system T tubules: continuous with sarcolemma; forms grid perforated by fibrils; space between 2 layers is continuous with extracellular; contact A+I bands twice each sarcomere; allows rapid transmission of AP from cell membrane to all fibrils in muscle Sarcoplasmic reticulum: surrounds each myofibril; has enlarged terminal cisterns in close contact with T system at junctions between A+I bands at triads; involved in Ca movement and muscle metabolism Dystrophin: large protein that connects actin (thin filament) to -dystroglycan (protein in sarcolemma); -dystroglycan attached by -dystroglycan to laminin in extracellular matrix; sarcoglycans also involved; dystrophin-glycoprotein complex provides strength and scaffolding by connecting to extracellular enviro Striations: due to diff refractive indexes of diff parts of muscle fibres; each thick filament surrounded by 6 thin filaments in hexagonal patter  I band: light, thin filament Thin filament: actin (300-400 molecules), tropomyosin (40-60 molecules) and troponin Actin: 2 chainsthat form long double helix Tropomyosin: located in groove between 2 actin molecules; covers site where myosin binds actin Troponin: globular units at intervals along tropomyosin molecules Troponin T: binds troponin to tropomyosin Troponin I: inhibits interaction of myosin with actin by tightly binding actin Troponin C: contains binding sites for Ca to initiate contraction A band: dark, thick filament; has lighter H band in centre (where actin and myosin dont overlap when muscle relaxed); transverse M line in middle of H band (site of reversal of polarity of myosin molecules in thick filaments) Thick filament: myosin II (700 molecules) (2 globular heads and long tail); heads of myosin form cross-links with actin at actin-binding site, hydrolyse ATP at catalytic site Z line: sarcomere between 2 Z lines; transect fibrils and connected to thin filaments by actinin; connected to M line by titin (provides scaffolding at beginning of stretching domains unfold so little resistance, but provides protection as stretch continues); Z line bound to plasma membrane by desmin Contraction In contraction: width of A band constant, distance between Z lines decreases Myosin head binds actin ( power-stroke needing hydrolysis of ATP shortening sarcomere by 10nm per powerstroke ( detach; each head cycles 5x/sec Excitation-contraction coupling: discharge of motor neuron ( release of Ach at motor end plate ( Ach binds nicotinic receptors ( end plate potential ( AP ( AP transmitted to all fibrils by T tubules ( dihydropyridine receptors (voltage gated Ca channels) in T tubule membrane activated ( trigger release of Ca via ryanodine receptor in SR (ligand gated channel related to IP3) from terminal cisterns of SR ( Ca binds troponin C ( binding of trop I to actin weakened ( tropomyosin moves laterally uncovering binding sites for myosin ( myosin binds ( ATP split ( contraction. Relaxation: Ca it is reabsorbed into ST by ATP-mediated active transport in Ca-Mg ATPase ( returns to terminal cisterns to be stored (if this cant occur muscle cant relax ( contracture) ( once Ca conc decreased by taking back up into SR, myosin and actin action ceases ( relax (ATP needed for contraction and relaxation). Electrical Events RMP = -90mV AP is 2-4ms long Speed of AP is 5m/s Absolute refractory period = 1-3ms After-polarisations are long Distribution of ions across membrane similar to that in nerves (Na high extracellular, K high intracellular, CL high extracellular, HCO3 high extracellular) Depolarisation occurs from NA INFLUX, repolarisation from K EFFLUX; begins at motor end plate, AP conduction results in contractile response; 1 AP results in muscle twitch beginning 2ms following depolaristation Fast-twitch: fine, rapid, precise movement; 7.5ms twitch duration Slow-twitch: strong, gross, sustained movement; 100ms twitch duration Principles of Contraction Isometric contraction: when contraction occurs without change in length of muscle; do not do work Isotonic contraction: contraction against constant load; do work Summation of contractions: muscle DOES NOT have refractory period so repeated stimulation before relaxation ( added power to contraction already occurring Tetanic contraction: repeated stimulation fuse into one continuous contraction; complete if no relaxation between contraction, incomplete if partial relaxtion between; stimulation frequency required determined by twitch duration of fibre Treppe (staircase phenomenon): when max stimuli delivered at frequency just below tetanizing f ( tension during each twitch increases until same tension per contraction achieved; due to increased availability of Ca for binding trop C Tension: total tension tension developed when muscle stimulated Passive tension tension when muscle not stimulated Active tension difference between passive and total tension; amount of tension ACTUALLY generated by contractile process Resting length length of muscle when active tension is maximal Tension developed proportionate to no. cross linkages between actin and myosin Overstretched decr overlap Too short decr distance thin filaments can move on thick Velocity of contraction is maximal at resting length and declines if longer/shorter Fibre Types Type IType IISlow, oxidative, redFast, glycolytic, whiteATPase rateSlowFastCa-pumping capacity of SRModHighDiameterModLargeGlycolytic capacityModHighOxidative capacity (no. mitochondria, capillary density, myoglobin content)HighLow Type I long, slow, posture-maintaining movements Type II fine, skilled, short-twitch (eg. Eye, hand) Multiple forms of myosin-heavy chains, tropomyosin and troponin determine diff types of muscle; determined by genes, activity, innervation, hormones Energy ATP mades by ADP + PO this needs energy, provided by: 1) Aerobic glycolysis: breakdown of glucose (some from glycogen) ( pyruvate ( citric acid cycle ( respiratory enzyme pathway ( CO2 + H2O + ATP 2) Anaerobic glycolysis: glucose ( lactate + ATP; does not need O2; produces less E; lactate enters bloodstream but will accumulate in muscles and exceed buffering system ( decr pH ( inhibits enzymes so this pathway can only be used for short period of time 3) Phosporylcreatine provided by muscle, hydrolysed at junction between myosin heads and actin ( creatine and PO ( releasing energy; at rest ATP used to build up stores 4) Lipids ( free fas not fast enough during exercise; trained athletes can use these better Oxygen debt: after exertion O2 needed to remove XS lactate, replenish ATP and phosphorylcreatine, replace O2 from myoglobin; trained athletes more efficient so less O2 debt Rigor: when muscle completely depleted of ATP and phosphorylcreatine (eg. Death) Resting heat: heat given off at rest (from BMR) Initial heat: XS heat created during contraction; = activation heat (created whenever muscle contracting) + shortening heat (proportionate to amount muscle shortens) Recovery heat: produced following contraction; metabolic processes restoring muscle to precontractile state; equal to initial heat Relaxation heat: additional released when restore muscle to prev length; requires work Denervation ( muscle atrophy ( abnormal excitability of muscle, incr sensitivity to Ach (denervation sensitivity) ( fibrillations (LMN lesion, not visible grossly) CARDIAC MUSCLE Functions as synctium Striated Large no. elongated mitochondria Branching interdigitating muscle fibres at Z lines they form intercalated discs strong cell-cell cohesion, pull of one contractile unit transmitted to next Cell membranes of adjacent fibres fuse gap junctions bridges for spread of excitation T system located a Z lines (A-I junction in skeletal) (From pharmacology text book: note) When cell permeable to ion, movement across membrane determined by Ohms Law: Current = voltage Current = voltage x conductance Resistance Conductance determined by properties of ion channel Voltage determined by diff between actual MP and reversal potential for that ion (ie. MP at which no current would flow if channels were open dependent on elec and chem grads; calculated by Nernst equation) note K is most important ion here In pacemaker cells, spontaneous depolarization occurs during diastole (phase 4) K concs v important HyperK ( decr grad (as intracellular K is usually high), but incr K conductance ( Decr AP duration, slowed conduction, decr pacemaker rate, decr pacemaker arrhythmogenesiss HypoK ( incr grad but decr conductance ( prolonged AP, incr pacemaker rate, incr pacemaker arrhythmogenesis Electrical Properties  RMP = -90mV affected by extracellular K conc Phase 0: Depolarisation to threshold rapid (2ms) (affected by extracellular Na conc), with overshoot ( Opening of activation (m) gates of fast Na channels ( NA INFLUX Membrane potential approaches +70mV Na channel has 2 gates: Outer gate open at start of depolarization (at -70 to -80mV) Inner gate closes and prevent further influx until AP over Phase 1: initial rapid repolarisation Closing of inactivation (h) gates of Na channels ( inactivation Phase 2: Plateau (200ms) Slower prolonged opening of L-type Ca channels ( slow CA INFLUX Phase 3: Repolarisation (not complete until contraction is half over) Closure of Ca channels, opening of K channels ( K EFFLUX (Ik current) Note, a different K current is found in SAN cells, so durgs can affect Purkinje and ventricular cells but have little effect on SAN repolarisation Phase 4: Repolarisation complete; h gates of Na channels reopen so they are again ready for excitation (From pharmacology text book: note) Time between phase 0 and point in phase 3 when Na channels recovered is refractory period; important in suppression / genesis of arrhythmias Note, RP is important in generation of AP Na channels close over -75 to -55mV range, so at -60mV less Na channels available than at -80mV; this can alter AP amplitude, excitability, conduction velocity, refractory period; at anything +ive of -55mV there can be no Na currents meaning that AP can only fire due to incr Ca permeability and decr K permeability this is mechanism in SAN and AVN, and is important in certain arrhythmias Mechanical Properties Contraction begins just after start of depolarization; last 1.5x longer than AP Absolute refractory period: until halfway through phase 3 (reaches -50mV); prevents tetany Relative refractory period: until phase 4 Excitation-contraction coupling similar to skeletal Slow-twitch; low ATPase activity; dependent on oxidative metabolism Contains MHC (higher ATPase activity) and MHC (lower ATPase activity) (myosin heavy chain) in atria, only MHC in ventricles Similar relation between fibre length and tension as in skeletal; dependent on degree of diastolic filling; pressure in V  total tension developed  Starling s law of heart  tension will increase as diastolic vol increases until limit, then will decrease 2Y to disruption of myocardial fibres (NOT decrease in cross-bridges between actin and myosin as in skeletal muscle) Adrenaline ( activate 1-adrenergic receptors ( increase cAMP ( activates protein kinase A ( phosphorylation of voltage-dependent Ca channels ( open longer ( incr active transport of Ca to SR ( accelerated relaxation and shorted systole, permitting adequate diastolic filling at incr HR Digoxin ( inhibit Na-K-ATPase ( incr intracellular Na ( less Na influx ( less Ca efflux via Na-Ca antiporter ( incr intracellular Ca Hypertrophy can occur via mutations of genes coding contractile apparatus; can dilate due to dystrophin gene in muscular dystrophy Metabolism Large blood supply; numerous mitochondria, high myoglobin content <1% is anaerobic may rise to 10% in hypoxia 35% E from carbohydrate, 5% ketones, 60% fat (esp. free fas) Pacemaker Pacemaker tissue has no Na channels so membrane potentials slowly rise when voltage-gated Ca channels open Arrhythmias (from pharmacology text book) Caused by: 1) Disturbances of impulse formation: Time between depolarisation of pacemaker cell = duration of AP + duration of diastolic interval Diastolic interval determined by slope of phase 4 (pacemaker potential) paraS discharge and beta-blockers slow HR by decr phase 4 slope; hypokalaemia, sym discharge, positive chronotropic drugs, fibre stretch, acidosis and partial depolarisations incr HR by incr phase 4 slope (esp in latent pacemakers such as some Purkinje fibres, although all cardiac cells will display this under correct conditions) Afterdepolarisations: depolarisations that interrupt phase 3 (early, thought to contribute to prolonged QT, worse when slow HR) or phase 4 (delayed, can occur with incr intracellular Ca, thought to cause arrhythmias related to digoxin, NE and MI; worse when fast HR) 2) Disturbances of impulse conduction: can cause block (paraS control of AVN conduction important); re-entry (may be small/large area, may be multiple random or specific anatomical area (eg. WPW); for re-entry there must be: a) Anatomic/physiological obstacle to conduction for circuit to go around b) Unidirectional block at some point in circuit c) Conduction time around circuit must be long enough so retrograde impulse doesnt enter refractory tissue as it travels around (conduction time > refractory period); slowing of conduction can be due to decr Na/Ca current drugs that help further decr this current or prolonging refractory period SMOOTH MUSCLE Not-striated Actin and myosin not arranged in regular arrays; dense bodies in cytoplasm and attached to cell membrane instead of Z lines, bound to actin by -actinin No troponin Poorly developed SR Few mitochondria; depend on glycolysis for metabolic needs Types: visceral/unitary SM  in large sheets; many low resistance gap-junction bridges; syncytial (eg. Hollow viscera walls) Multiunit SM individual units without interconnecting bridges (eg. In iris) Visceral Smooth Muscle Electrical properties: unstable membrane potential no true resting MP, relatively low when active and high when inhibited ave -50mV; on top of this are various waves Slow sine wave-like fluctuations Spikes sometimes overshoot 0 potential May have short duration, may have plateau phase; continuous irregular contractions independent of nerve supply ( maintained state of partial contractions = tone; excitation-contraction coupling is long process initiation of contraction after 150ms (10ms in heart/skeletal), peak contraction 500ms after spike Contraction: since SR poorly developed, Ca must enter from ECF via voltage-gated Ca channels; myosin must be phosphorylated for activation of myosin ATPase Ach binds muscarinic receptors ( Ca influx ( Ca binds calmodulin ( calmodulin-dependent myosin light chain kinase activated ( catalyses phosphorylation of myosin light chain ( incr myosin ATPase activity (differs to skeletal and cardiac muscle where contraction caused by Ca binding troponin C) ( myosin binds actin ( contraction ( myosin dephosphorylated by myosin light chain phosphatase; myosin remains attached to actin for some time after intracellular Ca decreased latch bridge sustained contraction tonic contraction Note incr cAMP in cardiac muscle ( incr contraction; in vascular SM ( decr contraction as it phosphorylates myosin light chain kinase ( decr affinity for calmodulin Stimulation: contracts when stretched without any extrinsic innervation; stretch ( decr MP, incr frequency spikes, incr tone; add epinephrine ( incr MP, decr f spikes, decr tone; add Ach ( decr MP, incr f spikes, incr tone If stretch SM, increased tension will gradually decrease; no resting length can be ascertained plasticity Multiunit SM Non-syncytial; contractions dont spread widely, they are more discrete; contractile response usually irregular tetanus rather than single twitch; long duration of contraction Synaptic and Junctional Transmission Impulses transmitted from one nerve cell to another at synapses. Impulse in pre-synaptic cell causes release of neurotransmitter which binds to postsynaptic cell ( effect which may be excitatory/inhibitory. May be electrical/chemical. Most drugs act on specific receptors that modulate synaptic transmission; RMP of neuron is -70mV Channels 3 types of channels in nerve cells (numerous natural toxins can block these channels): Voltage-gated: response to changes in MP Concentrated on initial segment and axon, responsible for fast AP transmitting signal from cell body to nerve terminal Also Ca and K channels on cell body, dendrites and initial segment that are slower and modulate rate at which neuron discharges (eg. K channels open on depolarization of cell, and slow further depolarization) Ligand-gated (inotropic receptors): open by binding of NT; formed of subunits; activation causes brief opening; responsible for fast synaptic transmission Metabotropic receptors: G protein linked receptors which NTs bind; effects can last longer Modulate voltage-gated channels (usually Ca and K) via G protein eg. Inhibit Ca channel function ( presynaptic inhibition eg. Activate K channel ( slow postsynaptic inhibition Generally membrane delimited (ie. Local); can also generate diffusible 2nd messengers (eg. cAMP via adenylyl cyclase); can occur over greater distances Synapses AP in presynaptic fibre ( activates voltage-gated Ca channels in synaptic terminal membrane ( Ca enters synaptic terminal ( fusion of synaptic vesicles with presynaptic membrane ( NT released into synaptic cleft ( NT binds with receptor on postsynaptic membrane ( change in membrane conductance ( postsynaptic response (takes 0.5ms, mostly due to time taken for Ca channels to open) Presynaptic fibre: each nerve divides to form 2000 synaptic endings; form terminal buttons (synaptic knobs) which may end on Axodendritic on dendrite/dendritic spine Axosomatic on cell body Axoaxonal on axon Contains mitochondria, membrane-enclosed vesicles contains NTs (made in cell body ( transported along axon by fast axoplasmic transport; contents of smaller vesicles may be recycled at synaptic ending). Vesicles may be Small, clear synaptic vesicles containing Ach, glycine, GABA, glutamate Small vesicles with dense core containing catecholamines Large vesicles with dense core containing neuropeptides The contents are discharged into synaptic cleft: Via exocytosis/endocytosis cycle: early endosome buds off vesicles ( vesicle filled with NT ( primed at cell membrane ( AP ( exocytosis of contents ( may undergo endocytosis, hence recycling ( fuse with endosome; involves use of v-snare protein synaptobrevin in vesicle membrane locking with t-snare protein syntaxin in cell membrane (eg. Large vesicles) Via kiss and run discharge: vesicle discharges contents through small hole in cell membrane which reseals rapidly, vesicle always staying inside Exocytosis occurs from all parts of terminal; small vesicles discharge at areas of membrane thickening called active zones which contain many proteins and rows of Ca channels; Ca influx causes NT release Neurexins: proteins bound to presynaptic neuron which bind neurexin receptors in postsynaptic neuron; aid to hold synapses together Synaptic cleft: presynaptic terminal separated from postsynaptic structure by synaptic cleft, 20-40nm wide Postsynaptic structure: has postsynaptic density complex of specific receptors, binding proteins and enzymes induced by postsynaptic effects Tetanus toxin: causes spastic paralysis by blocking presynaptic NT release Botulinum toxin: causes flaccid paralysis by blocking release of Ach at NMJ Receptors Every ligand acts on many subtypes of receptors (eg. Alpha 1,2,3) There are receptors on presynaptic and postsynaptic membrane presynaptic = autoreceptors, provide feedback control Receptors usually concentrated in clusters on postsynaptic membrane near neurons that secrete NTs specific for them, due to presence of specific binding proteins for them (eg. Nicotinic Ach receptor rapsyn, glutaminergic receptors PB2-binding proteins, GABA gephyrin) receptors bind to the protein in cell membrane during activity Prolonged exposure to ligands causes desensitization (eg. In -adrenergic receptors due to phosphorylation of carboxyl terminal by -ARK or by binding -arrestin) Homologous  loss of responsiveness only to specific ligand Heterologous  loss of responsiveness to all ligands Reuptake Can occur via 2 families of transporter proteins: Co-transports NT with Na and Cl (eg. NE. dopamine, serotonin, GABA, glycine, choline) Transporters that re-uptake glutamate into neurons/astrocytes coupled to cotransport of Na and countertransport of K Are also 2 vesicular monoamine transporters (VMAT1, VMAT2) that transport NTs from cytoplasm to synaptic vesicles (eg. Dopamine, NE, E, serotonin, histamine) inhibited by reserpine Vesicular GABA transporter (VGAT) moves GABA and glycine into vesicles Inhibition of reuptake has big effect cocaine inhibits reuptake of dopamine, when glutamate reuptake inhibited ( neuronal damage Excitatory Postsynaptic Potential Single stimulus (excitatory NT on inotropic receptor) ( transient depolarizing response (but not an actually propagated AP) from depolarization of postsynaptic cell membrane immediately under presynaptic ending (via opening of Na/Ca/K channels in postsynaptic membrane) called excitatory postsynaptic potential (EPSP) during potential, excitability of neuron to other stimuli increased (if incr presynaptic fibres activated, incr size of depolarization ( threshold ( all-or-none AP). Depolarisations produced by multiple synaptic knobs summate: Spatial summation: activity in >1 knob; facilitate eachother to reach firing level Temporal summation: repeated stimuli causes new EPSP before old EPSP finished EPSP is not all-or-none, but proportionate to strength of stimulus Inhibitory Postsynaptic Potential Stimulation of some input may cause hyperpolarizing rather than depolarizing response via (eg. opening of Cl channels ( Cl enters postsynaptic cell along conc grad ( incr membrane potential ( closure of Na/Ca channels; opening of K channels allowing efflux) ( decr excitability due to movement of MP away from firing level; peak in 1-1.5ms then decrease over 3ms; decrease excitability; spatial and temporal summation can occur here also Results in postsynaptic/direct inhibition Slow Postsynaptic Potentials Occur in autonomic ganglia, cardiac muscle, SM, cortical neurons; last several secs; EPSP due to decr K conductance, IPSP due to incr K conductance Action Potentials Initial segment has lowest threshold for generation of AP once fired it goes down axon and retrogradely back into soma; constantly fluctuating MP 2Y to factors above, AP occurs when 10-15mV of depolarization to reach firing level occurs Synaptic Delay 0.5ms delay between impulse reaching presynaptic terminal and response in postsynaptic neuron; due to time it takes for synaptic mediator to be released and cause effect; conduction along chain of neurons slowed by multiple synapses Inhibition at Synapses Post-synaptic inhibition: eg. Afferent nerves from muscle spindles ( EPSP and propagated AP in motor neurons supplying muscle, IPSP in antagonist muscles via inhibitory NT glycine Pre-synaptic inhibition: mediated by neurons that end of excitatory endings forming axoaxonal synapses ( decr NT release; can occur in 3 different ways (eg. GABA) (eg. Used in gating pain transmission): Activation of presynaptic receptor may incr Cl conductance ( decr size AP reaching excitatory ending ( decr Ca entry ( decr amount excitatory NT released Activation ( open voltage gated K channels ( K efflux ( decr Ca influx ( decr NT released Direct inhibition of NT release Afferent inhibition: inhibition usually caused by stimulation of certain systems acting on one postsynaptic neuron Negative feedback inhibition: when neuron may inhibit itself (eg. Occurs in spinal motor neurons via inhibitory interneuron, activated by AP in motor neuron, it releases inhibitory mediator to slow/stop discharge at motor neuron). Feed-forward inhibition: when inhibitory cell and excitatory cell both stimulated by same stimulus; limits duration of excitation (eg. Purkinje cells) Neuromodulation: non-synaptic action of substance on neurons which alters their sensitivity to synaptic stimulation/inhibition (eg. Steroids) Facilitation at Synapses Opposite to inhibition; eg. Serotonin causes incr intraneuronal cAMP levels ( phosphorylation of K channels ( closure of K channels ( slow repolarisation, prolonged AP The Brain Hierarchal systems: All pathways involved in sensory perception and motor control; clearly delineated (made of large myelinated fibres); info processed sequentially at each relay nucleus on way to cortex; Each nucleus contains: Relay/projection neurons (excitatory; use glutatmate; large axons, many collaterals; transmit signals over long distances) Local circuit neurons (inhibitory; use GABA or glycine; smaller; synapse with projection neurons, inhibiting them; some may from axoaxonic synapses on sensory axons) 3 types of pathways for inhibition: Recurrent feedback pathways Feed-forward pathways Axoaxonic interaction Since only 3 main NTs used, drugs can easily target these pathways (eg. GABAa antagonists ( convulsions) Nonspecific/diffuse neuronal systems: Involved in more global functions (eg. Sleeping, appetite, emotion) Eg. Monoamines (NE, dopamine, 5-HT), peptide-containing pathways Eg. Noradrenergic axons fine and unmyelinated; slow multiple branching, one neuron can go to many diff parts of CNS fibres studded with varicosities containing vesicles NTs usually act on metabotropic receptors therefore have longer-lasting effects Neurotransmitters May be Amines (eg. Dopamine, norepinephrine, epinephrine, serotonin, histamine) Amino acids (eg. Glutamate, aspartate, glycine, GABA) Polypeptides (eg. Substance P, vasopressin, oxytocin, CRH, TRH, GRH, somatostatin, GnRH, endothelins, enkaphalins etc) Purines (eg. Adenosine, ATP) Gases (eg. NO, CO) Excitatory Amino Acids  Gluta -mateRelay neurons at all levels, some interneuronsNMDAExcitatory: incr cation conductance esp CaNMDA2-amino-5-phosphonovalerate, dizocilipineAMPAExcitatory: incr cation conductanceAMPACNQXKainateExcitatory: incr cation conductanceKainic acid, domoic acidMetabo tropicInhibitory (presynaptic): decr Ca conductance, decr cAMP Excitatory: decr K conductance, incr IP3 and DAGACPD, quisqualateMCPG Glutamate: Responsible for 75% excitatory transmission of brain Formation: reductive amination of -ketoglutarate in cytoplasm ( glutamate becomes concentrated in synaptic vesicles by transporter BPN1 Cytoplasmic store kept high by transporters which import glutamate from interstitial fluid and reuptake it from synaptic clefts via Na-dependent uptake systems, if glutamate is allowed to accumulate ( excitotoxic damage and cell death Mediates excitatory synaptic transmission by activation of ionotropic and metabotropic receptors: 1) Metabotropic: serpentine G protein linked receptors that act indirectly on ion channels; incr IP3 and DAG levels, or decr intracellular cAMP levels; widely distributed in brain; involved in production of synaptic plasticity; located just outside postsynaptic density Can be pre-synaptic (group II and III, act as inhibitory autoreceptors via inhibition of Ca channels ( decr NT release) Can be postsynaptic (group I, activate cation channel, activate PLc ( incr IP3 ( intracellular Ca release) 2) Ionotropic: ligand gated ion channels; 3 types Kainite (KA) simple ion channels; Na influx, K efflux; high levels in hippocampus, cerebellum and SC may be pre- or post-synaptic AMPA present on all neurons; permeable to Na and K; activation results in channel opening at RMP; located at periphery of postsynaptic density NMDA present on all neurons; highly permeable to Ca, Na and K ( rise in intracellular Ca ( long-lasting enhanced synaptic strength (long term potentiation, LTP) important in learning and memory; only opens in concomitant glycine binding; channel will not open at RMP due to block of channel by extracellular Mg which is expelled when neuron depolarized (ie. By activation of other channels such as AMPA); located in centre of postsynaptic density Clearance: glutamate transporters on surrounding glia ( converted to glutamine by glutamine synthetase ( released from glia ( taken up by nerve terminal ( converted to glutamate by enzyme glutaminase ( transported into vesicles by vesicular glutamate transporter (VGLUT) Anaesthetics may inhibit NMDA and AMPA receptors Inhibitory Amino Acids Typically released from local interneurons Anaesthetics are thought to work on GABAa and glycine receptors ( incr Cl conductance GABA (gamma-aminobutyric acid): GABASupraspinal and spinal interneuronsGABAaInhibitory: incr Cl conductanceMuscimolBiuculline, picrotoxinGABAbInhibitory (presynaptic): decr Ca confuctance Inhibitory (postsynaptic): incr K conductanceBaclofen2-OH saclofen Present in whole CNS; transmitter at 20% CNS synapses Responsible for presynpatic inhibition Formation: decarboxylation of glutamate catalysed by glutamate decarboxylase ( metabolized to succinic semialdehyde then succinate by GABA transaminase; cofactor for both these enzymes is pyridoxal phosphate Effect = incr Cl influx, incr K efflux, decr Ca influx ( hyperpolarisation ( IPSP Receptors: GABAa found in CNS; ionotropic receptors (Cl ion channel) made of 5 subunits; chronically stimulated by GABA in interstitial fluid ( cuts down on noise from incidental discharge of neurons; involved in fast component of IPSPs; benzos bind this GABAb found in CNS; metabotropic (coupled to G protein) ( incr K efflux, inhibit adenylyl cyclase, decr cAMP, inhibit Ca influx (so prevent NT release); involved in slow component (due to indirect coupling of G protein receptor) of IPSPs; found in perisynaptic region GABAc found in retina; Cl ion channel made of 5 subunits Clearance: GABA is reuptook via transporter 2) Glycine GlycineSpinal and brainstem interneuronsInhibitory: incr Cl conductanceTaurine, -alanineStrychine Present in brainstem and SC Inhibitory and excitatory Bind receptors that are selectively permeable to Cl NB. Activates NMDA receptors Acetylcholine AchCell bodies at all levelsM1Excitatory: decr K conductance, incr IP3 and DAGMuscarinePirenzipine, atropineM2Inhibitory: incr K conductance, decr cAMPMuscarine, bethanecholAtropine, methoctramineMotoneuron-Renshaw cell synapseNicotinicExcitatory: incr cation conductanceNicotineDihydro--erythroidine, -bungarotoxin Important role in cognitive function and memory Formation: made from choline (made in neurons and reuptook from synaptic cleft) and acetate (activated by combination with reduced coenzyme A) ( catalysed by choline acetyltransferase ( acetylcholine ( taken into synaptic vesicles by vesicular transporter VAChT ( released into synaptic cleft Muscarinic receptors in smooth muscle, brain and glands; M1-M4 are G protein-coupled receptors; affect adenylyl cyclase, K channels or phospholipase C M1 in brain; causes slow excitation M2 in heart; causes slow inhibition M3+M4 in smooth muscle M4 in pancreas ( increased secretion of pancreatic enzymes and insulin Nicotinic receptors in autonomic ganglia, CNS and NMJ; made of 5 subunits that form central channel; when activated  subunit binds Ach ( change in protein ( allows passage of Na and other cations ( depolarizing potential Clearance: hydrolysed to choline and acetate by acetylcholinesterase in postsynaptic membrane (Pseudocholinesterase: found in plasma, hydrolyses other choline esters; under endocrine control) Monoamines Catecholamines: E, NE, dopamine NB. Cocaine blocks reuptake of dopamine and NE Amphetamines cause presynaptic terminals to release NTs  Formation: all made by hydroxylation and decarboxylation of amino acid tyrosine Some tyrosine made from phenylalanine in liver, but most from dietary origin Tyrosine transported into catecholamine-secreting (dopaminergic, adrenergic, noradrenergic) neurons or adrenal medulla ( dopa ( dopamine in cytoplasm; TYROSINE ( DOPA is RATE-LIMITING PROCESS Dopamine enters granulated vesicles ( converted to norepinephrine ( transported into vesicles by vesicular transporters NE leaves vesicles, is converted to E, then enters other storage vesicles Released from neurons by exocytosis Removed from synaptic cleft by: Binding with postsynaptic receptor Binding to presynaptic receptor Re-uptake into presynaptic neurons: important for NE Catabolism: Oxidation catalysed by monoamine oxidase (MAO-A and MAO-B) on outer surface of mitochondria found esp in neurons; measure 3-methoxy-4-hydroxymandelic acid in urine Methylation catalysed by catechol-O-methyl-transferase (esp in liver, kidneys, smooth muscle, glial cells); accounts for catabolism of extracellular E and NE; measure normetanephrine and meanephrine in urine Receptors are metabotropic (serpentine with G proteins) - NE has higher affinity for -receptors E has higher affinity for -receptors Norepinephrine  made by noradrenergic neurons; at most sym postganglionic endings; noradrenergic neurons located in reticular formation, but most regions of CNS receive input; all receptors are metabotropic; stored in synaptic knobs in small granulated vesicles; NE and E bound to ATP and associated with protein called chromogranin A in vesicles; may also contain neuropeptide Y and dopamine beta-hydroxylase which get released with NE + E on exocytosis; can hyperpolarize neurons by increasing K conductance, or may enhance excitatory output via disinhibition or blockage of K channels NECell bodies in pons and brainstem, project to all levels 1Excitatory: decr K conductance, incr IP3 and DAGPhenylephrinePrazosin 2Inhibitory (presynaptic): decr Ca conductance, incr K conductance, decr cAMPClonidineYohimbine 1Excitatory: decr K conductance, incr cAMPIsoproterenol, dobutamineAtenolol, practolol 2Inhibitory: incr Na conductance, incr cAMPAlbuterolButoxamine Dopamine  slow inhibitory effect on CNS neurons; mainly used in projection linking substantia nigra to neostriatum (function of antiparkinsonian drugs), and projection to limbal structures (function of antipsychotic drugs), and in hypothalamus; in small intensely fluorescent (SIF) cells; receptors are all metabotropic; reuptake via Na and Cl-dependent transporter; metabolized via MAO and COMT D1-like receptors: D1, D5 D2-like receptors: D2, 3, 4 Dopa -mineCell bodies at all levelsD1Inhibitory: incr cAMPPhenothiazinesD2Inhibitory (presynaptic): decr Ca Inhibitory (postsynaptic): incr K conductance, decr cAMPBromocriptinePhenothiazines, butyrophenones Tyrosine hydroxylase gets negative feedback from dopamine and norepinephrine; tyrosine hydroxylase needs a co-factor named tetrahydrobiopterin Phenylketonuria: build up of phenylalanine 2Y to mutation of gene for phenylalanine hydroxylase; NE and E can still be made from tyrosine; if caused by deficiency of tetrahydrobiopterin, since this is involved in many steps above as cofactor, will also get deficiency of NE and E Serotonin (5-hydroxytryptamine) 5-HTCell bodies in midbrain and pons; project to all levels5-HT1AInhibitory: incr K conductance, decr cAMPLSDMetergoline, spiperone5-HT2AExcitatory: decr K conductance, inc IP3 and DAGLSDKetanserin5-HT3Excitatory: incr cation conductance2-methyl-5-HTOndansetron5-HT4Excitatory: decr K conductance  Found in enterochromaffin cells, myenteric plexus, brain (pons and upper brainstem), retina; found in unmyelinated neurons that innervate most regions of CNS Inhibitory usually via 5-HT1a (membrane hyperpolarisation via incr K conductance); 5-HT3 or 4 may be slow excitatory; may be excitatory and inhibitory on same neuron; involved in sleep, temp, appetitie, neuroendocrine control Formation: hydroxylation and decarboxylation of aa tryptophan Deactivated by: reuptake Breakdown to 5-hydroxyindoleacetic acid by MAO Converted to melatonin by pineal gland Multiple receptors, all metabotropic (coupled to adenylyl cyclase or phospholipase C) except 5-HT3 which is ionotropic 5-HT2A for platelet aggregation and SM contraction 5-HT2C mediate food intake 5-HT3 in GI tract, related to vomiting 5-HT4 in GI tract, related to peristalsis and secretion Histamine Histaminergic neurons have cells bodies in tuberomammillary nucleus of post hypothalamus ( axons to all brain; also found in gastric mucosa and mast cells (in pituitary gland)  Formed by decarboxylation of aa histidine; most histamine is converted to methylhistamine H1-3 are known found in peripheral tissues and brain; related to arousal and sexual behaviour, BP, pain threshold, itch H1 activate phospholipase H2 increase cAMP H3 mostly presynaptic, work in negative feedback Tachykinins Substance P: receptor is serpentine acting via G protein ( activation of phospholipase C, formation of IP3 and DAG ( slow EPSP in neurons transmitting noxious stimuli; involved in slow pain; also found in nigrostriatal system and hypothalamus, involved in peristalsis in intestine Other tachykinins are neurokinin A, neuropeptide K, neurokinin B Opioid Peptides Opioid peptidesCell bodies at all levelsMuInhibitory (presynaptic): decr Ca conductance, decr cAMPBendorphinNaloxoneDeltaInhibitory (postsynaptic): incr K conductance, decr cAMPEnkephalinNaloxoneKappaInhibitory (postsynaptic): incr K conductance, decr cAMPDynorphinNaloxone Enkephalins bind opioid receptors (eg. Met-enkephalin and leu-enkephalin); found in GI tract and brain; decr intestinal motility, pain relieving; they come from precursors from which the peptide is cleaved Prokephalin ( met-enkephalin, leu-enkephalin, octapeptide, heptapeptide Pro-opiomelamocortin ( beta-endorphin, other endorphins Prodynorphin ( dynorphins, neoendorphins Enkephalins are metabolized by enkephalinase A and B and aminopeptidase 3 receptors characterized, serpentine receptors coupled to Gq, inhibit adenylyl cyclase:   analgesia, resp depression, constipation, euphoria, sedation, miosis, incr secretion GH and PL; incr K conductance ( hyperpolarisation; bind endorphins   analgesia, diuresis, sedation, miosis, dysphoria; close Ca channels   analgesia; close Ca channels; bind enkephalins Other Polypeptides Somatostatin: sensory input, locomotor activity, cognitive function; inhibits insulin secretion from pancreas, inhibits GI hormones; 5 different G protein coupled receptors Vasopressin, oxytocin, neurotensin, cholecystokinin, VIP, neuropeptide Y Purine and Pyrimidine Transmitters ATP: released with other NTs during exocytosis; may act via G proteins or ligand-gated ion channels Adenosine: general CNS depressant; vasodilator in heart; works via different serpentine G protein linked receptors changing cAMP concs Gases NO: made from arginine catalysed by NO synthase; activates guanylyl cyclase Endocannabinoids Triangle9-THC is psychoactive ingredient of cannabis; activates receptor CB1 (also activated by endogenous anandamide and 2-arachidonylglycerol) can function as retrograde synaptic messengers (released from POSTsynaptic neurons ( activate CB1 on PREsynaptic neurons ( suppress NT release) Cotransmitters When NT released with eg. A polypeptide one may potentiate the effect of another Synaptic Plasticity and Learning Posttetanic potentiation: enhanced postsynaptic potentials in response to stimulation; enhancement lasts up to 60secs; tetanising stimulation causes accumulation of Ca in presynaptic neuron until intracellular binding sites are saturated Habituation: when benign stimulus is repeated, response to stimulus decreases; due to decr release of NT from presynaptic terminal 2Y to decr intracellular Ca due to gradual inactivation of Ca channels Sensitisation: prolonged occurrence of augmented responses after a stimulus to which animal has been habituated is paired with noxious stimulus; may be transient/longer term; due to Ca-mediated change in adenylyl cyclase ( incr production cAMP Long term potentiation: persistent enhancement of postsynaptic potential response to presynaptic stimulation after brief period of rapidly repeated stimulation; much more prolonged than posttetanic potentiation; due to accumulation of Ca in postsynaptic neuron Long term depression: decreased synaptic strength NEUROMUSCULAR TRANMISSION NMJ As axon approaches termination, loses myelin sheath and divides into terminal buttons/endfeet contains small clear vesicles containing Ach; endfeet fit into junctional folds (depressions in motor end plate thickened part of muscle membrane, containing 15-40 million Ach receptors); 1 nerve fibre per end plate, no convergence of multiple inputs Impulse arrives at end of motor neuron Incr permeability to Ca ( Ca INFLUX Incr exocytosis of Ach-containing vesicles (approx 60 per impulse, each vesicle containing 10,000 Ach molecules 10x more than needed to depolarize) Ach diffuses to nictonic receptors Incr Na and K conductance of muscle membrane ( Na INFLUX ( depolarizing end plate potential Adjacent muscle membrane depolarized to firing level ( AP conducted down fibre ( muscle contraction Acetycholinesterase removes Ach from synaptic cleft Drug curare competes with Ach at endplate; endplate potentials undergo temporal summation At rest, small quanta of Ach (size proportional to Ca, inversely propotional to Mg at end plate) released randomly ( miniature end plate potential (0.5mV) Myasthenia gravis: ab to nicotinic receptors ( destroy receptors or trigger removal by endocytosis Lambert-Eaton syndrome: antibodies to Ca channels in nerve endings ( decr Ca influx ( prevents Ach release Denervation hypersensitivity: when motor nerve to muscle cut, muscle becomes v sensitive to Ach, but muscle atrophies; this only affects the structure immediately innervated by neurons, not those further downstream; due to synthesis of more receptors; will result in wallerian degeneration with also retrograde degeneration up to site of nearest sustaining collateral; in cell body chromatolysis occurs (decr in Nissl substance); then regenerative sprouting with axon beginning to regrow this can be helped by giving neurotrophins Smooth and Cardiac Muscle Postganglionic neurons branch extensively and have beads (varicosities) not covered by Schwann cells containing vesicles; may contain clear vesicles with Ach, or dense-core vesicles with NE; NO END PLATES nerve fibres run membranes of muscles cells, so 1 neuron can innervate many effector cells (synapse en passant); fibres end on SAN, AVN, and Bundle of His (NE fibres also innervate ventricular muscle) In smooth muscle NE ( partial depolarization called excitatory junction potentials (EJPs); or partial hyperpolarisation called inhibitory junction potentials (IJPs) depending on whether NE is excitatory or not to that tissue Denervation hypersensitivity: when motor nerve to muscle cut, muscle becomes v sensitive to Ach; muscle DOES NOT atrophy IMPULSES IN SENSE ORGANS Sensory receptors transduce energy from environment (eg. Thermal, light, odour, taste) into APs in neurons; may be part of neuron or specialized cell that generates AP in neurons; receptor has much lower threshold to respond to adequate stimulus than other receptors (eg. For rods, this is light will respond to pressure on eyeball however, but has to be higher stimulus); there are 11 conscious senses Classification: special (smell, vision, hearing, rotational and linear acceleration, taste), cutaneous (touch-pressure, cold, warmth, pain receptors for this likely on naked nerve endings, CMR-1 for mod cold, VR1 and VRL-1 for extreme heat, latter 2 are nociceptive), visceral. Or teleceptors (events at a distance), exteroceptors (external enviro near), interoceptors (internal enviro), proprioceptors (position) Pacinian corpuscule: touch receptor; unmyelinated ending of sensory nerve fibre; large; surrounded by connective tissue; myelin sheath begins in corpuscule; responds only to transient touch; when small amount of pressure applied ( nonpropagated depolarizing potential occurs generator/receptor potential ( generator potential proportionate to magnitude of stimuli ( at 10mV AP generated, fires repetitively if pressure further increased ( sensory nerve at 1st node of Ranvier depolarized ( propagated. Frequency of APs proportionate to magnitude of applied stimuli. Adaptation/desensitisation: when maintained stimulus, frequency of APs decreases over time; this may be Rapidly adapting: eg. Light touch Slowly adapting: eg. Muscle spindles, nociceptive Doctrine of specific nerve energies: sensation evoked by receptor is due to specific part of brain they ultimately activate (eg. Irritation from a tumour in armpit on sensory nerve from pacinian corpuscule in hand will cause sensation of touch) Projection: no matter where in pathway is stimulated, sensation is referred to location of receptor (eg. Phantom limb) Intensity discrimination: vary frequency of AP, or vary no. receptors stimulated R (sensation felt) = K(constant) x S(intensity of stimulus)A(constant) Sensory unit: single sensory axon and its many peripheral branches supply a receptive field; as strength of stimulus increases it activates sense organs immediately in contact with it and recruits those in surrounding area as receptive fields overlap; stronger stimuli will also stimulate receptors with higher thresholds ( increase intensity of sensation REFLEXES Reflex arc: sense organ Needs adequate stimulus Receptor potential proportional to strength of stimulus ( all-or-none potential in AFFERENT neuron Enter via dorsal roots/CN; cell bodies in dorsal root ganglia/CN ganglia No. potentials proportionate to size of generator potential Synapses in central integrating system (eg. Brain/spinal cord) EFFERENT neuron (the final common path) Leave via ventral roots/motor CN Receive multiple other inputs Effector In above, spatial and temporal facilitation, occlusion, subliminal fringe effects all occur CNS can be in central excitatory/inhibitory state (eg. When excitatory, impulses radiate not only to somatic areas but also to autonomic areas (eg. Urination, sweating, - mass reflex)). Habituation and sensitization can be applied to reflexes Bell-Magendie law: dorsal roots sensory, ventral roots motor Monosynaptic reflex: eg. Stretch reflex (muscle spindle ( fast sensory fibres ( NT at central synapse = glutamate ( motor neuron ( muscle) Muscle spindle: 10 intrafusal muscle fibres enclosed in CT capsule, ends of which are contractile and attached to tendons at either end of muscle or to sides of extrafusal fibres. 2 types of intrafusal muscle fibre: Nuclear bag fibre: many nuclei in central dilated area; 2 fibres per spindle, 1 with high and 1 with low ATP-ase activity Nuclear chain fibre: thinner, shorter, no central bag; 4+ per spindle; attached to 1) Respond to changes in length and changes in rate of stretch: Stimulation of NBFs ( dynamic fusiform response (ie. Discharge most rapidly when muscle being stretched, less rapidly during sustained stretch) physiologic tremor would be worse if it wasnt for NBFs being sensitive to rate of stretch Stimulation of NCFs ( static fusiform response (ie. Discharges rapidly so long as muscle is stretched Motor nerve supply 1) Exclusive motor nerve supply ( efferents of Leksell / small motor nerve system)  3-6um diameter, 30% fibres in ventral roots, group A ; have motor end plates (plate endings) on NBF s and trailing endings on NCF s Stimulation causes contractile ends of intrafusal fibres to shorten (become shorter than extrafusal fibres) ( stretches NBF s ( stimulates Ia sensory fibres ( may cause reflex contraction of muscle (via  motor neurons); as there is - linkage, spindle shortens with muscle during contraction, so spindle discharge may continue throughout contraction, so spindle remains capable of responding to stretch; regulated by descending tracts from brain, regulating sensitivity for posture etc (discharge incr by anxiety, unexpected mvmt, Jendrassiks manouvre, noxious stimulus to skin) INCR DISCHARGE INCREASES SPINDLE SENSITIVITY  motor neurons  have motor end plates (plate endings) There are also  and  dynamic and static efferents  stimulation of dynamic efferents increases spindle sensitivity to rate of stretch; stimulation of static efferents increases sensitivity to steady, maintained stretch Sensory nerve supply Primary (annulospiral) ending: the terminations of rapid Ia sensory afferent fibres; 1 branch innervates NBF 1 and another NBF 2 and NCFs; nerve endings wrap around centre of fibres and go to motor neurons supplying extrafusal fibres of same muscle 2) Secondary (flowerspray) ending: the terminations of II sensory fibres; near ends of intrafusal fibres on NCF only Stimulation caused by stretching of muscle spindle ( receptor potential ( AP in Ia fibres at f proportionate to degree of stretching ( spinal cord ( motor neuron to extrafusal fibres (monosynaptic) Reaction time: time between application of stimulus and response (eg. 19-24ms for knee jerk) Central delay = reaction time time taken for impulse to travel to and from spinal cord = time taken for reflex activity to traverse spinal cord (0.6-0.9ms) II sensory fires may be involved in polysynaptic mechanisms. Feedback device that maintains muscle length if stretched, reflex contraction; if shortened, reflex relaxation Reciprocal innervation: Ia fibres cause postsynaptic inhibition of motor neurons to antagonists via inhibitory interneron (Golgi bottle neuron) BISYNAPTIC Inverse stretch reflex/autogenic inhibition: when tension becomes so great that there is no longer reflex contraction ( muscle relaxes; note, elastic muscle fibres take up much of stretch so takes strong stretch to cause relaxation; receptor is in Golgi tendon organ (net-like knobbly nerve endings along fasiscles of tendon; 3-25 muscle fibres per organ, Ib myelinated rapidly-conducting sensory nerve fibres; stimulated by both passive stretch and active contraction of muscle acts as feedback circuit to regulate muscle force; low threshold) Stimulation ( spinal cord ( inhibitory interneuron ( generation of IPSPs on motor neuron that supply that muscle, excitatory connections to motor neurons supplying antagonist muscle Tone: flaccid is  neurons cuts hypotonic if  efferent discharge low hypertonic if high (if you lengthen muscle passively, it wants to contract, so high tone ( further stretch causes inverse stretch reflex, sudden loss of resistence  clasp-knife effect/lengthening reaction); clonus regular rhythmic contractions in muscle exposed to sudden sustained stretch (spindle hyperactive so bursts of impulses discharge motor neurons all simultaneously ( muscle contraction stops spindle discharge ( we keep pushing and cause passive stretch again) ALL THE ABOVE DETERMINE RATE OF DISCHARGE OF  MOTOR NEURONS - SPINDLES FEEDBACK TO REGULATE MUSCLE LENGTH - GOLGIS FEEDBACK TO REGULATE MUSCLE FORCE Polysynaptic Reflexes Synaptic delay = approx 0.5ms, so the more synapses the slower the response Reverberating response: some pathways may turn back on self, activity reverberates until unable to cause propagated reponse ( dies out Withdrawal reflex: nociceptive stimulus ( flexion of agonist, inhibition of antagonist; it is prepotent (ie. Take priority over any other reflex activity occurring in spinal cord at that moment) Crossed extensor response: with withdrawal reflex, also get extension of contralateral limb Irradiation of the stimulus: when spinal cats paw pinched, limb withdrawn, contralateral hindlimb extended, ipsilateral forelimb extended, contralateral forelimb flexed spread of excitatory impulses up and down spinal cord causing recruitment of motor units Local sign: if noxious stimulus is medial aspect leg, also get some abduction of leg Fractionation: each input only goes to part of motor neuron pool for the flexors so doesnt produce maximal response Occlusion: various afferent inputs share some motor neurons ( submaximal response Stronger stimulus causes larger and more prolonged response due to repeated firing of motor neurons (after-discharge due to continuing stimulation of motor neurons along a polysynaptic path, many impulses arriving at different times). Stronger stimulus causes faster response due to temporal and spatial summation in polysynaptic pathway. SENSATION Cell bodies in dorsal root ganglia Dorsal horns arranged into laminas I-VII (I most superficial) I-VI: unilateral input II, III: substantia gelatinosa VII: bilateral input 3 types of sensory fibres: 1) A and A fibres: large, myelinated; mechanical stimuli; ( III-VI 2) A fibres: small, myelinated; mechanoreceptors (III + IV), cold, fast nociceptors (I + V) 3) C fibres: small, unmyelinated; pain, temperature, mechanoreceptors (I + II) Pathways Dorsal column / lemniscal system (fine touch (localization, spatial form, temporal pattern) and proprioception) Travel up dorsal column ( synapse in MEDULLA (gracile and cuneate nuclei) ( cross midline IN MEDIAL LEMNISCUS ( ventral posterior nucleus in thalamus Damage ( loss of vibratory sensation and proprioception, loss of localization of touch sensation, incr touch threshold, decr no touch-sensitive areas in skin Some collaterals synapse in dorsal horn, may modify input into other cutaneous sensory systems Dorsal horn acts as a gate allowing certain pain impulses through depending on impulses from descending tracts from brain and nature of input Lower axons more medial Anterolateral system / spinothalamic (touch (gross), pain, cold, warmth): Synapse in dorsal horn ( cross midline IN SPINAL CORD locally ( ascend in anterior spinal cord (touch) lateral spinal cord (pain and temp) ( relay nuclei in thalamus, projection nuclei near midline, reticular activating system Damage ( incr touch threshold, decr no touch-sensitive areas; touch localization normal; deficit less profound than dorsal columns Lower axons more lateral From thalamus sensory info goes to cortex: Somatic sensory area I (Brodmanns area 1, 2 and 3): in postcentral gyrus; legs at top and head at Bottom; hand and mouth have large amounts; cells organized in vertical columns, each column responds to a certain sensory modality Ablation ( deficits in position sense, discrimination of size and shape; also effects SII (hence SI processes stuff then projects it on to SII) Somatic sensory area II: in superior wall of sylvian fissure (separated temporal from frontal and parietal lobes); head at inf end of postcentral gyrus, feet at bottom of sylvian fissure Ablation ( deficits in tactile discrimination; has no effect on SI Cortical plasticity: above mapping can change rapidly to reflect use of represented area; cortical connections of sensory units to cortex have convergence and divergence, connections can become weak/strong with disuse/use; this doesnt only occur with touch Cortical lesions mainly effect proprioception and fine touch, affect temp and pain to lesser extent. Touch Not necessarily visible specialized receptors; numerous in fingers and lips, around hair follicles Receptor: associated with BNC1 Na channel (a degenerin when hyperexpressed, cause neurons they are in to degenerate) Nerve: A (5-12um diameter, conduction velocity 30-70m/s) and C fibres Pathway: transmitted in dorsal (more important) and spinothalamic columns, so rare to get complete loss Proprioception Nerve: A Pathway: dorsal Central: cerebellum, medial lemniscus, thalamus NB. Spray endings, touch receptors in skin, muscle spindles all convey info along antlat column to cortex for conscious awareness of position of body Temperature More cold sensitive (10-38deg) than heat sensitive (30-45deg) spots Receptor: from the TRP family of cation channels Moderate cold cold- and menthol-sensitive receptor 1 (CMR1) Severe heat VR1 and VRL-1 (both nociceptors) Nerve: A + C for cold, C for hot Pathway: spinothalamic column Central: postcentral gyrus, insular cortex Pain Sense organ: naked nerve endings; vanilloid receptor-1 (VR1) and VRL-1 discovered which respond to pain, protons, harmful temps Nociceptive substances: P factor (?may be K) causes pain in muscles not receiving enough blood supply, washed away when blood returned Nerve: A (small myelinated, 2-5um diameter, 12-30m/s) ( terminate in dorsal horn on lamina I + V; fast Pain (sharp); deficiency in deep structures Dorsal root C fibres (large unmyelinated, 0.4-1.2um diameter, 0.5-2m/s) ( terminate in dorsal horn lamina I + II; slow pain (dull) Neurotransmitter: mild pain = glutamate, severe pain = substance P - from 1Y afferent to dorsal cord Pathway: some in dorsal, some in lat spinothalamic Central: to ventral post nuclei in thalamus ( cortex (areas SI, SII, cingulates gyrus, mediofrontal cortex, insular cortex, cerebellum) Visceral pain: no proprioceptors, few temp or touch, sparse pain receptors (sensitive to distension and chemical irritation); afferent fibres reach CNS via paraS and sym fibres (splanchnic, pelvic, phrenic, intercostal, facial, GP, vagus, trigeminal) ( cell bodies in dorsal roots and CN ganglia ( travel in spinothalamic tracts, or may make connections with collaterals to postganglionic sym neurons for reflex control ( reflex contraction of nearby skeletal muscle Referred pain: visceral / deep somatic to somatic structure; may appear to radiate; referred to structure developed from same embryological segment / dermatome (dermatomal rule); due to plasticity of CNS and convergence of pain fibres on same 2nd order neurons (lamina 1-VI ipsilateral, lamina VII bilateral, hence can be referred to opp side of body) peri neurons dont usually fire the 2nd order neuron, but if visceral stimulation prolonged facilitation occurs at peri endings Central inhibition: inhibition of pain pathways in dorsal horn gate due to stimulation of large-diameter touch-p afferents Inflammatory pain: exaggerated response (hyperalgesia) and pain on normally non-painful stimuli (allodynia); due to release of cytokines and GFs facilitating perception and transmission in cut areas and dorsal horn Neuropathic pain: causalgia burning pain after trivial injury; reflex sympathetic dystrophy skin thin, shiny, incr hair growth; nerve inj causes growth of sym nerve fibres into dorsal root ganglia of sensory nerves from injured area ( sym discharge causes pain Analgesics: opiates can work peripherally in tissue, in dorsal horn where 1Y afferent synapses, in brainstem (activate inhibitory descending pathways that decr transmission of pain impulses); placebo can cause release of endogenous opioids Itch and Tickle Pathway: spinothalamic Relieved by scratching as activates large, fast-conducting neurons that gate transmission at dorsal horn Synthetic Senses Touch, warmth, cold, pain ( cortex makes vibratory sensation, 2-point discrimination, stereognosis Vibration: pacinian corpuscules ( dorsal column 2-point discrimination: smallest where touch receptors most numerous; back = 65mm, fingers = 3mm Stereognosis: ability to identify objects by handling them; also dorsal column VISION Anatomy Sclera: protective outer covering Cornea: transparent Choroid: BVs Retina: lining post 2/3 of choroid, neural tissue, extends almost to ciliary body (containing circular and longitudinal muscle fibres; makes aqueous humour that nourishes cornea and lens ( enters ant chamber ( through canal of Schlemm at iridocorneal angle Accomodation: must contract ( relax lens ligaments if object >6m away Near point of vision is closest object can be focused 9cm aged 10, 83cm aged 60 (presbyopia) due to hardness of lens Near response: accommodation + convergence of visual axes + papillary constriction Lens: held in place by lens ligament (zonule) attached to thickened choroid (ciliary body) Parallel (ie. >6m away) light rays strike biconvex lens are refracted (at cornea, ant lens and post lens) to point (principle focus) which is on line passing through centres of curvature of lens (principal axis); distance between lens and PF is principal focal distance (will be longer if object <6m away); refractive power increases with curvature of lens (measured in diopters) Hyperopia: short eyeball, far sighted; make up for this with sustained accommodation, but prolonged convergence of visual axes may cause strabismus; need convex lenses Myopia: long eyeball, short sighted; correct with biconcave lenses Astigmatism: irregular corneal curvature; part of retinal image is blurred; need cylindric lenses Iris: contains circular and radial muscles that change pupil Pupillary light reflex assoc with consensual light reflex (pathway is dorsal to that for near response so can lose response to light but retain accommodation Argyll Robertson pupil) Nerves leave near lat geniculate bodies to enter midbrain at sup colliculus ( terminate in pretectal nucleus ( 2nd order neurons to ipsilateral and contralateral Edinger-Westphal nucleus ( 3rd order neuron to ciliary ganglion in oculomotor nerve ( 4th order neuron to ciliary body) Vitreous humour: between lens and retina Macula lutea: near post pole of eye, location of fovea centralis (rod free, dense cones which each synapse with only 1 bipolar cell which synapses with 1 ganglion cell; high VA) Lacrimal gland: moistens cornea ( lacrimal duct Photoreceptor Mechanism Visible light 397-723nm wavelength DARK: Na channels in outer segments open ( current flows from outer to inner segment and to synaptic ending; Na-K-ATPase in inner segment maintains ionic equilibrium; steady release of NT LIGHT: closure of some Na channels ( hyperpolarizing receptor potential ( decr release of NT ( signal in bipolar cells ( AP in ganglion cells ( optic nerve Light absorbed by photosensitive pigments ( change in structure ( electrical response Pigments made of opsin (protein) and retinene (aldehyde of vit A1; vit A def causes visual abnormalities eg. Nyctalopia night blindness, prolonged def causes degeneration of neural tissues) RODS: Rhodopsin (visual purple): made of scotopsin and retinene1 (can be made from vit A); peak sensitivity wavelength 505nm; molecular weight 41000; makes up 90% of protein in rods membranes; serpentine receptor coupled to G protein (transducin, Gt1); light changes shape of retinene1 (from cis-11 config to all-trans isomer) ( alters configuration of scotopsin ( activates G protein ( exchanges GDP for GTP (  subunit separates (active until GTPase hydrolyses GTP, which is accelerated by -arrestin) ( activates cGMP phosphodiesterase ( converts cGMP (which normally keeps Na channels open) to 5 -GMP ( Na channels close ( hyperpolarizing potential; reaction amplifies light signal ( retinene1 separates from scotopsin (bleaching) ( some converted back to 11-cis config by retinal isomerase ( reassociates with scotopsin ( rhodopsin CONES: 3 diff types responding to wavelengths 440 (blue, short/S, blue-violet portion) 535 (green, Middle/M, green portion) 565 (red, long/L, yellow portion) nm Each contains different pigment which is maximally sensitive to one of 1Y colours (Young- Helmholtz theory); green and red pigment similar, blue different; contains an opsin and retinene1; light activates retinene1 ( activates Gt2 ( activates phosphodiesterase ( cGMP to 5-GMP ( closure of Na channels between ECF and cone cytoplasm ( decr intracellular Na ( hyperpolarisation Light also decr Ca conc ( changes which speed recovery, reopening Na channels ( activates guanylyl cyclase ( makes more cGMP ( inhibits light-activated phosphodiesterase Axons that go to suprachiasmatic nuclei and lat geniculate nuclei contains melanopsin instead of above Cone receptor potential sharp onset and offset; cone responses  stimulus intentity at high levels of light when rod response are at max and don t change Rod receptor potential  sharp onset, slow offset; rod responses  stimulus intensity at levels of light lower than threshold for cones; better at detecting absolute illumination Genetics Gene for rhodopsin on C3; for blue-sensitive cone pigment on C7, for red and green sensitive cone pigment on q arm of CX recombination results in shifted spectral sensitivities Dichromats only have 2 colour pigments; trichromats have all 3; monochromats have only one -anomaly = colour weakness; -anopia = colour blindness; prot- = red; deuter- = green; trit- = blue Colour blindness usually inherited (8% males, 0.4% females; recessive X-linked), but can be caused by lesions of V8 Retina 10 layers; contains rods and cones ( synapse with bipolar cells (rod bipolar cells for rods, flat bipolar cells for cones) (signal may be altered by horizontal cells) ( synapse with ganglion cells (105:1 convergence) Signal may be altered by amacrine cells Large/M/magno ganglion cells for movement, depth, flicker and stereopsis Small/P/parvo ganglion cells for colour, texture, fine detail and shape Ganglion cells subtract/add input from one type of cone to input from another ( axons converge and form optic nerve 3mm medial to post pole of globe @ optic disc which is blind spot as no rods/cones there ( decussate at optic chiasm ( optic tract to ( hypothalamus ( endocrine and circadian rhythms for light-dark cycle or ( lat geniculate body (in thalamus) Contains 6 layers; 1+2 have large cells, magnocellular, receives M ganglion cells 3-6 have small cells, parvocellular, receive P ganglion cells Interlaminar region receives P ganglion cells 1+4+6 input from contralat eye 2+3+5 input from ipsilat eye Precise representation of retina; input not only from retina, but also cortex for perception of orientation and motion Upper retina (lower visual field) to medial half; lower retina (upper visual field) to lat half to ( geniculocalcarine tract (divergence, 2x more fibres than in optic nerve) med geniculate body to superior calcarine fissure, lat to inf, from macula to post meaning macular sparing is possible) ( via magnocellular and parvocellular pathways 3 different pathways red/green pathway (difference between L+M) blue/yellow pathway (difference between S+L/M) luminance pathway (sum of L+M) ( occipital lobe (Brodmanns area / 1Y visual cortex / V1 at calcarine fissure); 1000x more nerves involved than in optic; precise mapping of retina; arranged in vertical columns depending on orientation in degrees; also has 6 layers Parvo and magnocellular to layer 4 Interlaminar region to layer 2+3 (have clusters of cells containing cytochrome oxidase called blobs, for colour vision) Feature detectors: half receive input from both eyes Simple cells respond to bars of light, lines, edges at certain orientations Complex cells less dependent on location of stimulus in visual field ( project from V1 to dorsal/parietal pathway for motion ventral/temporal pathway for recognition of forms and faces connect with sensory areas area V8 for colour vision or ( pretectal region of midbrain and sup colliculus ( papillary reflexes and eye mvmt These fibres leave optic tract near geniculate bodies so blindness with papillary reactions due to lesion behind optic tract or ( frontal cortex ( control of saccades, vergence and near response Rods and cones rest on pigment epithelium next to choroid (ie. Deep) so light must pass through ganglion an bipolar cell layer to reach them; pigment epithelium absorbs light, preventing its reflection, preventing blurring of vision; have outer segment (modified cilia, discs composed of membrane which contain photosensitive compounds that initiate APs), inner segment (has nuclear region, rich in mitochondria) and synaptic zone Rod: 12 million; has saccules rather than discs; thin outer segments constantly renewed by formation of new discs at inner edge with phagocytosis of old discs at outer edge; predominate extrafovealy, much convergence; sensitive receptors for night vision (scotopic) Cones: 6 million; has discs; thick inner segments, conical outer segments; diffuse renewal at multiple sites; higher threshold for bright vision (photopic) Duplicity theory: input from rods and cones Horizontal cells: connect receptor cells to one another in outer layer Amacrine cells: connect ganglion cells to one another in inner layer Gap junctions; connect retinal neurons to one another Muller cells: bind neural elements together Retinal BV supply bipolar and ganglion cells, choroidal BV for rods and cones Only ganglion cells have all-or-none APs; others have local, graded potentials Rods, cones and horizontal cells hyperpolarizing Bipolar cells hyper/depolarizing Amacrine cells depolarizing which may act as GP for ganglion cells Image Formation When there is light, the surrounding area is inhibited mediated by hyperpolarisation of horizontal cells ( inhibits response of photoreceptor (lateral / afferent inhibition); helps sharpen image and improve discrimination Processing occurs by amacrine cells Dopamine affects structure of gap junctions, allowing current to pass freely between horizontal cells in dark, enlarging receptive field Dark adaptation: max at 20mins; due to adaptation of rods; time due to time required to build up rhodopsin stores as in bright light much has been broken down Light adaptation: 5 mins Colour Vision Hue, intensity, saturation Complementary colour: ever colour has a colour that combines with it to produce white Black: absence of colour Colour perceived depends on colour of other objects in visual field Primary colours - Red light: 723-647nm Green light: 575-492nm Blue light: 492-450nm Visual Acuity Degree to which details and contours of objects perceived Min seperable: shortest distance 2 lines can be apart Critical Fusion Frequency: f at which stimuli can be presented and still be perceived as separate Binocular vision: images from 2 retinas fused at cortical level; points on retina on which image must fall to be seen as single images are corresponding points Strabismus: when images no longer fall on corresponding points; in young children diplopia settles when one image is suppressed (suppression scotoma) occurs in cortex, permanent Ambylopia ex anopsia: suppressed vision when refractive error in one eye Eye Movements When eye looking nasally IO elevates, SO depresses When eye looking laterally SR elevates, IR depresses Saccades: sudden jerking movement; bring objects onto fovea; prevent adaptation that would occur if gaze fixed on one object for long time; in frontal cortex and sup colliculi (innervated by M fibres, and from cerebral cortex; projections to cerebellum and areas for reflex mvmt of head and nect via tectospinal tract) Smooth pursuit movement: tracking; cerebellum Vestibular movement: due to stimuli from semicircular canals, maintain as fixation as head moves Convergence movement: focus near HEARING AND EQUILIBRIUM Anatomy: Eustachian tube: opens into nasopharynx; opens on yawning, chewing, swallowing Malleus: has Manubrium, attached to TM, head attached to wall, process attached to incus Stapes: footplate attached by annular lig to oval window Tensor tympani: pulls Manubrium medially, decr vibration of TM Stapedius: pulls footplate out of OW Labyrinth: inner ear; bony in petrous temporal bone; membranous surrounded by perilymph, filled with endolymph (do not communicate) Cochlea: basilar membrane and Reissners membrane divide into 3 chambers (scalae); scala vestibule upper, scala tympani lower, scala media inbetween; contain perilymph; communicate at helicotrema; scala vestibule ends at OW; scala tympani ends at round window closed by 2Y TM Organ of Corti: on basilar membrane; contain hair cells which are auditory receptors which pierce reticular lamina supported by rods of Corti; arranged in outer and inner hair cell rows; covered by tectorial membrane in which tips of outer hair cells are embedded; nerves go to spiral ganglion in modiolus in core around which cochlea wound ( form auditory division of VIII Basilar membrane permeable to perilymph in scala tympani, so hair cells bathed in perilymph Semicircular canals: orientated in 3 planes; membranous canals suspended in perilymph; crista ampullaris located in ampulla of each canal, made of hair cells and sustentacular cells; hair cells in contact with vestibular division of VIII Utricle: contains macula on floor; contain sustentacular cells and hair cells in which are embedded otoliths; nerve cells join vestibular division of VIII Saccule: contains macula in semivertical position; as above Hair Cells Sensory receptors of ear throughout membranous labyrinth embedded in epithelium made of supporting/sustentacular cells, basal end in contact with afferent neurons; apical end has rod like processes (hairs, stereocilia composed of actin) and one true cilium kinocilium MP -60mV; when stereocilia pushed toward kinocilium MP decr to -50mV, when pushed away hyperpolarizes; if pushed in direction perpendicular to this, no change in MP; intermediate produces intermediate de/hyperpolarisation; so shows change in direction Tip links tie tip of stereocilia to side of its higher neighbour when short stereocilia pushed towards taller one, opens channels ( K and Ca enter channel from endolymph ( depolarization ( release of NT ( depolarization of neuron; K enters sustentacular cells ( reaches cochlea ( secreted back into endolymph Bases of hair cells bathed in perilymph (formed from plasma), tips in endolymph (formed in scala media by stria vascularis (via N-K-ATPase and K channels), high conc of K, low conc of Na) In Organ of Corti for hearing In utricle for horizontal acceleration In sacculus for vertical acceleration 3 in semicircular canals for rotational acceleration Central Pathways Auditory pathway: afferent ( dorsal and ventral cochlear nuclei ( inf colliculi for auditory reflexes ( medial geniculate body ( auditory cortex in Brodmanns area 41 Most neurons respond to inputs from both ears; several auditory association areas ( reticular formation Also efferent olivocochlear bundle which arises from auditory nerve and end around bases of hair cells in Organ of Corti Vestibular pathway: Afferent in cristae and macula ( vestibular nucleus and flocculonodular lobe of cerebellum Afferent in semicircular canals ( vestibular nucleus (sup and med division) ( nuclei controlling eye movement Afferent in utricle and saccule ( Deiters nucleus (lat division) ( spinal cord, cerebellum, reticular formation Also input to thalamus and 1Y somatosensory cortex Hearing: NOT DONE VESTIBULAR FUNCTION Rotational acceleration in semicircular canals ( stimulates crista ( endolymph displaced in opp direction to that of rotation ( fluid pushes cupula ( bends hair cells; when continuous rotation fluid spins at same rate, cupula returns to normal ( deceleration displaces fluid in same direction as rotation ( cupula moves again ( 25-30 secs to settle; note endolymph displaced toward ampulla on one side of head, and away on other side, so can detect direction as well as rotation via pattern of impulses to brain; linear acceleration doesnt stimulate Vestibular nuclei maintain position of head in space CN nuclei eye movements Caloric stimulation convection currents in endolymph on change in temp ( nystagmus, vertigo, N Linear acceleration: urticle (horizontal) and saccule (vertical) respond; also discharge tonically in absence of movement due to gravity ( reflex righting of head, postural adjustments; some go to cortex for conscious perception of motion and orientation in space (also need proproception, touch and pressure receptors, visual info). Vertigo when labyrinthe inflamed. Nystagmus: reflex to maintain fixation on stationary objects while body rotates Vestibulo-ocular reflex: eyes slowly move to maintain visual fixation at beginning of rotation (impulses from labyrinths) ( snap back to another fixation point (trigger by brainstem) ( slow movement again; can be horizontal, vertical or rotational (quick component in same direction as rotation, postrotatory nystagmus opp direction) Motion sickness: xs vestibular stimulation ( reflexes in brainstem and flocculonodular lobe of cerebellum Smell and taste: NOT DONE Behaviour, sleep: NOT DONE CONTROL OF POSTURE AND MOVEMENT Movement: 1) Reflexive eg. Reflexes (inc. swallowing, chewing, scratching, walking which can have voluntary adjustment) 2) Voluntary performance improves with repetition (synaptic plasticity) a) Idea b) Cortical association areas where commands originate c) Planned cortex basal ganglia and lat cerebellum d) Via thalamus e) Premotor and motor cortex make commands M1 = motor cortex: in precentral gyrus, feet at top, face at bottom; face represented bilaterally; prox limbs ant edge of gyrus, distal limbs post edge; 30% corticospinal/bulbar from here Supplementary motor area above cingulated sulcus on med side of hemisphere; projects to motor cortex; involved in programming motor sequences, involved in complex activities Premotor cortex on lat surface; 30% cotricospinal/bulbar from here; projects to cortex and brainstem; involved in postural control 40% corticospinal/bulbar come from parietal lobe (esp somatic sensory area) f) Tracts to motor neurons in brainstem (corticobulbar) and SC (corticospinal) Collaterals end on brainstem nuclei ( motor neurons in brainstem and SC Damage to corticospinal tract ALONE doesnt cause spasticity Lat corticospinal crosses midline at medulla (80%); skilled movement; destruction ( loss of pincer grip, wrist movement affected Ant corticospinal crosses midline at levels of SC (20%); destruction ( difficulty with balance, walking, climbing ( fibres end on interneurons that contact motor neurons bilaterally In brainstem: medial/ventral pathways for control of trunk and prox limbs (gross movements) Lateral pathways for control of distal limbs (fine movements) In CS tracts: ventral/medial pathways (tectospinal, reticulospinal, vestibulospinal) for prox muscles and posture lateral pathways (rubrospinal) for distal limbs g) Change in sensory input ( feedback info ( motor cortex ( spinocerebellum ( brainstem (rubrospinal, reticulospinal, tectospinal, vestibulospinal) Pyramidal system = CS tract as if forms pyramids in medulla Extrapyramidal system = other descending brainstem and spinal pathways; for posture Somatic sensory area and portions of post parietal lobe project to premotor area; lesions of SSA ( inability to perform learned tasks Spinal Cord and Posture ReflexStimulusResponseReceptorIntergrated InStretchStretchMuscle contractionMuscle spindlesSC, medulla+ive supporting reactionContact with sole/palmFoot extendedProprioceptors in distal flexorsSC-ive supporting reactionStretchRelease of +iveProprioceptors in extensorsSC Spinal cord: reflex responses; affected by variation of threshold of spinal stretch reflexes, due to change in excitability of motor neurons and change of rate of discharge of efferents to muscle spindles Lesion: ( period of spinal shock (reflexes depressed, RMP 2-6mV greater than normal; length of time proportionate to degree of encephalisation of motor function) ( reflexes return after 2/52(first is flexion of leg flexors and adductors to noxious stimuli / knee jerk) ( become hyperactive (reflexes released from central control and may be accentuated ie. Removal of inhibition, dennervation hypersensitivity to mediators released by excitatory endings, sprouting of collaterals causing additional excitatory endings) as threshold steadily drops (minor stimuli causes prolonged flexion-extension patterns, eg. Positive supporting reaction when put finger on sole of foot; may be assoc with pain if transaction incomplete) - Negative N balance, catabolise body proteinm ulcers, incr Ca; glucocorticoids decr inflamm response Pattern generators: in SC, in neck and lumbar; causes walking; turned on by discharge from mesencephalic locomotor region so must be incomplete transaction Bladder function: reflex contractions occur BP: baroreceptor reflexes disturbed; wide swings in BP Sex: can still get erection of minimal stimulation Mass reflex: afferent stimuli radiate from one reflex centre to another; may even radiate to other autonomic centres (eg. ( urination, sweating, altered BP) Static reflexes: Phasic reflexes: short term, dynamic Medulla in Posture (decerebrate) Tonic labyrinthine reflexesGravityContraction of limb extensorsOtolithic organsMedullaTonic neck reflexesHead turning To side Up Down Extension of limbs on side to which head turned Hind legs flex Forelegs flexNeck proprioceptorsMedulla Lesion ( Decerebrate rigidity: Due to lesions in brainstem; spasticity due to diffuse facilitation of stretch reflexes; spastic extensor muscles (uncovers static postural reflex, not affected by phasic postural reflexes, able to stand) Due to incr excitability of motor neuron pool incr rate of discharge of  efferent neurons ( incr spindle sensitivity Incr facilitation: reticular facilitatory area (discharges spontaneously, always functions), vestibular nuclei, some descending pathways (in ant funiculus of SC; have direction action on  motor neurons to incr excitability) Decr facilitation: motor cortex, basal ganglia, cerebellum, reticular inhibitory area (driven by fibres from cortex and cerebellum so if brainstem transected from higher control, ceases to function) Facilitatory area sends impulses through lat funiculus of SC; damage causes balance to shift to facilitation ( spasticity Midbrain in Posture Labyrinthine righting reflexesGravityHead kept levelOtolithic organsMidbrainNeck righting reflexesStretch of neck musclesRighting thorax, shoulders, pelvisMuscle spindlesMidbrainBody on head righting reflexesP on side of bodyRighting of headExteroceptorsMidbrainBody on body righting reflexesP on side of bodyRighting of bodyExteroceptorsMidbrain Lesion ( extensor rigidity only present when lying on back (affected by phasic postural reflexes); can rise to standing, walk and right themselves Righting reflexes: maintain normal standing and keep head upright Grasp reflex: if above thalamus removed and laid on side, limbs near ground extended, other arm flexed and hand grasps any object brought near it Other midbrain reflexes: pupillary light reflex, nystagmus; vestibular pacing reaction (if lowered quickly forelegs extend and toes spread) Cortex in Posture (decorticate) Optical righting reflexesVisionRighting of headEyesCortexPlacing reactionsVisual, exteroceptive, proprioceptiveFoot places on supporting surfaceVariousCortexHopping reactionsLat displacement when standingHopsMuscle spindlesCortex Reflexes intact if no cortex; normal temp regulation etc Inability to react in terms of past experience Lesion ( Decorticate rigidity: due to loss of fibres which inhibit  efferent discharge via reticular formation (poss at ant edge of precentral gyrus  suppressor strip, 4s); spastic flexion only at rest (affected by phasic postural reflexes) Basal Ganglia in Posture High 02 consumption, high copper content Caudate nucleus: cognitive processes Putamen Globus pallidus: divided into internal and external segments Subthalamic nucleus (body of Luys) Substantia nigra: divided into pars compacta and pars reticulata Striatum = 1) and 2); made up of patches/striosomes composed of nerve endings in a matrix Receives afferent connections Corticostriate projection from layer 5 of cortex ( patches layers 2+3 (matrix A projection from thalamus Lenticular nucleus = 2) and 3) Projections: Substantia nigra ( striatum ( globus pallidus ( subthalamic nucleus ( globus pallidus and substantia nigra; projections that end on patches ( dopaminergic neurons in pars compacta of SN; end on matrix ( GABAergic neurons in pars reticulate of SN Pathways: Nigrostriatal dopaminergic system inhibitory to putamen stimulate D1 (which inhibit internal segment of GP) and inhibit D2 (which inhibits int segment of GP) balance maintains normal function; affected in Parkinsons (loss of dopaminergic input to putamen (decr inhibition, incr excitation of subthalamic nuclei and int segment of GP); symptoms when 60-80% lost), normally lost with age Intrastriatal cholinergic system excitatory; affected in HC GABAergic system from striatum to globus pallidus and substantia nigra inhibitory; affected in HC; loss of inhibition ( hyperkinesia Output: From cortex ( striatum ( internal segment of globus pallidus ( inhibitory to thalamic fasciculus ( thalamus (ventral lat, ventral ant, centromedian nuclei) ( excitatory to prefrontal and premotor cortex LOOP From substantia nigra ( thalamus Also to habenula and sup colliculus Function: involved in planning and programming movement; role in cognitive processes; involved in speech. Can result in hypo/hyperkinetic state (eg. Chorea, athetosis, ballism, akinesia, bradykinesia) Eg. Huntingtons disease jerky movement, chorea, slurred speech; autosomal dominant (short arm C4); caused by trinucleotide repeat expansion; onset 30-50yrs; protein huntingtin involved Eg. Parkinsons disease also occurs with meds that block D2 receptors; hypokinetic and hyperkinetic (lead pipe rigidity (agonists and antagonists affected), cogwheel rigidity and tremor) aspects, decr associated movements (eg. Swinging arms when walking, facial expression); trt with decr cholinergic system or give L-dopa; proteins -synuclein and barkin involved Cerebellum in Movement Connected to brainstem by sup/mid/inf peduncles; medial vermis and lat hemispheres; large SA; divided into 3 parts by 2 transverse fissures; consists of 10 lobules Lesion ( hypotonia, ataxia (incoordination due to errors in rate, range, force, direction of mvmt); compensation will occur if only cortex affected, permanent if nuclei; scanning speech; past-pointing; intention tremor (inability to correct); rebound phenomenon; adiadochokinesia; decomposition of movement Function: flucculonodular lobe/vestibulocerebellum nodulus in vermis, flocculus in hemispheres; equilibrium and learning-induced changes in VOR; lesion ( staggering, broad base spinocerebellum rest of vermis and medial hemispheres; receives proprioceptive info from body and plan from cerebral cortex; smooths and coordinates mvmts; vermis for axial and prox limb, hemisphere for distal limb cerebrocerebellum/neocerebellum lat hemispheres; plan and program mvmts also: learned adjustments that make coordination easier as brain activity shifts from prefrontal area to parietal and motor cortex and cerebellum; via olivary nuclei input via climbing fibre External cerebellar cortex: 3 layers: external molecular, Purkinje cell, internal granular layers Contains Purkinje cells (only output from cerebral cortex, pass to deep nuclei) Granule cells (also found in cerebral cortex, innervate Purkinje cells) Granule cells have bodies in granular layer ( send axon to molecular layer ( bifurcates to form a T ( branches run parallely (parallel fibres) and synapse with dendrites of Purkinje cells by forming grid Basket cells (inhibitory; in molecular layer; input from parallel fibres; project to Purkinje cells) Stellate cells (inhibitory; similar to basket but superficial) Golgi cells (inhibitory; in granular layer ( axons project to molecular layer and granule cells; and have input from parallel fibres and Purkinje cells) All use GABA (acting on GABAa receptors) except granule cells, which use glutamate Separated from white matter by deep cerebellar nuclei: Dentate nucleus: neo Globose nucleus: spino Emboliform nucleus: spino Fastigial nucleus: spino Interpositus nucleus = 2) + 3) Input: Climbing fibres excitatory; come from inferior olivary nuclei (which receives proprioceptive input from body); strong excitatory effect on dendrites of Purkinje cell; 1 climbing fibre has 2000-3000 synapses on Purkinje cells Mossy fibres excitatory; provide proprioceptive info from body and info from cerebral cortex via pontine nucleus; weak excitatory effect on dendrites of granule cells in groupings called glomeruli ( excitatory effect on Purkinje cells; each Purkinje cell has input from 250000-1000000 mossy fibres Circuit: Climbing and mossy fibres excite Purkinje cells and granule cells (Granule cells excite basket and stellate cells via parallel fibres ( basket and stellate cells inhibit Purkinje cells (feed-forward inhibition) Mossy fibre and Purkinje collaterals and parallel fibres excite Golgi cells ( inhibit transmission from mossy fibres to granule cells Purkinje cells inhibit deep cerebellar nuclei Climbing and mossy fibres excite deep cerebellar nuclei Output: from deep cerebellar nuclei; always excitatory vestibulocerebellum ( brainstem Neocerebellum and spinocerebellum ( nuclei ( brainstem (neo also to thalamus) Autonomic NS: not done Central regulation of visceral function: not done TEMPERATURE REGULATION Speed of chemical reactions and enzyme systems have narrow temp ranges Poikilothermic: cold-blooded; large fluctuations in temp Homeothermic: warm-blooded; reflex responses from hypothalamus maintain temp in narrow range (36.3 37.1); scrotum 32; oral 0.5 lower than rectal; core has circadian fluctuation of 0.5-0.7; lowest at 6am, highest in evenings; raise during time of ovulation; 0.5 higher in children; incr to 40 during exercise Heat production: exercise, assimilation of food, BMR; incr by E and NE (fast) and thyroid (slow), incr during sym discharge; brown fat is source of heat in infants Heat loss: radiation (transfer of heat by infrared electromagnetic radiation, not in contact; altered by colour of clothing; important in lower temps) conduction (exchange between objects in contact; transfer is  temp difference  thermal gradient  temp of skin determines how much heat is transferred, altered by vasoD/C, rate at which heat transferred from deep tissues to skin = tissue conductance; horripilation erection of hairs, insulated and decreases heat loss; aided by convection movement of molecules away from area of contact) vaporization of water on skin and m membranes of resp tract (vaporization of 1g H20 removes 0.6kcal of heat; insensible loss 50mL/h (1600ml/h during exercise); degree to which sweat vaporizes depends on humidity; can vary from 30-900kcal/h; panting incr loss; important in higher temps) urine, poo Temp-regulating mechanisms: reflex responses to cold (threshold 36.8 for vasoC, 36 for non-shivering thermogenesis, 35.5 for shivering) controlled by post hypothalamus, to heat (threshold 37 for sweating and vasoD) controlled by ant hypothalamus; receives afferents from sensory receptors in skin, deep tissue, SC, brain Incr heat loss cut vasoD, sweating, incr RR Decr heat prod anorexia, apathy, inertia Decr heat loss cut vaso C, curling up (decr body SA), horripilation, countercurrent exchanges (in animals living in cold H20, heat transferred from arteries to venae comitantes, extremities remain cold, conserve heat) Incr heat prod shivering (involuntary), hunger, incr voluntary activity (semivoluntary), incr NE + E (when cut BVs cold, have incr response to NE+E) Fever: thermostat reset to point >37 ( receptors indicate temp is 41 can cause brain damage, >43 causes heat stroke) Malignant hyperthermia: mutations in gene coding for ryanodine receptor ( XS Ca release during muscle contraction during stress ( contractures, incr metabolism ( incr heat Hypothermia: slow HR, slow RR, decr BP, decr LOC; ability to spontaneously return to temp to N lost <28 Neural basis of instinctual behaviour and emotions: not done Conditioned reflexes, learning and related phenomena: not done CARDIOVASCULAR SYSTEM Electrical Activity of Heart Pacemaker Potentials  1) Pacemaker potential (prepotential) slowly increases until 2) Action potential triggered 3) At peak efflux of K (IK) begins ( repolarisation 4) IK decay: K efflux decreases, membrane begins to depolarize ( prepotential develops again 5) Transient Ca channels open ( complete prepotential; may also be Ca sparks (local release of Ca from SR) contributing to this 6) Long-lasting Ca channels open ( causes AP Vagal stimulation ( hyperpolarized membrane, slope decreases Ach ( M2 receptors ( G protein response ( open K channels ( incr K conductance so longer for Ik decay ( decr cAMP ( slowed opening of Ca channels Sym stimulation ( incr r of spontaneous discharge NE ( 1 receptors ( incr intracellular cAMP ( opens L channels ( more rapid depolarisation NB. AP s due to Ca with no contribution from Na (so no rapid depolarizing spike) NB. There are latent pacemakers in other parts of heart that have prepotentials and take over when SAN goes pear-shaped. A and V muscle only discharge spontaneously when injured/abnormal. Spread of Excitation Conduction system composed of modified cardiac muscle (fewer striations, indistinct boundaries); RMP of -90mV; act as syncytium due to gap junctions SAN: located at junction of SVC and RA; contains P cells (small round cells with few organelles connected by gap junctions); receives mainly R vagus nerve (endocardial fibres) and R sym innervation (from stellate ganglion, epicardial fibres); conduction speed 0.05m/s ( 3 bundles that connect SAN and AVN; anterior internodal tract of Bachman, middle internodal tract of Wenckebach, post internodal tract of Thorel; slower conduction through atrial myocytes; conduction speed 1m/s; conduction speed 1m/s ( AVN: located in R post interatrial septum; only conducting pathway between A and V due to fibrous ring; contains P cells (small round cells with few organelles connected by gap junctions); receives mainly L vagus nerve (endocardial fibres) and L sym innervation (from stellate ganglion, epicardial fibres); conduction speed 0.05m/s Atrial depolarization complete in 0.1s (AV nodal delay), before excitation spreads to Vs Delay shortened by SNS, lengthened by PNS ( Bundle of His: LBB at top of IV septum (later splits into ant and post fascicle) then continues as RBB Branches and fascicles run subendocardially down either side of septum, coming into contact with Purkinje system whose fibres spread to whole V; conduction speed 1m/s BOH, 4m/s Purkinje system Ventricular depolarization complete in 0.08-0.1s; starts from L IV septum ( to R across septum ( down spetum to apex ( along V walls to AV groove ( from endocardium to epicardium ( finally to posterobasal portion of LV, pul conus, and upper portion of septum ECG Create equilateral (Einthovens) triangle with electrodes on both arms and L leg; measure potential difference between 2 electrodes ( deflection on paper Bipolar leads: use 2 active electrodes; standard limb leads (I, II, III) record differences in potential between 2 limbs; deflection here indicates magnitude and direction in axis of electromotive force produced by heart (cardiac axis) and can be calculated if heart is at centre of Einthovens triangle ( can calculate mean QRS vector by estimating net differences between QRS +ive and ive peaks (normal is -30 to +110 deg) Lead I: electrodes on RA and LA; LA positive (upward deflection when LA +ive compared to R) Lead II: electrodes on RA and LL; leg positive Lead III: electrodes on LA and LL; leg positive Unipolar leads: use 1 active electrode and 1 indifferent electrode 6 chest leads: V1-V6 3 limb leads: aVR, aVL, aVF; augmented as measure between one limb and TWO other limbs  P wave = atrial depol QRS = V depol ST and T wave = V repol U wave = slow repolarisation of papillary muscles Note: atria located posteriorly V form base and ant surface RV is antlat to LV DRAW CHEST DIAGRAM AND EXPLAIN LEADS Using ECG, phonocardiogram and carotid pulse can work out QS2 (total electromechanical systole): period from onset of QRS to closure of AV (S2) PEP (pre-ejection period): diff between QS2 and LVEP; time for electrical and mechanical events that precede systolic ejection LVEP (LV ejection time): fro beginning of caroitid pressure rise to dicrotic notch PEP:LVEP = normal is 0.35; incr due to poor LV performance Echos: use 2.25MHz frequency His Bundle Electrogram: catheter places through vein to R heart close to tricuspid valve  Cardiac Arrhythmias Sinus arrhythmia: accelerates during inspiration, decelerates during expiration; due to fluctuations of paraS input impulses from vagal nerves from stretch receptors in lung inhibit cardioinhibitory area in medulla oblongata ( decr vagal input ( incr HR on inspiration Sick sinus syndrome: marked bradycardia 1st deg HB: PR long 2nd deg HB: not all A impulses conducted to V 2:1, 3:1 Wenckebach phenomenon: PR lengthens until misses beat Complete heart block: when conduction from A(V completely interrupted due to AV nodal block / infranodal block (due to septal MI, surgery) ( V beat at slow r (idioventricular rhythm) independent of A AV nodal block, AVN takes over as pacemaker (45bpm) Infranodal, V pacemakers (35bpm) Cerebral ischaemia ( Stokes-Adams syndrome (faints and dizziness) L ant hemiblock: ( L axis deviation L post hemiblock: ( R axis deviation Increased automaticity: when other myocardial fibres discharge spontaneously Ectopic beats: from ectopic focus; if repetitive may ( paroxysmal tachycardia/A flutter Reentry: defect in conduction that permits wave of excitation to propogate continuously in closed circuit (circus movement); if reentry in AVN ( depolarizes A ( echo beat, if goes down to V ( paroxysmal nodal tachycardia; may have abnormal bundle of conducting tissue connecting A and V (bundle of Kent), passes in one direction through AVN then the other through bundle ( can involve both A+V Atrial ectopic: abnormal P wave but normal QRST; may depolarize SAN which must repolarise then reach firing level before can fire again ( pause before next beat; cause reseting of normal rhythm Atrial tachycardia: regular discharge of atrial focus / reentrant activity; in atrial flutter large counterclockwise circus movement in RA ( sawtooth pattern due to atrial contractions, usually assoc with AV blocks as AVN cant conduct >230bpm; in AF, due to circulating reentrant excitation waves in both atria, AVN discharges at irregular intervals ( V beat at irregular rate (80-160) Ventricular ectopics: bizarre QRS due to slow spread of impulse from focus through V muscle; cant excite BOH so retrograde conduction of A doesnt occur; normal SAN depolarizes atria but P wave hidden in QRS, if it reaches V they will still be in repolarisation phase; however next SAN impulse produces normal beat after compensatory pause (longer than pause from atrial ectopic) Ventricular tachycardia: due to circus movement in Vs VF: rapid discharge from multiple V ectopic foci / circus movement; can be produced by electric shock / extrasystole during vulnerable period (midportion of T wave, when some of V myocardium depolarized and some incompletely repolarised, some completely repolarised) Accelerated AV conduction (WPW syndrome): bundle of Kent is aberrant muscular/nodal tissue connection between A+V which conducts more rapidly than AVN ( 1V excited early ( short PR and slurred QRS deflection, with normal PJ interval; tachycardias often follow atrial premature beat which conducts down AVN then sprads to aberrant bundle and back up to A ( circus movement (or vice versa less often) Lown-Ganong-Levine syndrome: short PR but normal QRS; depolarization down aberrant pathway but enter IV conducting system distal to node Other ECG Changes MI: MP of infarcted area greater than in normal area ( current flows from +ive infarct into -ive normal area ( flows toward electrodes over injured area ( ST elevation ST elevation 1) MP of infarcted area greater than in normal area ( current flows from infarct into normal area ( flows toward electrodes over injured area ( ST elevation 2) Rapid repolarisation due accelerated opening of K channels ( ST segment elevation, within secs, lasting few mins 3) Decr RMP due to K loss ( current flow into infarct during V diastole ( TQ segment depression (looks like ST elevation); within mins 4) Delayed depolarization ( again infracted area +ive comparied to normal ( ST segment elevation; within 30mins Normalisation of ST segment over days/weeks Dead muscle becomes electrically silent so becomes ive relative to normal myocardium during systole and doesnt contribute to positivity of complexes ( Q wave development, incr size of Q wave; failure of progression of R wave; may get BBB if septum involved Ventricular arrhythmias occur during 1st 30 mins (due to reentry) ( after 12hrs (due to incr automaticity) ( after 3/7 to several wks (due to reentry) Infarcts affecting epicardium interrupt sym nerve fibres ( dennervation supersensitivity to NE+E in area beyond infarct; endocardial infarct lesions affect vagal fibres Hyponatraemia: low voltage complexes Hyperkalaemia: peaked T waves (altered repolarisation) ( prolonged QRS, paralysis of atria ( V arrhythmia; decr RMP ( fibres become unexcitable ( heart stops in diastole Hypokalaemia: prolonged PR, prominent U waves, late T wave inversion; if T and U waves merge, apparent prolonged QT Hypercalcaemia: stops in systole (Ca rigor) Hypocalcaemia: prolonged ST Phenothiazines, tricyclic antidepressants: prolonged ST The Heart As A Pump Pericardial sac contains 5-30ml clear fluid Cardiac muscle contracts faster when incr HR; duration of systole fomr 0.16-0.27s; duration of diastole from 0.14-0.62; cannot be tetanised as will not contrat until near end of another contraction due to prolonged refractory period (theoretical max HR 400; AVN will not conduct faster than 230 so higher HR only seen in V tachy Contraction starts just after depolarization and lasts until 50ms ater repolarisation is completed; atrial systole starts after P wave; V systole starts near end of R wave and ends just after T wave  Jugular Venous Pulse: shows atrial p changes; decr during inspiration due to ive intrathoracic p a wave: atrial systole due to regurg of blood into veins and stopping of venous inflow; in CHB will be asynchronous a waves with giant a waves (cannon wave) when A contract against close TV c wave: rise in Ap due to bulging of TV into A during isovolumetric V contraction; giant c wave in tricuspid insufficiency v wave: incr Ap before TV opens during diastole z: drop in Ap during ejection phase of V as MV and TV pulled downward Heart Sounds: S1: lub; closure of MV and TV at start of V systole; 0.15s long, low f S2: dup; closure of AV and PV after end of V systole; 0.12s long, higher f; loud and sharp when incr diastolic p in aorta/pul art S3: 1/3 way through diastole due to rapid V filling and inrush of blood; 0.1s long S4: just before S1; if high Ap or stiff V (eg. LVH) Arterial pulse: Rate at which wave travels is independent of and greater than velocity of blood flow (4m/s in aorta, 8m/s in large arteries, 16m/s in small arteries moves faster in older people); pulse in radial artery felt 0.1s after peak systolic ejection Strength of pulse: determined by pulse pressure; not affected by MAP STRONG: large SV incompetent AV (may be so strong than head nods with heartbeat; collapsing / Corrigan / water-hammer pulse) WEAK: shock Dicrotic notch: oscillation in falling phase of pulse wave when aortic valve shuts; not palpable Cardiac Output SV: amount of blood pumped by each V in 1 HB = 70ml CO: output per unit time; ave 5L/min; controlled by SV (inotropic) and HR (chonotropic) Cardiac index: output per min per square metre body surface; ave 3.2L Preload: degree to which myocardium is stretched before it contracts Afterload: resistance against which blood is expelled Measure with: Doppler and echo Direct Fick Method: only applies when arterial blood is only source of substance being taken up; measure amount of O2 used by body in period and divide by AV difference across lungs; use ABG and pul art blood from cardiac catheter Fick principle: Amount of substance taken up by organ per unit time = (arterial level of substance venous level (A-V difference)) X blood flow CO = O2 consumption (mL/min) / [AO2] [VO2] Indicator dilution method: dye/radioactive isotope (which must stay in blood stream; can use cold saline injected into RA and measure temp change in pul art - thermodilution technique) injected into vein and conc in arterial blood determined serially CO = amount injected / av. arterial conc after single circ through heart Starlings Law of Heart  Energy of contraction proportional to initial length of cardiac muscle fibre (in heart, this is proportionate to end-diastolic vol SV/EDV = Frank-Starling curve): when stretched tension incr to max then declines Heterometric regulation: change in CO due to muscle fibre length Homometric regulation: change in CO due to contractility EDV: affected by intrapericardial p (incr ( V cannot fill) V stiffness (incr by eg. MI) VR (incr by incr blood vol, venoconstriction, decr intrathoracic p, muscular activity, lying down) Contractility: SNS shifts length-tension curve up and left; NE+E work on 1 receptors and Gs ( adenylyl cyclase, incr cAMP Small incr contractility with incr HR Postextrasystolic potentiation  V extrasystole makes succeeding contraction stronger due to incr availability of intracellular Ca Depressed by incr CO2, decr O2, acidosis, quinidine, procainamide, barbs Intrinsic depression in CCF, ? cause NB. Athletes have lower HR, greater end-systolic V vol, greater SV @ rest O2 Consumption of Heart Determined by: intramyocardial tension, contractile state, HR; correlates with V work (= SV x MAP in pul art or aorta; approx 7x higher for LV as aortic p higher) for unknown reason incr MAP has bigger effect in workload than incr vol (ie. afterload has bigger effect than preload; ie. AS will be greater problem than regurg) Basal: 2ml/100g/min (higher than resting skeletal muscle) Beating: 9ml/100g/min Extracts most O2 from blood so incr O2 must be provided by incr coronary blood flow NB. Law of Laplace: tension of wall of hollow viscus proportionate to radius of viscus ( stretch myocardial fibres ( incr SV NB. Incr HR ( incr velocity and strength of contraction BUT decr end-systolic vol and hence radius of heart Dynamics of Blood and Lymph Flow Move blood forward: heart pump, diastolic recoil of arteries, compression of veins by skeletal muscle, negative pressure of thorax Blood Vessels In vessels: SM innervated by noradrenegeric fibres ( constriction, cholinergic fibres ( dilation Artery ( arteriole ( metarterioles (may be connected to venule via thoroughfare vessel) ( capillaries (openings surrounded on upstream side by precapillary sphincters (not innervated, but respond to local vasoconstrictors; when dilated RBC can pass in single file in thimble shape) Arteries: 0.4cm diameter, 1mm wall thickness, 20cm2 cross-sectional area, 8% blood Outer layer adventitia (CT), middle layer media (SM), inner layer intima (endothelium secretes growth regulators, vasoactive substances - and CT) Large amount elastic tissue in inner and outer layers ( recoil during diastole Resistance vessels: principle site of PVR Arterioles: 30m diameter, 20m wall thickness, 400cm2 cross-sectional area, 1% blood Less elastic tissue, more SM Major site of PVR 2% blood in aorta Capillaries: 5m diameter at arterial end, 9m diameter at venous end, 1m wall thickness (single layer of endothelial cells); 4500m2 cross-sectional area, 5% blood; typical p is 32mmHg at arteriolar end, 15mmHg at venous end; pulse p 5mmHg at arteriolar end, 0 at venous end; blood travels at 0.07cm/s; transit time is 1-2secs; 24L fluid filtered per day Junctions between cells permit passage of molecules <10nm diameter (tighter in brain) Vesicular transport in cells via endo- then exocytosis of plasma and proteins Fenestrations: in endocrine/intestinal villi/kidneys; cytoplasm attenuated to form gaps; 20-100nm diameter closed by thin discontinuous membrane which permit passage of large molecules; no membrane in glomerulus and sinusoids of liver; in sinusoids gaps 600- 3000nm diameter Fluid movement = k (related to permeability of capillary and area of filtration[(HPG) (OPG)] Diffusion important for exchange of nutrients and waste materials; filtration also important, depends on balance of Starling forces (eg. hydrostatic pressure gradient and osmotic pressure gradient) HPG = HP in capillary HP in interstitial fluid (directed outward) OPG = OP in plasma OP of interstitial fluid (directed inward) Fluid moves into interstitium at arteriolar end (filtration > oncotic p), into capillary at venous end (oncotic p > filtration) If fluid reaches equilibrium in tissue diffn can be increased by incr flow (flow-limited) If doesnt, diffn is diffusion-limited Pericytes: outside endothelial cells; long contractile processes wrap around vessels and react to local vasoactive agents to regulate flow esp in inflamm In resting tissues, most capillaries collapsed and bypassed via thoroughfare vessels; in active tissues metarterioles and precapillary sphincters dilate Noxious stimulus ( release of substance P, bradykinin and histamine ( incr cap permeability AV anastomoses (shunts): in fingers, palms, earlobes; have thick, muscular walls; abundant innervation Venules: 20m diameter; 2m wall thickness; 4000cm2 cross sectional area Veins: 0.5cm diameter; 0.5mm wall thickness (thin and easily distended); 40cm2 cross sectional area; pressure 12-18mmHg (5mmHg in gt veins; 4.6mmHg is CVP as enters RA); affected by gravity; velocity incr as blood enters larger veins Little SM but capable of much venoconstriction from noradrenergic nerves and circulating vasoC Intima folded to form venous valves (not in small veins, great veins, brain, viscera) Capacitance vessels: can ake large amount of blood before incr venous p Flow encouraged by negative intrathoracic p on inspiration (falls to -6 from -2.5mmHg ( decr CVP to 2 from 6mmHg ( aids VR; also diaphragm produces +ive intraabdo p ( pushes blood into thorax) and muscle pump Muscle pump, also pulsations of arteries near veins Gravity causes pooling ( decr CO Veins above heart collapse, but dural sinuses dont as rigid walls so have p that is subatmospheric Veins and venules contain 54% blood 12% blood in heart cavities Veins + pul circ + RA, LA, RV = low pressure system LV + arterial system = high pressure system Smooth muscle: contains Ca, K and Cl channels; contraction by myosin light-chain and latch-bridge mechanism Influx of Ca through voltage-gated channels ( incr cytosolic Ca ( contraction ( Ca release from SR via ryanodine receptors ( Ca sparks ( incr activity of Ca-activated K channels (big K/BK channels) ( incr K effluex ( incr MP ( closed voltage gated Ca channels ( relaxation; important in control of vascular tone Angiogenesis: in embryo development network of leaky capillaries formed from angioblasts (vasculogenesis) ( vessels hook up with capillaries which give then SM ( maturation; vascular endothelial GF (VEGF) important, also involved in lymphangiogenesis Blood Flow Flow = Effective perfusion pressure / Resistance Flow = vol per unit time (cm3/s) Flow and resistance markedly affected by small changes in caliber of vessels Flow x2 by 19% incr radius Laminar flow: infinitely thin layer of blood in contact with wall doesnt move next layer has low velocity flow fastest in centre of stream Occurs up to critical velocity higher than this causes turbulent flow; probability of this related to diameter of vessel (more turbulent with smaller diameter) and viscosity of blood (more turbulent with decr viscosity eg. anaemia) Measuring blood flow: electromagnetic flow metres, Doppler flow metres, adaptations of Fick and indicator dilution techniques, plethysmography Shear Stress: flow blood creates force on endothelium that is parallel to long axis of vessel; change in shear stress ( change in genes in endothelial cells related to CV function ( produce integrins, GF s etc& Shear stress () = viscosity () X shear rate (rate at which velocity increases from vessel wall toward lumen) Windkessel effect: recoil during diastole of stretched vessels during systole (ie. elastic) ( forward flow Air embolism: forward movement of blood depends on blood being incompressible; air compressible so if enters heart can stop heart; bubbles lodge in small vessels and markedly incr resistance to flow Effective perfusion p = mean intraluminal p @ arterial end mean p @ venous end Pulse pressure = systolic diastolic p = normal is 50mmHg; incr with incr age Mean pressure = diastolic p + 1/3 pulse pressure; av p throughout cardiac cycle; systole shorter than diastole so slightly less Critical closing pressure: when p in small BV decreased to < tissue p ( no blood flows and vessel collapses (even tho p is not 0) Pressure falls rapidly in small arteries/arterioles as high resistance to flow; p at arterioles 30-38mmHg (pulse p 5mmHg) Pressure incr below heart level, decr above heart level Resistance (in R units) = pressure (mmHg) / flow (ml/s) Also determined by radius of BVs (vascular hindrance), viscosity of blood (plasma 1.8x more viscous than water, blood 3-4x more viscous than water depending on hematocrit; hematocrit has greater effect on viscosity in larger vessels due to difference of nature of flow in small vessels; must be v large incr viscosity to have effevt on PVR; decr viscosity incr blood flow) Velocity = displacement per unit time (cm/s) = flow / area of conduit Average velocity: incr area ( incr velocity; high in aorta, decr in arteries, incr in veins, high in IVC (but lower than aorta); measure by injecting bile salt in arm and measuring time til bitter taste; ave arm-to-tongue circulation time = 15secs Mean velocity in prox portion of aorta = 40cm/s (from ive value in diastole to 120 during systole) Law of Laplace: tension in wall = (transmural p x radius of vessel) / wall thickness Transmural p = pressure inside pressure outside Protects small diameter vessels from rupture the smaller then vessel the lower the tension needed to balance transmural p; in dilated heart large radius, so greater tension must be developed to produce any given pressure ( dilated heart must do more work Measuring BP Auscultatory method: using Riva-Rocci cuff attached to sphygmomanometer; use sounds of Korotkoff; in hyperthyroidism, children, aortic insufficiency and after exercise diastolic is sound when muffles, not disappears; constriction causes critical velocity to be exceeded; tapping due to turbulent flow at peak of systole which is staccato; then as approached diastolic turbulent flow becomes more continuous so becomes muffled; artificially high in fat people as some cuff pressure dissipated so use wider cuff; if left inflated too long reflex vasoC falsly incr BP; auscultatory gap when sound disappear above diastolic then return, may accidentally get low BP Palpation method: 2-5mmHg lower than auscultatory method Lymphatics Normal flow in 24hrs = 2-4L; return protein to blood Capillary efflux > influx ( extra fluid enters lymphatics (prevents incr IFp) ( enter R and L subclavian veins at junction with IJV; contain valves; regular LNs; no fenestrations, little basal lamina, open junction between endothelial cells with no tight intercellular connections 2 types: initial lymphatics: no valves or SM; found in intestine and skeletal muscle; fluid enters through loose junctions between endothelial cells. Drain into collecting lymphatics: have valves and SM which have peristalsis, aided by skeletal muscle pump, negative intrathoracic p during insp, high velocity blood flow in veins in which lymph terminates Lymphagogues: incr lymph flow Incr interstitial fluid vol and oedema: Incr filtration p arteriolar dilatation venular constriction incr venous p (CCF, incompetent valves, venous obstruction, incr total ECF vol due to salt and water retention (eg. cirrhosis, nephrosis), gravity) Decr osmotic p gradient across capillary decr plasma protein level (eg. cirrhosis, nephrosis) accum of osmotically active substance in interstitial space Incr cap permeability substance O, histamine, kinins etc Also depends on: capillary p, IFp, capillary filtration coefficient, no. active capillaries, lymph flow, ratio of precap to postcp venular resistance (precap constriction lower filtration p, postcap incr) In active tissues ( incr cap pressure ( osmotically active particles cant enter capillaries as osmotic p overcome ( accumulation ( affect osmotic gradient so fluid leaves capillaries ( incr lymph flow, but still incr vol in muscles Lymphoedema: high protein content lymph fluid accumulates ( chronic inflamm condition ( fibrosis of interstitial tissue ( elephantitis Cardiovascular Regulatory Mechanisms Central Control BP controlled by vasomotor centre in MO Excitatory: CO2, hypoxia cortex via hypoT (emotion, sexual excitement) pain pathways via reticular formation and exercising muscles (pressor response to stim of somatic afferent nerves is somtatosympathetic reflex) carotid and aortic (in carotid and aortic bodies) chemoreceptors discharge causes production of Mayer waves (slow regular oscillations in arterial p); carotid body ( glossopharyngeal, aortic body ( vagus stimulation ( vasoC and bradycardia however hypoxia ( inc RR, incr E+NE release from adrenal medulla ( incr HR, BP, CO hypercapnia ( stimulates vasomotor area but CO2 is vasoD so no vasoC incr ICP ( compromised blood supply to vasomotor centre ( local hypoxia and hypercapnia ( incr discharge ( Cushing reflex ( incr BP, decr HR (due to baroreceptor reflex) Inhibitory: cortex via hypoT inflation of lungs carotid (small dilation of ICA just above bifurcation of CCA, in carotid sinus) + aortic (in wall of AoA in aortic arch, monitor arterial circ) and cardiopul (in walls of atria type A discharges mainly during A systole, type B mainly late in diastole during peak A filling; type B discharge incr when VR incr) baroreceptors resembling Golgi tendon organs located in adventitia of vessels stimulated by distension ( incr discharge r ( afferent fibres via glossophargyngeal (for carotid) and vagus (for aortic) nerves (buffer nerves) to MO ( nucleus of tractus solitarius ( secrete glutamate to stimulated GABA-secreting inhibitory neurons and vagal motor neurons ( incr PNS, decr SNS ( vasoD, decr BP, decr HR, decr CO, incr renin (retain H20); reach max discharge at 150mmHg but linear increase with BP til then; respond to sustained p, change in p and pulse p ( incr release of vasopressin In chronic incr BP reset to maintain incr BP Bainbridge reflex: rapid infusion of blood/saline ( incr HR if initial HR slow Coronary chemoreflex / Bezold-Jarisch reflex: injections of serotonin/veratridine/capsaicin into CA supplying LV cause apnea followed by rapid breathing, hypotension and bradycardia Pulmonary chemoreflex: injections of drugs into PA cause same effect Valsalva manouvre: incr BP due to incr intrathoracic p added to p of blood in aorta ( decr BP as incr intrathoracic p causes decr VR and CO ( decr pp and MAP ( inhibit baroreceptors ( incr HR and PVR ( stop manouvre ( CO restored but still incr PVR so incr BP ( stimulate baroreceptors ( decr HR; will fail to show these responses in autonomic insufficiency; still have responses in sympathectomy as still have vagal tone intact LV stretch receptors may play a role in vagal tone SNS ( cell bodies in rostral ventrolateral medulla ( sym preganglionic neurons in interomediolateral gray column of SC ( secrete excitatory NT glutamate PNS ( dorsal motor nucleus of vagus and nucleus ambiguous Mechanisms for Regulation 1) Alter output of heart SNS ( +ive chonotropic effect and inotropic effect; inhibit vagal stimulation; mod sym tone (tonic discharge) PNS ( -ive chonotropic effect; high vagal tone (tonic discharge) 2) Change diameter of resistance vessels: 1) Autoregulation: compensate for changes in perfusion pressure; esp good in kidneys Intrinsic contractile response of SM to stretch (myogenic theory of autoregulation) Law of Laplace: wall tension proportionate to distending p X radius of vessel 2) Locally produced vasoD metabolites accumulate in active tissues (metabolic theory of autoreg); decr blood flow (decr O2 tension, decr pH, incr CO2 esp important in skin and brain, incr osmolality) causes accum ( relaxation of arterioles and precapillary sphincters eg. K (important in skeletal muscle); lactate; adenosine (in cardiac muscle) 3) Substances secretes by endothelium Serotonin released from platelets in injured arteries ( sticks to vessel wall ( vasoC Prostacyclin from endothelial cells: inhibits plt aggregation and causes vasoD Thromboxane A2 from plts: promotes plt aggregation and vasoC ( together localize plt aggregation and clot formation; shifted towards prostacyclin by aspirin (inhibits COX ( decr TA2 and prostacyclin, but endothelial cells can create new TA2 in hours but new plts need to be formed in 4 days) NO (endothelium-derived relaxing factor, EDRF): made from arginine, catalysed by NO synthase (NOS1 in NS, NOS2 in macrophages and other immune cells, NOS3 in endothelial cells; 1+3 activated by agents that incr intracellular Ca inc Ach and bradykinin; 2 activated by cytokines); when flow to tissue incr by arteriolar dilation, large arteries to tissue also dilate mediated by NO; products of plt aggregation cause NO release to keep blood flow patent; tonic release of NO needed for normal BP; involved in angiogenesis ( activates guanylyl cyclase ( cGMP ( vasoD Endothelin-1: made from prohormone big endothelin-1 ( endothelin via endothelin- converting enzyme; secreted into media of BVs, act in paracrine fashion; stimulators (AII, NE+E, GFs, hypoxia, insulin, HDL, shear stress, thrombin), inhibitors (NO, ANP, PGE2, prostacyclin); incr circulating conc in CCF and after MI; endothelin-1 in brain, kidneys and endothelial cells; endothelin-2 in kidneys and intestine; endothelin-3 in blood, brain, kidneys, GI tract; play role in regulating passage across BBB, decr GFR in kidneys ( G protein coupled receptor ( phospholipase C ( vasoC Kinins bradykinin (precursor high-molecular-weight kininogen) lysylbradykinin (kallidin, can be converted to bradykinin; precursor low-molecular-weight kininogen) Act on B1 (pain producing effects) and B2 receptors Proteases (kallikreins plasma kallikrein circulates in inactive form, tissue kallikrein located on apical membranes of cells) release BK and LBK) Inactive kallikrein (prekallikrein) converted to active form by active factor XII (CF XII and kallikrein exert +ive feedback; HMWK activates CF XII) both metabolized to inactive fragments by kininase I and II (which is same as ACE) ( contraction of visceral SM; relax vascular SM via NO; incr capillary permeability, chemotaxis; responsible for incr blood flow when glands are secreting products CO produces by heme, catalysed by HO2 ( vasoD 4) Circulating vasoactive substances: VasoD: Adrenomedullin (AM) inhibits aldosterone secretion, incr production NO, inhibit peri SNS action; found in plasma, tissues, adrenal medulla, kidney, brain ANP secreted by heart; antagonizes vasoC substances VIP, histamine, substance P, E in skeletal muscle and liver VasoC: vasopressin causes little change in BP NE generalized effect; circulating levels unimportant, more effecting when released from nerves E other than skeletal muscle and liver AII generalized effect; also causes incr H20 intake and stimulates aldosterone secretion Urotensin-II in cardiac and vascular tissue, very potent AVP, Na-K ATPase inhibitor, neuropeptide Y 5) Nerves: resistance vessels more densely innervated than capacitance (except splanchnic) Noradrenergic ( vasoC (resistance and capacitance not necessarily the same), all over body; have tonic activity (lack of activity ( vasoD); may also contain neuropeptide Y Sympathetic vasodilator system: cholinergic sym vasoD fibres of which postganglionic neurons to BVs in skeletal muscle secrete Ach ( vasoD in skeletal muscle to run through thoroughfare channels Cholingergic ( vasoD; in skeletal muscel, heart, lungs, kidneys, uterus; travel with sym fibres; no tonic activity; may also contain VIP Form plexus on adventitia of arterioles ( fibres extend to media and end on outer surface of SM ( transmitters diffuse into media and current spreads through gap junctions NB. Afferent impulses from sensory nerves in skin relayed down branches to blood vessels ( release substance P ( vasoD and incr cap permeability (axon reflex) 6) Incr temp in active tissues ( vasoD 3) Alter amount of blood pooled in capacitance vessels: circulating vasoactive substances, nerves Venocontriction ( incr VR ( shift blood to arterial side of circulation Circulation Through Special Regions Fick principle: blood flow of organ = amount of substance removed from blood stream by organ in unit time / (conc of substance in arterial blood) (conc substance in venous blood) Cerebral Circulation Ave blood flow is 54ml/100g/min (756ml/min to brain; 69ml/100g/min to gray matter, 28 to white matter) In carotids more important than vertebrals; little crossing over from contralateral side, anastomotic channels dont permit much flow and insufficient to prevent infarction; capillaries surrounded by endfeet of astrocytes close to basal lamina with gaps of 20nm between endfeet; total blood flow remains relatively constant autoregulation important and keeps arterial p at 65-140mmHg Kety method: uses Fick principle using inhaled N2O; measures flow to perfused areas of brain only, gives ave blood flow to brain Measuring blood flow to specific parts of brain: use position emission tomography (2-deoxyglucose uptake is good indication of blood flow; can measure concs of dopamine etc); MRI can image amount of blood in area Awake: blood in premotor and frontal regions Sequential movements: blood in supplementary motor area Creative speech: Brocas and Wernickes area Problem solving, reasoning, motor ideation without movement: premotor and frontal cortex R handed verbal task ( L hemisphere, spatial task ( R hemisphere Alzheimers: decr blood to sup parietal cortex, then temporal then frontal Huntingtons: decr blood to caudate nucleus Manic depression: decr blood to cortex when depressed Schizophrenia: decr blood to frontal and temporal lobes and basal ganlgia Innervation: postganglionic sym neurons (cell bodies in sup cervical ganglia) ( NE, neuropeptide Y; end on large arteries cholinergic neurons (from sphenopalatine ganglia) ( Ach, VIP; end on large arteries sensory nerves (cell bodies in trigeminal ganglia) ( substance P, neurokinin A, CGRP; end on more distal arteries Incr BP ( incr noradrenergic discharge ( decr the incr in blood flow and protects BBB; so has effect on autoregulation and p-flow curve shifted to R (greater incr p can occur without incr flow) Choroid plexus: choroid epithelial cells connected by tight junctions CSF: CSF vol 150ml, produce 550ml/day, turnover 3.7x per day; lumbar CSFp 70-180mm (112 ave); formation independent of IVp, but absorption is proportionate to IVp (and stops <68 ( external/communicating hydrocephalus); same composition as brain ECF with free communication; 50-70% formed in choroid plexuses, rest in BVs along ventricular wall ( foramen of Magendie and Luschka to SA space ( absorbed through arachnoid villi (projections of arachnoid membrane and endothelium of sinuses into venous sinuses) which permit bulk flow (500ml/day) of CSF into veins and cerebral venous sinuses, or 50ml/day diffuse into cerebral BVs Function: protect brain; brain supported within arachnoid by BVs and nerve roots and multiple fine arachnoid trabeculae BBB: maintains constant enviro of neurons in CNS as minor variations have large consequences; immature in neonates ( kernicterus; tends to breakdown in areas of infection/injury (tumours lack tight junctions, so take up drugs better); capillaries resemble non-fenestrated capillaries in skeletal muscle, but tight junctions between endothelial cells limiting passage of substances; flow greater out of than into brain Little vesicular transport Limited passive diffusion - easy: water, CO2, O2, lipid-soluble steroid hormones - hard: proteins and polypeptides dont - slow: H, HCO3, glu Numerous carrier mediated and AT systems Glu: GLUT1 55k in capillaries; major source of E; 55mg/100g/min = 77mg/min total; insulin not required from brain cells to use glu Na-K-2Cl cotransporter (stimulated by ET-1 and 3): leeps brain K conc low Tranporters for thyroid hormones, choline, nucleic acid precursors, aas Multidrug non-specific transporter P-glycoprotein: transport OUT drugs that diffuse IN to brain Diffusion easy: water, CO2, O2, lipid-soluble steroid hormones Diffusion hard: proteins and polypeptides dont; slow penetration of H and HCO3 Outside BBB (circumventricular organs): have fenestrated capillaries therefore are permeable; may function as neurohemal organs (substances secreted enter circulation); may act as chemoreceptor zone circulating substances change brain function Posterior pituitary and median eminence of hypothalamus neurohemal organ Area postrema chemoreceptor zone, initiates vomiting in response to chemical changes Organum vasculosum of lamina terminalis mediate H20 intake; site of osmoreceptor controlling vasopressin secretion; fever produced by IL-1 Subfornical organ mediate H20 intake ICP: brain (1400g) + SC + spinal fluid (75ml) + blood (75ml) + cerebral vessels, which are relatively incompressible, in rigid bony box vol must remain constant (Monro-Kellie doctrine) cerebral vessels compressed when ICP rises, incr venous p decreases cerebral blood flow eg. body accelerated upwards (positive g) ( blood moves towards feet ( decr venous p and ICP in head ( less p on arteries ( blood flow less severely compromises; may cause vision loss and LOC @ over 5g eg. body accelerated down (negative g) ( raise ICP and arterial p at head ( vessels supported and dont rupture; may cause congestion of head and neck vessels, ecchymoses around eyes, severe throbbing headache and confusion Cerebral metabolic rate for O2: 3.5ml/100g/min (49ml/min for brain) = 20% total body resting O2 consumption; brainstem more resistant to hypoxia; basal ganglia, thalamus and inf colliculus esp susceptible Ammonia removal: glutamate taken up by brain ( takes up ammonia ( leaves as glutamine; ischaemia can decr glutamate uptake Coronary Circulation Coronary flow at rest = 250ml.min (5% CO) Extracts 70-80% O2 can incr only by incr blood flow CA ( coronary sinus / ant cardiac veins / arteriosinusoidal vessels (connect arterioles to chambers) / thebesian veins (connect capillaries to chambers) / arterioluminal vessels (small arteries draining into chambers) / some anastomoses between coronary arterioles and extracardiac arterioles Measuring flow: use Kety method by inserting catheter into coronary sinus; can injected radionucleotides and determine their uptake into myocardial cells by Na-K ATPase which is proportionate to blood flow / selectively uptaken by damaged cells Flow: Diastole shorter when incr HR so decr LV CA blood flow during tachycardia Flow in subendocardial portion of LV in diastole therefore prone to ischaemic damage and aortic stenosis (as higher LV systolic p needed to eject so CAs severely compressed) Flow in more superficial portions throughout cardiac cycle as systolic force is dissipated Decr blood flow if decr aortic diastolic p Decr blood flow if incr venous p as decr effective coronary perfusion p Chemical factors: decr O2, incr CO2/H/K/lactate/PG/adenine nucleotides/adenosine, occlusion of artery then release (reactive hyperemia) ( vasoD; adenosine helps to decr reperfusion injury Neural factors: -receptors mediate vasoC; -receptors mediate vasoD; NE causes incr HR and contractility ( incr release of vasoD metabolites ( vasoD, but direct effect theoretically is vasoC; vagal ( vasoD Angina: due to  P factor ; irreversible changes in muscle; note lipoprotein(a) interferes with fibrinolysis by down-regulating plasmin generation; homocysteine damages endothelial cells; inflammatory process involved Splanchnic Circulation Liver and viscera receive 30% of CO via celiac/sup mesenteric/inf mesenteric arteries (vasoC decreases portal inflow; in severe shock may get hepatic necrosis) Intestine: higher blood flow to mucosa; much anastomoses Hepatic: Liver receives 1000ml/min from portal vein, and 500ml/min from hepatic artery (mean p = 90mmHg; walls innervated by SNS via hepatic sym plexus ( vasoC diverts blood from liver); no vasoD nerve fibres to liver; 25-30% vol of liver is blood so contraction of capacitance vessels causes much blood to enter arterial circ Intestines/pancreas/spleen ( portal vein (portal venous p = 10mmHg; walls innervated by SNS via splanchnic nerves ( asoC when decr BP ( raised portal pressure and brisk passage of blood through liver bypassing most; dilates due to passive mechanism when incr BP ( incr blood flow) ( through acinus of liver (zone 1 well oxygenated, zone 3 poorly; p in sinusoids lower than in portal vein; large gaps between endothelial cells in walls of hepatic sinusoids, highly permeable) ( terminal branches of hepatic vein (hepatic venous p = 5mmHg) at periphery ( IVC There is inverse relationship between hepatic arterial and portal venous blood flow as portal flow decr, accum of adenosine causes dilation of arterioles Spleen: SNS ( contraction ( discharge pool of blood into circulation Cutaneous Circulation Blood flow can vary rom 1-150ml/100g/min Fingers, toes, palms, earlobes contain anastomotic connections between arterioles and venules ( vary blood flow; cold blue skin = arterioles constricted, capillaries dilated; warm red skin = arterioles and capillaries dilated SNS, E+NE ( cut vasoC; painful stimuli ( incr SNS output ( cut vasoC No known vasoD nerve fibres to skin; vasoD due to decr SNS tone and local vasoD substances Exercise ( cut vasoD despite incr SNS due to incr hypothalamuc temp; shock is more profound if incr temp White reaction: pressure ( contraction of precapillary sphincters so blood frains out; lasts 15secs Triple response: present in total sympathectomy; due to axon reflex (C fibres centrally release substance P) Firm pressure ( 1) red reaction (due to capillary dilation) after 10secs ( 2) local swelling (wheal, local oedema due to incr permeability of cap and post-cap venules) 3) diffuse reddening (flare, due to arteriolar dilation) absent in LA skin and sensory denervation; present after nerve block Reactive hyperemia: incr blood to region when circ re-established after period of occlusion; vasoD occurs due to hypoxia during occlusion then filled when occlusion relieved Placental and Fetal Circulation Uterus: incr blood flow during pregnancy; oestrogens incr blood flow Placenta: villi containing fetal umbilical artery and vein branches project into placenta which is large blood sinus; exchange less efficient than in lungs as villi layers thicker and less permeable than alveoli Fetal circulation: 55% fetal CO passes through placenta; L+R heart pump together due to PFO and PDA RA ( foramen ovale ( LA ( LV ( aorta / RV ( ductus arteriosus ( aorta ( umbilical arteries to placenta (60% saturated with O2) ( placenta ( umbilical vein (80% saturated with O2) from placenta ( ductus venosus ( IVC (mixed blood 67% saturated with O2) ( RA ( portal blood of fetus (26% saturated with oxygen) ( IVC ( RA Most blood from SVC enters RV ( pul artery ( ductus arteriosus as resistance in lungs high so pul art p > aortic p @ birth: incr PVR, gasps causing negative intrathoracic p causing expansion of lungs ( aortic p > pul art p (decr to 20% of in utero p) ( incr p in LA ( PFO closes ( PDA constricts within hours thought to be due to arterial O2 tension Fetal respiration: fetal cells have greater affinity for O2 (HbF) than maternal cells (HbA); fetus has good resistance to hypoxia Cardiovascular Homeostasis in Health and Disease Gravity Effects greater when decr blood vol Postural hypotension in sympatholytic drugs, diabetes/syphilis damaging SNS, 1Y autonomic failure, abnormal baroreceptor reflexes in 1Y hyperaldosteronism In feet: MAP = 180-200mmHg, venous p = 85-90mmHg; if dont move 300-500ml pool in capacitance vessels of legs ( oedema, decr SV In head: MAP = 60-75mmHg, venous p = 0 Stand up ( decr BP in baroreceptors ( incr HR, maintain CO; incr renin and aldosterone; arteriole constrict ( MAP in head drops by 20-40mmHg, JVP drops 5-8mmHg so less drop in perfusion p (MAP-VP); ICp decr so less vascular resistance as less p on cerebral vessels ( more O2 taken from each unit of blood ( muscle pump needed on prolonged standing to maintain VR Blood flow decr by only 20% on standing; effects multiplied by acceleration 0 gravity ( atrophy of mechanisms that usually maintain normal CO ( postural hypotension Space motion sickness: headward shift of body fluids ( loss of plasma vol, diuresis; loss of muscle mass and bone minerals (incr Ca excretion), loss of red cell mass, altered plasma lymphocytes Exercise Resting skeletal muscle blood flow = 2-4ml/100g/min Contraction ( compression of blood vessels if >10% tension; total stop of blood flow if >70% tension; however between contraction massive incr blood flow so overall 30x more; impulses in sym vasoD system and decr SNS tonicity may be involved Local mechanisms: Hypoxia, hypercapnia, accum of K (esp important in early exercise) and vasoD metabolites, incr T ( dilation of arterioles and precapillary sphincters (10-100x incr in open capillaries) ( incr area of vascular bed, decr velocity of flow, incr cap p > oncotic p, accum of osmotically active metabolites faster than can be taken away decr osmotic grad across cap walls ( fluid transudation into ISF and incr lymph flow Decr pH and incr T ( shift dissociation curve of Hb to R ( more O2 given up from blood Incr 2,3-DPG ( decr affinity of Hb for O2 Anaerobic metabolism: uses glu; muscle incurs O2 debt Systemic mechanisms: Isometric muscle contraction ( incr HR and BP due to decr vagal tone (little change in SV); likely due to psychic stimuli acting on MO; decr blood flow to muscles due to compression of BVs Isotonic muscle contraction ( incr HR (max HR decr with age, in adults rarely >195) and SV and CO, decr PVR due to vasoD in exercising muscles; only mod incr in SBP, unchanged or decr DBP; incr VR due to muscle and thoracic pump, mobilization of blood from viscera (may incr arterial blood by 30%), incr p from dilated arterioles on veins, venoconstriction; after exercise BP may become subnormal due to continued local vasoD Temp regulation: lost through skin, resp, vaporization of sweat, dilation of cut vessels (inhibition of SNS tone) Trained athletes: decr HR, incr SV, incr max O2 consumption possible (related to max CO and max O2 extraction by tissues), incr mitochondria, enzymes, capillaries in skeletal muscle ( less lactate production; improved production of NO and prostracyclin by CAs Inflamm Inflammation: localized response to foreign substances; involves cytokines, neutrophils, adhesion molecules, complement, IgG, PAF, monocytes, lymphocytes; arterioles dilate, cap incr permeability; nuclear factor-B plays important role (cytokines/viruses/oxidants activate it ( binds DNA ( icnr production and secretion of inflammatory mediators; activation inhibited by glucocorticoids) Systemic response: cytokines ( acute phase proteins (proteins in which levels change by 25% following injury) eg. CRP, serum amyloid A, haptoglobin, fibrinogen, albumin, transferring Wound healing Tissue damage ( plts adhere to exposed matrix via integrins that bind collagen and laminin ( plt aggregation and granule release encouraged by thrombin ( granules ( inflamm response ( selectins attract WBC ( bind to integrins on endothelial cells ( extravasation through BV walls ( WCC and plt release cytokines ( up-regulate intergrins on macrophages ( migrate to injury fibroblasts and epithelial cells ( mediate wound healing and scar formation ( plasmin removes excess fibrin ( aids migration of keratinocytes into wound to restore epithelium under scab ( collagen proliferation ( scar Shock Inadequate tissue perfusion and CO Hypovolaemic shock: inadequate fluid; haemorrhage, trauma (may get rhabdo, accum of myoglobin in kidneys clogging tubules), surgery, burns (more plasma loss so haemoconcentration; haemolytic anaemia, inc BMR), vomiting, diarrhoea Effects: Decr VR ( decr CO (if mod pp decr but MAP normal) and inadequate perfusion ( anaerobic metabolism ( lactic acidosis ( depress myocardium and peri vascular responsiveness to NE+E Loss of RBC ( decr O2 carrying capacity ( low BP, incr HR, thready pulse, cold pale clammy skin, thirst, incr RR Compensatory mechanisms: 1) Baroreceptors less stretched ( incr SNS ( incr HR vasoC (spare brain and heart; marked in skin, kidneys (afferent leaving lung as more O2 enters than CO2 leaves Cant measure with spirometer: Total lung capacity = Residual vol (gas still in lung after max expiration) Functional residual vol (gas still in lung after normal expiration) 1) Gas dilution technique: breath helium (due to low solubility in blood) from spirometer which equilibrates in lungs without any lost; measures only communicating gas 1 = in machine; 2 = in lung Amount before equilibration of helium = C1 x V1 Amount helium after equilibration = C2 x (V1 +V2) Amount of helium is unchanged so C1 x V1 = C2 x (V1 + V2) ( V2 = V1 x (C1 C2) C2 2) Body plethysmograph: sit in box; breath out ( shutter closes ( try to breath in by increasing vol of lung ( incr p in box; measures all gas in lung inc that in closed airways that doesnt communicate with mouth; in diseased lungs there is big difference Boyles law: PV=K at constant pressure P 1 and 2 = pressure in box before and after insp effort; V = vol in box P3 and 4 = pressure in mouth before and after insp effort; V2 = FRC P1 x V1 = P2 x (V1 V) P3 x V2 = P4 x (V2  V) Blood vessels: R heart ( pul art ( capillaries ( pul vein; low resistance; initially art, vein and bronchus run together but in periphery veins pass between lobules, but bronchi and art travel together down centre of lobules ( dense capillary network (diameter 10m) in walls of alveoli; each RBC spends 3-4secs in cap network transversing 2-3 alveoli  complete equilibrium occurs in this time; capillaries easily damaged (eg. high cap p, high lung vol) ( leak plasma and RBC into alveolar spaces Conducting system blood supply comes from bronchial circ; v small blood flow compared to above Pul cap blood = 70ml Pul blood flow = 5000ml/min Diffusion Diffusion determined by Ficks law: Rate of diffusion through tissue slice proportional to area (50-100m2) inversely proportional to thickness (0.3m in places) Diffusion rate proportional to partial pressure difference between 2 sides proportional to solubility of gas in blood-gas barrier inversely proportional to square root of molecular weight Diffusion limited (eg. CO): RBC enters capillary ( CO moves from alveolar gas into RBC rapidly ( CO binds with Hb so little incr in partial pressure so CO can continue to enter RBCs; not limited by amount of blood available but diffusion properties of blood-gas barrier Diffusing capacity CO depends on area and thickness of blood-gas barrier vol of blood in pul capillaries alveolar vol Reaction rate of CO can be altered by high alveolar pO2 as they compete for Hb Perfusion limited (eg. NO): no combination with Hb ( incr pp after RBC has travelled only 1/10 along capillary so no further NO transferred; depends on blood flow and not properties of blood-gas barrier For O2: pO2 in RBC entering capillary = 40mmHg pO2 in alveoli = 100mmHg so passes into RBC; capillary pO2 reaches alveolar pO2 1/3 of way along capillary then transfer becomes PERFUSION LIMITED ( little diff between alveolar gas and end-capillary blood O2 combines with Hb in 0.2s (less avidily than CO) ( some raise in pp, delaying loading of O2 into RBC so increasing overall diffusion distance Resistance of uptake of O2 due to reaction rate = resistance due to blood-gas barrier For CO2: diffusion 20x faster than O2 as has higher solubility, but can still be diff between end-capillary blood and alveolar gas in diseased lung DM = diffusion membrane  = rate of reaction of Hb with O2 (in ml per minute of O2 = diffusion capacity of 1ml of blood VC = vol of capillary blood 1/DL = 1/DM (resistance of blood-gas barrier) + 1/( x VC = effective  diffusing capacity of rate of reaction of Hb with O2 Challenges: Exercise ( incr pul blood flow ( RBC usually spends 0.75s in capillary, but decr to 0.25s ( less time available for oxygenation, but no fall in end-capillary pO2 in normal people If tissue slice thickened ( poor diffusion ( doesnt equilibrate fully even by end of capillary (diffusion limited) ( diff between alveolar gas and end-capillary blood Lower alvolar pO2 (eg. high altitude) ( decr pp diff so O2 moves more slowly ( fails to reach alveolar pO2 Measuring diffusing capacity: Normal = 25ml/min-1/mmHg-1 ie. vol CO transferred per min per mmHg of alveolar pp CO used as uptake is diffusion-limited; note as p capillary blood slow low, can usually be ignored Vgas (amount gas transferred) = DL (diffusing capacity of lung) x (p alveolar gas p capillary blood) Single breath of CO ( rate of disappearance of CO from alveolar gas during 10sec breathhold calculated by measuring expired CO; incr by 2-3x on exercise Blood Flow and Metabolism RV ( main PA (walls thin with little SM so work of R heart as small as possible) ( branches accompany airways as far as terminal bronchioles ( capillary bed around alveolar wall (variable pressure, most p drop occurs here) ( pul veins running between lobules ( 4 large pul veins ( LA Pul capillaries (alveolar vessels): surrounded by gas in alveoli so collapse/distend depending on alvolear p; pressure around caps decr by surface tension of surfactant; diff between p inside and outside capillaries = transmural p Pul arts and veins (extraalveolar vessels): less p surrounding them; as lung expands, pulled open by parenchyma dependent on lung vol V large vessels are outside lung substance and dependent on intrapleural p Pul Vascular Resistance Vascular resistance = input p output p blood flow Main PA = 15mmHg LA = 5mmHg Difference = 10mmHg (Pul circ) Pul blood flow = 6L/min Vascular resistance = (15-5)/6 = 1.7mmHg/L-1/min (low as just for distribution) Any incr pul art/venous p ( pul vascular resistance falls (ie. on exercise) Due to recruitment: spare capillaries which under normal conditions are closed/open with no flow, as p rises they begin to conduct; important when high arterial p distension: widening of capillary segments; important when high vascular p Inc resistance at low vol (Extra-alveolar vessels have high resistance when lung vol low causing high critical opening pressure for pul art ( regional change in blood flow starting at base where parenchyma less expanded) high vol (Alveolar vessels if alveolar p incr compared to capillary p ( incr resistance (eg. on deep inspiration; calibre of capillaries decr at large lung vol due to stretching of alveolar walls ( incr resistance) Incr resistance if hypoxia as causes constriction of small pul arteries Drugs that cause incr resistance = serotonin, histamine, NE; esp effective when decr lung vol as affect extra-alveolar vessels Drugs that decr resistance = Ach, isoproterenol Aorta = 100mmHg RA = 2mmHg Difference = 98mmHg (Systemic circ) Higher resistance due to muscular arterioles Measuring Pul Blood Flow Using Fick Principle: O2 consumption per minute = amount of O2 taken up by blood in lungs per minute VO2 = O2 consumption per minute (collect expired gas in spirometer) Q = vol of blood passing through lungs each minute CaO2 = O2 content in blood leaving lungs (arterial, via ABG) CVO2 = O2 content in blood entering lungs (pul art, via catheter) VO2 = Q (CaO2 CVO2) ( Q = VO2 CaO2 CVO2 Passive Distribution of Blood Flow In human upright lung blood flow lower at apices in zone 1 alveolar p > cap p ( no flow if decr arterial p (eg. severe haemorrhage) or incr alveolar p (eg. PPV). Becomes alveolar dead space as is ventilated but not perfused. Zone 2: below apices; sufficient arterial p but low venous p; blood flow determined by diff between arterial and alveolar p as opposed to the normal arterial/venous p difference (Starling resistor / waterfall effect when chamber p greater than downstream p, downstream p has no effect on flow so venous p has no effect here) Zone 3: venous p > alveolar p so flow determined by arterial/venous p difference; incr blood flow in this region of lung due to distension of capillaries; transmural p difference increases the further down lung you go as cap p incr but alveolar p is same throughout lung Zone 4: region where get decr blood flow at low lung vols due to narrowing of extra-alveolar vessels Affected by posture (lying increases flow to apices, but doesnt affect basal flow; incr post flow, decr ant flow) and exercise (upper and lower blood flow increases) Active Control of Circulation Decr pO2 alveolar gas ( hypoxic pulmonary vasoconstriction (contraction in hypoxic region; doesnt need CNS ?due to release of vasoC substance by perivascular tissue ?due to inhibitors of NO ?causes inhibition fo voltage-gated K channels ( membrane depolarisation ( incr Ca channels in cytoplasm ( SM contraction; changes more marked when alveolar pO2 <70mmHg; directs blood away from hypoxic regions of lung decr deleterious effect of lung segment. NB. Occurs in fetus Decr pH also causes vasoC Water Balance in Lung Starlings law: pushing out of capillary = capillary hydrostatic p interstitial fluid hydrostatic p pulling into capillary = blood osmotic p  interstital fluid osmotic p Involved in this is reflection coefficient ()  effectiveness of cap wall in preventing passage of proteins across it Net fluid out = K (filtration co-efficient)[(Pc  Pi)  (c  i)] Likely net OUTWARDS push ( likely into interstitium of alveolar wall then to perivascular (have low p so aid this) and peribronchial space (interstitial oedema) ( enter lymphatics; in later pul oedema fluid may enter alveolar spaces (poss when max drainage rate exceeded), fluid pumped out by Na-K ATPase in epithelial cells Other Functions of Lung Lungs also act as reservoir of blood; filters blood (small thrombi removed); makes vasoactive substances (eg. leukotrienes (airway constriction in asthma) and PGs (relax PDA in fetus, role in bronchoconstriction in asthma) from arachidonic acid), modifies blood-borne substances (AI ( AII); inactivates bradykinin, some PG, removes serotonin (uptake and storage), NE; angiotensin II, E and ADH unaffected by lungs; can secrete IgA into bronchial mucosa; plays role in clotting mechanism; makes dipalmitoyl phosphatidylcholine (in surfactant); protein synthesis Ventilation-Perfusion Relationships pO2 inspired air = 149mmHg ( by time reaches alveoli pO2 = 100mmHg (1/3 decrease) 2 contributing processes removal of O2 by pul capillary blood (governed by O2 consumption of tissues), continual replacement by alveolar ventilation Alveolar pCO2 = 40mmHg Causes of Hypoxaemia Hypoventilation ( decr alveolar pO2 (unless additional O2 inspired), incr pCO2 (always); fall in alveolar pO2 slightly larger than pCO2 Following normal ventilation again, pCO2 will take longer to normalize as CO2 stores greater than O2 stores due to large amount of bicarb in blood VCO2 = CO2 production VA = alveolar ventilation R = respiratory exchange ratio or resp quotient (CO2 production / O2 consumption; determined by metabolism of tissues) = 0.8 F = correction factor pCO2 = VCO2 x K VA Alveolar gas equation: PAO2 = PIO2 PACO2 + F R Causes: morphine, barbs, damage to chest wall, paralysis of resp muscles, high resistance to breathing Diffusion There is always a pO2 diff between alveolar gas and end-capillary blood due to incomplete diffusion; diff enlarged by exercise, thickened blood-gas barrier, low O2 mixture inhaled Shunt Blood that enters arterial system without going through ventilated areas of lung (eg. bronchial artery blood entering pul veins, coronary venous blood entering LV, pul AV fistula, VSD) ( addition of poorly oxygenated blood depressing arterial pO2 Hypoxaemia CANNOT be fully abolished by giving 100% O2 as blood still bypasses alveoli ( will cause incr dissolved O2 in blood as Hb will be saturated Doesnt cause hypercapnia as chemoreceptors sense incr pCO2 and incr ventilation ( decr pCO2 of shunted blood This equation can be used if shunt caused by mixed venous blood QT = total blood flow CaO2 = O2 concentration in arterial blood QT x CaO2 = total amount of O2 leaving system = amount of O2 in shunted blood (Qs x CVO2) + end capillary blood (QT-Qs) x ccO2 (calculated from alveolar pO2 and O2 dissociation curve) So Qs = CcO2 CaO2 QT CcO2 CVO2 Ventilation-Perfusion Rate VQ determines GE in any single lung unit If O2 added at Vgm/min-1 and blood pumped through at Qlitres/min-1 then conc of O2 in alveolar compartment and leaving blood is V/Qgm/L-1 Inspired air has pO2 150mmHg, pCO2 0mmHg Venous blood entering unit has pO2 40mmHg, pCO2 45mmHg Addition of pO2 by ventilation and removal by blood flow ( alveolar pO2 100mmHg, pCO2 40mmHg Obstruct ventilation completely ( O2 and CO2 of alveolar gas and end-capillary blood = mixed venous blood Obstruct blood flow completely ( alveolar O2 and CO2 will increase until reaches same as inspired gas Note: CO2 may not incr as chemoreceptors stimulate incr RR which will usually make normal pCO2 in arteries (as CO2 dissociation curve almost linear, so incr RR will incr CO2 output by lung units with low and high VQ ratios). Wasted ventilation = ventilation in XS of what would usually require. This may not incr O2 thought due to O2 dissociation curve being nonlinear (so only units with low VQ ratio will benefit from incr RR, some hypoxaemia will still remain though). Regional Gas Exchange Ventilation: higher at bottom than top, smaller difference Difference greater in O2 than CO2 (as CO2 more reliant on ventilation than blood flow) ( resp exchange ratio (CO2 output / O2 uptake) greater in apex than base Perfusion: higher at bottom than top, more difference Little contribution of apex O2 to pH due to poor blood flow there On exercise blood flow incr to apex ( assumes larger share of O2 uptake Ventilation:perfusion ratio high at top of lung VQ mismatch: ( decr O2 uptake, decr CO2 output High ventilation: perfusion = obstruction to blood (these units are alveolar dead space) ( depression of arterial pO2 to below alveolar pO2 (alveolar-arterial O2 difference) (high pO2 doesnt incr O2 conc of blood due to nonlinear shape of O2 dissociation curve; CO2 doesnt rise in same way as curve is almost linear) Decr CO2 elimination Low ventilation:perfusion = obstruction to ventilation Decr O2 uptake Measuring VQ Inject dissolved inert gas and measure conc in arterial blood and expired gas Measure alveolar-arterial pO2 difference: arterial pO2 ideal alveolar pO2 (pO2 lung would have if no VQ inequality) PAO2 (alveolar) = PIO2 (inspired pO2 = 140mmHg) PACO2 (arterial CO2) + F R (0.8) AA gradient = PAO2 arterial pO2 Gas Transport By The Blood Dissolved O2: obeys Henrys law = amount dissolved proportional to partial pressure 1mmHg pO2 = 0.003ml O2/100ml of blood so 100mmHg O2 arterial blood = 0.3mlO2/100ml (3mlO2/L) Haemoglobin-bound O2: heme (iron porphyrin compound) joined to globin (4 polypeptide chains, 2 alpha 2 beta); HbA normal, HbF fetal, HbS sickle (valine instead of glutamic acid in beta chains, shift in dissociation curve to R, deoxygenated form poorly soluble and crystalises in red cell ( change in shape to crescent, fragile, thrombus formation) Oxygenated state is R (relaxed) state Deoxygenated state is T (tense) state O2 dissociation curve: Flat upper portion: if pO2 falls, loading unaffected as RBC takes up O2, large pp diff between alveolar gas and blood exists even when most O2 transferred Steep lower portion: peri tissues can withdraw large amounts of O2 with only small drop in capillary pO2 so O2 can easily enter cells Shift to R ( decr affinity of Hb for O2 (incr H, pCO2, T, 2,3-DPG which is end product of RBC metabolism, may be depleted in stored blood) ( more offloading Shift to L ( incr affinity of Hb for O2 Effect of pCO2 (due to effect on H conc) is Bohr effect  O2 concentration: (1.39 x Hb x Sat/100) + 0.003pO2 Remember: if pt has Hb 10, their O2 capacity is 20.8 x 10/15 = 13.9ml/100ml; 13.5ml/100ml combined at sats 97.5%. 0.3ml dissolved ( overall 13.8ml/100ml total O2 conc. CO interferes by combining with Hb ( carboxyhaemoglobin; 240x higher affinity for Hb than O2 ( normal pO2 but much decreased O2 conc; shifts curve to L, interfering with unloading CO2 dissociation curve:  Carbon Dioxide Lung excretes 10,000mEq carbonic acid per day Dissolved: obeys Henrys law; 20x more soluble than O2; 10% of CO2 is in dissolved form Bicarbonate: contains bulk of CO2 (60%) CO2 + H2O ( (carbonic anhydrase) ( H2CO3 ( H(+) + HCO3(-) (last 2 steps are Henderson-Hasselbalch equation First reaction slow in plasma, fast in RBC due to presence of CA Second reaction fast When conc of H and HCO3, HCO3 diffuses out but H cant as membrane is impermeable ( Cl ions moves into cell from plasma (chloride shift) in accordance with Gibbs-Donnan equilibrium ( some bind to reduced Hb as it is less acidic than oxygenated Hb; deoxygenated/reduced Hb helps loading of CO2 (Haldane effect; increases osmolar content of RBC ( water enters RBC ( incr vol), while oxygenation in pul capillary assists unloading (cells shrink on passing through lung) H+ + HbO2 ( H+Hb + O2 Carbamino compounds: 30%; combination of CO2 with amine groups in blood proteins, esp globin of Hb ( carbaminohaemoglobin; rapid reaction, no enzyme; reduced Hb can make HbNHCOOH easier than HbO2; unloading of O2 in peri tissue facilitates binding of CO2 and vice versa HbNH2 + CO2 ( HbNHCOOH Acid-Base Status Henderson-Haselbalch equation gives H2CO3 ( H+ + HCO3- KA (dissociation constant of carbonic acid) = H+ x HCO3- H2CO3 As H2CO3 conc is proportional to CO2 conc, KA = H+ x HCO3 CO2 - log of this is pH: -log (H+) = -log KA + log HCO3/CO2 pH = pH = pKA + log HCO3/CO2 As CO2 obeys Henrys law: pH = pKA (=6.1) + log (HCO2 = 24 in normal blood) / (0.03 x pCO2)   Metabolic alkalosis Incr ratio HCO2:pCO2 ( incr pH (A(E); resp compensation incr pCO2 ( decr HCO3:pCO2 (E(D) ( base XS; resp compensation often small and may be absent Blood-tissue Gas Exchange O2 delivery = CO x arterial O2 conc Caused by: low pO2 due to pul disease (hypoxic hypoxia) decr ability of blood to carry O2 (anaemic hypoxia) decr tissue blood flow (circulatory hypoxia) toxic substance that interfere with ability of tissue to use O2 (histotoxic hypoxia) (eg. cyanide prevents used of O2 by cytochrome oxidase) O2 and CO2 move from blood into tissue by simple diffusion; thickness 50m (more than blood-gas barrier); when exercising capillaries open up incr area for diffusion; since CO2 diffuses faster, elimination is OK; if intercapillary distance or consumption O2 incr ( inadequate tissue perfusion at point in middle between capillaries ( critical situation when pO2 <3mmHg ( may get anoxic region where aerobic metabolism not possible ( anaerobic glycolysis; high cap O2 ensures diffusion of O2 to mitochondria Mechanics of Breathing Muscles of Respiration Inspiration: diaphragm (supplied by phrenic nerve, C345; in tidal breathing moves 1cm; on forced up to 10cm; paradoxical movement when paralysed, moves up on inspiration) ex intercostal muscle (bucket-handle ( lat movement; IC nerves) accessory muscles (scalene, SCM) Expiration: passive on quiet breathing due to elasticity active needs abdo wall muscles (RA, IO, EO, TA); in intercostals  Elastic Properties Pressure-Vol curve:  Surface Tension = force acting across imaginary line 1cm long in surface of liquid Due to attractive forces between adjacent molecules of liquid are stronger than between liquid and gas ( liquid SA becomes as small as poss; aim to form a sphere (smallest SA for given vol) ( generate p within bubble determined by Laplaces law: p = (4 x surface tension) / radius Cells lining alveoli secrete surfactant (phospholipids containing DPPC dipalmitoyl phosphatidylcholine made for fas made by lung or extracted from blood) made by type II alveolar cells which decreases surface tension of alveolar lining fluid; has rapid turnover DPPC molecules are hydrophobic at one end and hydrophilic at the other ( when they align intermolecular repulsive forces act ( decr surface tension; actions more strong in small SA as molecules are closer together so repulsive forces better Surfactants Uses 1) Incr compliance of lung ( decr work required; absences ( decr compliance 2) Incr alveolar stability: there is tendancy for small alveoli to collapse and inflate larger ones; since p generated by surface forces inversely proportional to radius ( p higher in smaller vol bubble; however surface tension decr in small SA, opposing this; absence ( atelectasis 3) Keep alveoli dry: surface tension tends to suck fluid from capillaries into alveoli due to decr hydrostatic p in tissue; so surfactant prevents transudation; absence ( pul oedema Interdependence: since all alveoli are connected, if one bunch collapses ( tissue exerts expansive forces on them Regional Differences in Ventilation Lower regions ventilate better than upper: intrapleural p less ive at bottom due to weight of lung and +ive p required to support it ( so basal lung is relatively compressed in resting state and has small resting vol, but it expands more on inspiration than apex since ventilation is change in vol per unit resting vol, this area has high ventilation; apex has large expanding p, big resting vol, small change in vol on inspiration At low lung vols: lung easier to inflate as compliance is high; so at full expiration, intrapleural ps less ive ( intrapleural p at base > airway (atmospheric) p ( airway closure (air trapping occurs; occurs easier in older lungs due to loss of elastic recoil, so intrapleural p less ive)) and not ventilated at base during small tidal vols, whereas apex can still ventilated Uneven Ventilation In normal lung, vol change on insp is large and rapid Low compliance: change in vol is rapid but small High airway resistance: inspiration is slow and not complete before it is time to inhale; so if high RR, will be smaller inspired vol; this unit has a long time constant Incomplete diffusion: if there is dilatation of airways in resp bronchioles, distance to be covered by diffusion increased ( inspired gas not distributed uniformly Elastic Properties of Chest Wall If put air into intrapleural space ( lung collapses, chest wall springs outward At FRC: relaxation p of lung and chest wall = atmospheric (ie. inward pul of lung balanced by outward spring of chest wall) Lung retracts at all vols above minimal vol Chest wall tends to expand at vols up to 75% vital capacity Airway Resistance P difference between mouth and alveoli Flow rate Airflow Through Tubes If air flows through tube, diff in p between ends Determining whether flow will be laminar or turbulent is Reynolds number which gives ratio of inertial to viscous forces; in straight smooth tubes, turbulent when Re>2000 (wide tube, high velocity) (less likely if low-density gas (eg. helium)) Re = 2rvd (radius, velocity, density) n (viscosity) Entrance conditions to tube important: if eddy formation occurs at branch point, disturbance will be carried downstream; laminar flow likely to only occur in small terminal bronchioles; in most of tree, flow is transitional; turbulence occurs in trachea Low flow rate: laminar flow; driving p is proportionate to flow rate (P=KV); Note that radius is more important to resistance than length In circular tubes: vol flow rate (V) = driving p (P) x  x r4 8 x viscosity (n) x length (l) Flow resistance = driving p / flow & so R = 8nl r4 High flow rate: formation of eddies, or even turbulence; has different properties as driving p is proportionate to square of flow r (P=KV2); viscosity of gas less important, but density more important Pressures During Breathing Cycle  Airway Resistance Major site of resistance is medium-sized bronchi; <20% is in small airways Factors: Lung vol: as lung vol decreases, airway resistance rises as airways arent held open by parenchyma; at low vols basal segments even close Contraction of bronchial SM: incr resistance; mostly 2 receptors relax SM; paraS causes incr resistance; decr pCO2 in alveolar gas ( incr resistance due to direct action Density and viscosity of gas: incr densitiy ( incr resistance Dynamic Compression of Airways Limits air flow during forced expiration (when you exhale, flow rises rapidly to high value then decreases over most of expiration) due to compression of airways by intrathoracic p High lung vol: rise in intrapleural p (via increasing exp effort), results in greater exp flow Mid and low vols: flow becomes independent of effort after certain intrapleural p is exceeded (ie. flow is effort independent) Preinspiration: airway p (flow) is 0, intrapleural p is -5cm; so airway held open by 5cm transmural p During inspiration: intrapleural and alveolar p decr; alveolar p -2cm, airway p -1cm, intrapleural p -7; flow begins; airway still held open by 6cm transmural p End-inspiration: airway p (flow) is 0, intrapleural p is -8cm; airway still held open by 8cm transmural p Forced expiration: intrapleural p and airway p increase; alveolar p 38cm, airway p 19cm, intrapleural p 30cm; p drop along airway, which tends to CLOSE airway (-11cm transmural p) If intrapleural p increased further by muscular effort in attempt to expel gas, effective driving p unaltered (as effective driving p is alveolar intrapleural p; NOT MOUTH P) Max flow decr with vol as diff between alveolar and intrapleural p decreases and airways become narrower Flow is independent of resistance of airways downstream of point of callapse (equal p point) As exp continues, EPP moves more distally down lung, as resistance of airways rises further as lung vol falls May occur easier in diseased lungs, even at low exp flow rates ( decr exercise ability Reduced lung elastic recoil Loss of radial contraction of airways Incr resistance of airways magnifies p drop across them ( decr intrabronchial p during expiration Low lungs vols Work of Breathing Work = pressure x volume  People with stiff lungs take small rapid breaths, patients with severe airway destruction take slow breaths these decr work done on lungs Work measured by measuring O2 cost of breathing; efficiency thought to be 5-10%; O2 cost can be 5% in quiet breathing, up to 30% in forceful breathing Efficiency % = useful work x 100 total E expended (or O2 cost) Control Of Ventilation Sensors: Central chemoreceptors: near ventral surface of medulla near exit of 9th and 10th CNs; surrounded by brain ECF (composition determined by CSF, local blood flow, local metabolism) ( respond to changes in H+ conc of ECF (ie. CSF) and hence CO2, NOT O2 CO2 effects pH of CSF: CSF separated from blood by BBB which is impermeable to H+ and HCO3, but permeable to CO2; normal pH of CSF is 7.32, and as CSF has less protein it has poor buffering capability ( change in CSF pH for given conc CO2 is greater than in blood; if CSF pH is wrong for longer time, compensatory change in HCO3 due to transport across BBB which is prompter than renal compensation in blood therefore CSF pH has greater effect on ventilation than blood CO2 incr CO2 ( CO2 enters CSF ( liberates H+ ions ( activate chemoreceptors; incr CO2 ( cerebral vasodilation ( enhanced diffusion of CO2 into CSF Peripheral chemoreceptors: carotid and aortic (in carotid and aortic bodies) chemoreceptors; carotid at bifurcation of carotid arteries, arotic bodies above and below aortic arch; contain 2 types of glomus cells; modulation of release of NT from cells ( change in discharge r of carotid body; have high blood flow Type I cells large dopamine content; close to ending of afferent carotid sinus nerve Type II cells in carotid body Respond to decr pO2, decr pH (only carotid), incr pCO2; nonlinear relation with pO2 no change in firing until pO2 <100mmHg, then rate rapidly increases; respond to arterial rather than venous pO2; responsible for all changes in RR 2Y to hypoxaemia, pCO2 less important peripherally; fast response Lung receptors: Pul stretch receptors: in airway SM; discharge 2Y to distension of lung ( impulses in vagus nerve ( slow RR via incr exp time (Hering-Breuer inflation reflex); similarily, deflation of lungs initiates insp activity (deflation reflex) Irritant receptors: lie between airway epithelial cells ( impulses in vagus nerve ( bronchoconstriction and hyperpnoea; show rapid adaptation J receptors: endings of nonmyelinated C fibres; in alveolar walls close to capillaries (supplied by pul circ); impulses in vagus nerve ( rapid, shallow breathing; may be stimulated in L heart failure and interstitial lung disease Bronchial C fibres: supplied by bronchial circ; ( rapid shallow breathing, bronchoC, mucous secretion Nose and upper airway receptors: respond to mechanical and chemical stimulation; ( sneeze, cough, bronchoC Other receptors: Joint and muscle receptors: stimulus to ventilation in exercise, esp in early stages Gamma system: intercostal muscles and diaphragm sense elongation of muscle ( reflexly controls strength of contraction; may be involved in sense of dyspnoea experienced on large resp efforts eg. in airway obstruction Arterial baroreceptors: incr BP ( stimulation of aortic and carotid sinus baroreceptors ( hypoV and apnoea; vice versa Pain and temp: heat ( hyperV; pain ( apnoea followed by hyperV Central controller: Impulses from brainstem (pons and medulla contain respiratory centres) Medulla: in reticular formation beneath floor of 4th ventricle Dorsal region of medulla: assoc with inspiration; have property of intrinsic periodic firing for basic rhythm of ventilation: normal pattern is several secs of no activity ( APs increasing over next few secs ( insp muscle activity becomes stronger in ramp-like pattern ( finally cease and insp muscle tone return to preinsp level; this ramp is turned off by pneumotaxic centre inhibitory impulses ( inspiration shortened, so incr RR; also modulated by vagal and GP nerves Ventral area assoc with expiration: only active in forceful breathing Apneustic centre in lower pons: excite insp area, prolonging ramp APs; may cause abnormal breathing in brain injury Pneumotaxic centre in upper pons: inhibits inspiration as above; for fine tuning Cortex can override for voluntary control Limbic system and hypothalamus: can alter breathing in emotional states Effectors: resp muscles; central controller keeps them working in coordinated manner Integrated Responses Response to CO2: pCO2 of arterial blood is most important factor, v sensitive; decr pCO2 ( decr stimulus to ventilation; most response 2Y to central chemoreceptors, but peri do contribute and are faster; response magnified if arterial pO2 low Response to pCO2 decreased by sleep, increasing age, genetric, racial and personability factors; athletes and divers have low pCO2 sensitivity; morphine and barbs depress resp centre Response to O2: response magnified if pCO2 high; role of pO2 in day-to-day alteration of ventilation small; hypoxic drive may become important in high altitude and severe lung disease (chronic CO2 retention ( pH of CSF normalizes, pH of blood normalized by renal compensation; arterial hypoxia is 1Y stimulus for ventilation; response 2Y to peripheral chemoreceptors Response to pH: this is independent of CO2; chief site of action is peri chemoreceptors, but large changes effect central chemoreceptors and resp centre Response to exercise: during exercise there is normally slight decr pCO2, slight incr pO2, pH constant (may fall during severe exercise due to lactic acidosis); may be due to joint and muscle receptors in early stages; multiple theories Abnormal Breathing Cheyne-Stokes respiration: periodic breathing due to severe hypoxaemia; apnoea ( waxing then waning hyperventilation Respiratory System Under Stress Exercise Incr GE demands Resting O2 consumption = 300ml/min ( 3000-6000ml/min Resting CO2 output = 240ml/min ( 3000ml/min Resting resp exchange ratio = 0.8 ( 1.0 (or higher on severe exercise when anaerobic glycolysis) (reflects greater reliance on carbohydrate rather than fat for E)  Overall result: arterial pO2, pCO2 and pH little affected unless at v high work level High Altitude Normal barometric p = 760mmHg; exponential decr as move upwards, with concurrent decr pO2. Acclimatisation involves: Hyperventilation: usually due to hypoxic stimulation of peri chemoreceptors ( low arterial pCO2 and alkalosis ( prevent hyperventilation by ive feedback until CSF and blood pH normalizes ( then can hyperventilate again; sensitivity of carotid bodies to hypoxia increases during acclimitisation Polycythaemia: incr O2-carrying capacity so even if arterial pO2 and sats decr ( normal O2 conc of arterial blood; slow to develop and of minor value R shift of O2 dissociation curve ( better O2 unloading; due to incr 2,3-DPG due to resp alkalosis; at even higher altitudes there is L shift to aid with loadin of O2 in pul caps Incr no caps beter unit vol in peri tissues Change in oxidative enzymes in cells Incr max breathing capacity as air is less dense Also: pul vasoconstriction due to alveolar hypoxia ( incr pul art p ( incr work by R heart ( RVH and hypertension, may get pul oedema. Acute mountain sickness is due to hypoxaemia and alkalosis O2 Toxicity Can cause changes in endothelial cells of pul caps, substernal distress, decr vital capacity; retrolental fibroplasias in newborn Absorption atelectasis: if part of airway is trapped by mucus, total p in alveolus is high, but venous pO2 is still low (remember fall in pO2 from arterial to venous is greater than rise in pCO2 due to different shapes of dissociation curves) ( gas diffuses into blood ( collapse of alveoli; can occur when air is breathed, but process is slower rate of collapse is prevented by absorption of N2 which is less soluble therefore moves less slowly out of alveoli; collapse most likely to occur at bottom of lung where parenchyma less well expanded Space Flight No gravity ( more uniform distribution of ventilation and blood flow ( improved GE ( incr thoracic blood vol as blood doesnt pool in legs ( incr pul cap blood vol ( incr diffusing capacity; postural hypotension on return to earth = cardiovascular deconditioning ( small decr haematocrit Increased Pressure During diving, p incr by 1 atmosphere per 10m descent; if lung, middle ear or intracranial sinus fails to communicate with outside ( p difference which may cause compression of descent, or overexpansion of ascent (must exhale on ascent to prevent overinflation of lungs) Incr density of gas at depth ( incr work of breathing Decompression sickness: when diving, high pp of N2 (usually poorly soluble) forces it into solution in body tissues, esp fat (since N2 diffuses slowly, blood cant carry N2, blood supply to adipose tissue is poor ( N2 between tissues and enviro takes hours) ( during ascent, N2 slowly removed from tissues; if ascent is rapid, bubbles of gaseous N2 form ( if large amount formed ( pain in joints, deafness, impaired vision, paralysis. Treatment is recompression ( forces bubbles back into solution ( then careful decompression; decr risk by using helium-O2 mixture (helium is as soluble as N2 so less dissolves in tissues, low molecular weight so diffuses more rapidly through tissue, less dense so decr work of breathing); cant use O2 as risk of O2 toxicity Inert gas narcosis: at high pp N2 affects CNS ( euphoria, loss of coordination, coma; thought to be due to high fat:water solubility of N2 O2 toxicity: O2 stimulates CNS ( convulsions, nausea, ringing in ears, twitching of face (possibly due to inactivation of enzymes); so O2 conc must be decreased for deeper dives to avoid toxic effects Training ( incr caps and mitochondria in skeletal muscle Hyperbaric O2 therapy: used in severe CO poisoning, to incr O2 dissolved in blood; anaemic crisis; gas gangrene Polluted Atmospheres NO ( inflamm of URT and eye irritation SO, ozone ( bronchial inflammation Ozone ( pul oedema CO ( ties up Hb Hydrocarbons ( carcinogenic Aerosols ( large particles removed by impaction in nose and pharynx ( swept away by mucus; medium-sized particles deposit in small airways (sedimentation) esp when flow velocity suddenly decreased occurs in terminal and resp bronchioles; small particles deposit in alveolar walls by diffusion ( engulfed by macrophages Liquid Breathing Can breathe liquid if high solubility of O2 and CO2; liquids have higher density so incr work of breathing; may develop CO2 retention and acidosis; can overcome opposite effect on O2 by incr inspired O2 conc Perinatal Breathing Placental GE: maternal blood enters intervillous sinusoids, fetal blood enters capillary loops that enter these spaces; GE across membrane 3.5m distance; less efficient resulting in pO2 of fetal blood of 30mmHg; Placenta ( mixes with venous blood from fetal tissues ( IVC ( RA ( LA through PFO (aing A ( brain and heart SVC ( RA ( RV ( pul art ( aorta via PDA Overall: best oxygenated blood reaches brain and heart (due to streaming in RA); lungs receive only 15% of CO First breath: fetal lung is inflated with liquid (secreted by alveolar cells, with low pH) to 40% total lung capacity as the larger the radius of curvature the smaller the pressure, this preinflation reduces pressure required; hypoxaemia and hypercapnia as placental GE interfered with, sudden incr sensitivity of chemoreceptors, external stimuli ( first breath (intrapleural p must fall to -40cm due to high viscosity of lung liquid compared to air) ( uneven expansion of lung, pulmonary surfactant stabilizes alveoli, lung liquid removed by lymphatics and capillaries Circulatory changes: decr PVR due to abrupt incr alveolar pO2 ( decr hypoxic vasoC effects on pul art, incr vol of lung widens caliber of extra-alveolar vessels ( incr pul blood flow ( incr LAp ( FO closes ( incr aortic p ( incr LAp ( decr RAp ( decr umbilical circulation ( incr LAp ( incr pO2 and locally circulating prostaglandins ( closes PDA Tests of Pulmonary Function Ventilation Forced expiration: FEV1 vol exhaled in 1 sec (usually 80% of FVC); decreased by incr airway resistance or decr elastic recoil of lung, independent of exp effort (due to dynamic compression of airways flow rate independent of resitance of airways downstream of collapse point, but determined by elastic recoil p of lung and resistance of airways upstream of collapse point, collapse point is in large airways FVC total vol exhaled Restrictive disease (eg. pul fibrosis): FEV and FVC reduced; FVC reduced 2Y to decr compliance of lung or weakness of insp muscles; FEV1:FVC normal / increased Obstructive disease (eg. bronchial asthma): FEV1 reduced more than FVC; abnormal TLC, but exp ends prematurely (due to early airway closure due to incr SM tone, oedema of bronchial walls, secretions in airways); FEV1:FVC reduced FEF25-75%: av flow rate over middle half of expiration FRC: get pt to breathe 100 O2 for several mins to wash out all N2; conc of N2 in lung usually 80%; can slo use helium dilution technique which measures only ventilated lung vol; blody plethysmograph also includes gas trapped in airways  Diffusion: diffusing capacity of O2 v difficult to measure Blood flow: Fick principle and indicator dilution technique Ventilation-Perfusion Relationships Regional differences: measured using radioactive xenon Inequality of ventilation: Single breath method: N2 conc at lips measured following single breath of O2, N2 dilution of expired alveolar gas is is uniform giving nearly flat alveolar plateau; in lung disease alveolar N2 conc continues to rise on expiration due to uneven dilution and poorly ventilated alveoli which empty last Multiple breath method: based on rate of washout of N2; if ventilation was uniform, N2 conc would decr by same fraction on each breath hence straight line; in diseased lung forms curved line as diff lung inuts have N2 diluted at diff rates Inequality of Ventilation-Perfusion Ratio: Based on measurement of pO2 and pCO2 in arterial blood and expired gas; can work out mixed alveolar-arterial pO2 difference (can only really be used if blood flow wrong and ventilation OK) and ideal alveolar-arterial pO2 difference (using alveolar gas equation); in normal lung there is no ventilation:perfusion inequality and all units can represented by one ideal point on graph of pO2 vs pCO2; as inequality develops units spread away DO FROM BOOK AND DRAW!!! Blood Gases and pH Note: hypoventilation ALWAYS assoc with incr arterial pCO2; pO2 only fails to rise on administration of 100% O2 when shunt present; ventilation-perfusion inequality causes incr pCO2 in absence of incr ventilation Mechanics of Breathing Lung compliance: vol change per unit pressure change across lung; oesophageal p is measured and assumed to be close to intrapleural p; get pt to breath out from TLC measuring oesophageal p ( p-vol curve; compliance = the slope of this curve; can also be measured during resting breathing by measuring intrapleral p at end-insp or end-exp which reflects elastic recoil forces unassociated with airflow (this doesnt work in lung disease as airflow in lung persists even when air at lips has stopped due to diff dynamics; indeed sometimes air still entering part of lung when exp elsewhere begins ( air enters that part of lung (pendelluft) ( as incr RR, less tidal vol enters partially obstructed area ( decr lung compliance) Airway resistance: p difference between alveoli and mouth per unit airflow; measured using blod plethysmograph USE DIAGRAMS FROM HERE RENAL PHYSIOLOGY Renal Anatomy The Nephron: human kidney contains 1.3 million nephrons; cortical nephrons have short LOH, juxtamedullar nephrons (15%) have long LOH extending into medullary pyramids; 45-65mm long 1) Renal tubule: total SA 12m2 a) PCT: 15mm long, 55m diameter; cells connected by tight junctions; between bases of cells are lateral intercellular spaces; luminal edges of cells have brush border b) ding LOH: thin, permeable cells c) thick aing LOH: thick cells containing many mitochondrial; reaches back up towards glomerulus and nestles between eff and afferent arterioles ( macula densa of specialized cells found here (lacis cells an renin-secreting juxtaglomerular cells form JGA) d) DCT: starts at MD; 5mm long; no BB e) CD: 20mm long; enter into renal pelvis at pyramids; contains principal (P) cells (tall with few organelles; for Na reabsorption and ADH-stimulated H20 reabsorption) and intercalated (I) cells (less, have microvilli, cytoplasmic vesicles and mitochondria, for acid secretion and HCO3 transport); some cells secrete PGE2 2) Glomerulus: 200m diameter; formed by invagination of capillaries into Bowman s capsule; capillaries supplied by afferent arterioles, drain into efferent arterioles; permits passage of neutral substances up to 4nm diameter Only 2 layers  endothelium of capillaries: fenestrated with pores 70-90nm diameter; total area 0.8m2 capsule epithelium: made up of podocytes which interdigitate to form filtration slits (25nm wide and closed by thin membrane) along capillary wall separated by basal lamina with mesangial cells between lamina and endothelium (contractile and control filtration, secrete substances, take up immune complexes) Blood vessels: 1.2-1.3L blood/min (approx 25% of CO); Vol of blood in renal caps at any time is 30-40mL Afferent arterioles (short, straight branches of interlobular arteries) ( multiple capillaries in glomerulus (capillary pressure usually approx 45mmHg; 40% SAP)) ( coalesce to efferent arteriole (contains little SM) ( peritubular capillaries in network to supply tubules in multiple nephrons (pressure usually approx 8mmHg) or if from juxtamedullary glomeruli ( vasa recta hairpin loops along LOH; ding have nonfenestrated epirhtleium containing transporter for urea, aing have fenestrated epithelium to conserve solute ( interlobular veins ( renal vein (pressure usually approx 4mmHg) Cortical blood flow: mostly for filtration through glomerulus; great (5ml/g/min) with little O2 extracted (pO2 50mmHg); Medullary blood flow: low (0.6-2.5ml/g/min); large amounts of O2 extracted (pO2 15mmHg); sensitive to hypoxia if flow decreased Priniciples of Renal Function Renal plasma flow = amount of substance exreted per unit time / renal AV difference (applying Ficks principle); can be measured using p-aminohippuric acid (has high extraction ratio; PAH is filtered and secreted); ave 625ml/min Effective renal plasma flow (doesnt use venous conc) = Urine conc X urine flow = clearance of PAH Plasma conc Actual renal plasma flow = effective / extraction ratio Extraction ratio = arterial conc venous conc arterial conc Renal blood flow = renal plasma flow x (1 / 1 Hct) (1.2-1.3L blood/min) Regulation of renal blood flow: NE constricts renal vells, mostly interlobular arteries and afferent arterioles Dopamine made in kidney ( vasodilation and natiuresis Angiotensin II ( efferent vasoC PG ( incr blood flow in renal cortex, decr blood flow in renal medulla Ach ( renal vasoD Autoregulation: probable direct contractile response of SM to stretch; NO may be involved; NO, PG, cardiovascular peptides involved in maintaining balance of medullary/cortical blood flow; renal blood flow maintained if efferent constriction > afferent Nerve supply: Sympathetic preganglionic innervation from lower thoracic and upper lumbar segments; cell bodies of postganglionic neurons in sym ganglion chain, in sup mesenteric ganglion and along renal artery; PCT, DCT and aing LOH richly innervated Stimulation ( incr renin secretion (via NE effect on 1-adrenoceptors on juxtaglomerular cells) ( incr Na reabsorption (via NE effect on renal tubular cells) ( renal vasoC ( decr filtration, decr renal blood flow (mostly via -adrenoceptors) Pain travels with sym efferents Glomerular filtration: normal = 125ml/min (7.5L/hr, 180L/day) ( 1L/day urine, so 99% reabsorbed; values for women are 10% lower; amount filtered is product of GFR and plasma level of substance Measured by measuring excretion and plasma level of substance freely filtered at glomerulus and neither secreted/reabsorbed by tubules; must be non-toxic and not metabolized by body eg. inulin (note creatinine is NOT accurate as some is secreted and reabsorbed) Amount in urine must be provided by filtering the exact amount of plasma that contained this amount so: GFR = (urine conc of Y) x (urine flow per unit time) = clearance of Y arterial plasma level of Y Factors governing filtration: Size of capillary bed - contraction of mesangial cells decreases this; angiotensin II important Permeability of capillaries 50x that of capillaries in skeletal muscle; cannot pass through if >8nm size; decr for anionic substances, incr for cationic substances; albumin is negatively charged (anion), albuminuria due to nephritis due to loss of negative charges in glomerular wall which usually decreases filtration of albumin Hydrostatic and osmotic p gradients across capillary wall high p in glomerular capillaries as efferent vessels have high resistance; osmotic p gradient is usually negligible; net filtration p is 15mmg at afferent end ( drops to 0 at efferent end as equilibrium reached (uncertain whether this is reached in humans); exchange across capillaries is flow-limited rather than diffusion limited, some portions of capillaries dont participate Kf = glomerular ultrafiltration coefficient (product of glomerular capillary wall permeability and filtration surface area) Pgc = mean hydrostatic p in glomerular capillaries Pt = mean hydrostatic p in tubule Ogc = osmotic pressure of plasma in glomerular capillaries Ot = osmotic pressure of plasma in tubule GFR = Kf [(Pgc - Pt) (Ogc Ot)] Filtration fraction: ratio of GFR to renal plasma flow; normally 0.16-0.2; when decr systemic BP ( GFR falls less than RPF ( incr filtration fraction Tubular Function: Amount excreted per unit time = amount filtered + net amount transferred by tubules Clearance = GFR if no net tubular secretion/reabsorption > GFR if net secretion < GFR if net reabsorption Reabsorption/secretion may occur by: Endocytosis Paracellular diffusion: through tight junctions Passive diffusion, facilitated diffusion, ion channels, exchangers, cotransporters, pumps AT systems have a transport maximum (max rate) at which they can transport solute at higher concs becomes saturated Lymphatics: abundant supply ( thoracic duct Renal capsule: thin but tough; limits swelling ( incr renal interstitial pressure ( decr glomerular filtration Arterioles and glomeruli secrete PGI2 (prostacyclin) In interstitium in medulla are type I medullary interstitial cells secrete PGE2 Reabsorption in Specific Areas PCT: AT of solutes (60-70%) H20 passively out (60-70%) along osmotic gradient via aquaporin-1 ( isotonicity maintained Na reabsorption (60%): Na-H exchange in PCT ( AT into interstitial space or lateral intercellular spaces via Na-K ATPase (3Na, 2K) Glu reabsorption: mostly reabsorbed in PCT; glu and Na bind carrier SGLT2 in luminal membrane (Na moves down gradient taking glu with it) ( Na pumped into interstitium, glu via GLUT2 (usually binds d isomer) aa reabsorption: Cotransport with Na in luminal membrane ( Na pumped out by Na-K ATPase, aa via passive/facilitated diffusion NB. Glu reabsorption: amount reabsorbed proportionate to (plasma glu level x GFR) up to transport maximum; filtered at approx 100mg/min; Renal threshold is level at which glu first appears in urine = 180mg/dl venous level (this is lower than expected as reabsorption splays from ideal curve as renal threshold not same in all tubules) LOH: fluid in ding LOH becomes hypertonic as H20 passes out ( becomes more dilute as moves up aing LOH as H20 trapped ( hypotonic to plasma at top; Bartters syndrome due to defective transport in aing LOH ( Na loss ( hypovolaemia ( stimulation of RAA ( hypertension, hyperkalaemia, alkalosis H20 reabsorption: 15% filtered water reabsorbed; ding limb permeable to H20; aing limb impermeable to H20 Na reabsorption (30%): Na-2Cl-K cotransporter in thick aing LOH ( AT into interstitium by Na- K ATPase K reabsoprtion: Na-2Cl-K cotransporter in thick aing LOH ( K diffuses back into tubular lumen or back into interstitium via ROMK Cl reabsorption: Na-2Cl-K cotransporter in thick aing LOH ( Cl enters interstitium via CIC-Kb channels Diuretics: loop (eg. frusemide, ethacrynic acid, bumetanide) inhibit Na-K-2Cl cotransporter ( natiuresis and kaliuresis DCT: relatively impermeable to H20; continued removal of solutes further dilutes urine H20 reabsorption: 5% filtered water reabsorbed Na (7%) and Cl reabsorption: Na-Cl cotransporter in DCT Diuretics: metolazone, thiazides (eg. chlorothiazide) inhibit Na-Cl cotransporter CDs: Na reabsorption (3%): ENaC channels in CD (regulated by aldosterone) H20 reabsorption (10% in cortex, 4.7% in medulla): depends on vasopressin (ADH from PPG which acts on V2 receptor ( cAMP and PKA ( incr permeability to H20 due to insertion of aquaporin-2 into apical membranes of cells from vesicles stored in cytoplasm of principal cells) ( H20 moves out of hypotonic CD ( cortical interstitium When ADH absent, CD relatively impermeable to H20 so urine stays hypotonic but 2% H20 can be reabsorbed in absence of ADH Diuretics: H20 inhibits ADH secretion ETOH inhibits ADH secretion V2 antagonists inhibits action of ADH on CD K-sparing (eg. spironolactone, triamterene, amiloride) inhibit Na-K exchange but inhibiting aldosterone (spironolactone) or ENaCs (amiloride) Conc mechanism dependent of maintenance of gradient of incr osmolality along medullary pyramids ( maintained by countercurrent mechanism of LOH and vasa recta (dependent on AT of Na and Cl out of aing limb and high permeability of ding limb to H20, inflow through PCT and outflow through DCT) see pics; this is greater in longer (JM) nephrons; osmotic gradient and hypertonicity of interstitium maintained by vasa recta countercurrent mechanism (solutes move out of vessels going towards cortex and into vessel descending into pyramid, H20 into descending vessels and out of ascending vessels ( solutes recirculate in medulla but H20 bypasses it; removes H20 from CDs Urea contributes to osmotic gradient in medullary pyramids; urea transporters are facilitated diffusion (UT-A1 4) Magnitude of osmotic gradient increased when decr r of flow in LOH ( urine becomes more concentrated H20 excretion: 180L filtered/day, at least 87% is reabsorbed; absorption of H20 can be altered without changing solute excretion; aquaporins 1,2,5,9 have been found in humans (9 in WBC, liver, lung spleen; 5 in lacrimal glands H20 diuresis: normal reabsorption of H20; begins 15mins, peaks 40mins post ingestion; max urine flow is 16ml/min H20 intoxication: swelling of cells when max urine flow reached Osmotic diuresis: decr reabsorption of H20; due to unreabsorbed solutes (eg. mannitol; glu when capacity exceeded) in tubules; note that conc grad against which Na can be pumped out of PCT is limited, usually maintained by H20 reabsorption in PCT but this is decreased if there are unreabsorbable solutes in PCT ( decr reabsorption of H20 and Na in LOH (mainly due to decr action of Na-K-2Cl cotransporter in aing LOH ) and CD due to decr medullary hypertonicity Free water clearance: CH20 is negative when urine is hypertonic, +ive when hypotonic CH20 = urine flow rate - (urine osmolality) x (urine flow rate) (plasma osmolality) Tubuloglomerular feedback: as rate of flow increases through aing LOH and DCT, filtration decreases so constant load delivered to distal tubule; sensor is macula densa (amount of fluid is related to amount of Na and Cl ( Na and Cl enter macula densa cells via Na-K-2Cl cotransporter in apical membranes ( incr Na causes incr Na-K ATPase activity ( incr ATP hydrolysis ( incr adenosine formed ( works via A1 receptors on macula densa cells to incr release of Ca to vascular SM in afferent arterioles ( afferent vasoC ( decr GFR Glomerulotubular balance: incr GFR causes incr reabsorption of solutes and water in PCT; occurs within seconds; thought to be due to oncotic p of capillaries Other diuretics: xanthines (eg. theophylline, caffeine) decr tubular reabsorption of Na, incr GFR acidifying salts (eg. CaCl2, NH4Cl) supply H ( H buffered and Na is replaced with H ( an anion is excreted with Na when this ability is exceeded CA inhibitors (eg. acetazolamide) decr H secretion ( incr Na and K excretion, depressed HCO3 reabsorption NB. Both thiazide and loops cause incr delivery of Na to Na-K exchange area if CD ( incr K excretion H Secretion in PCT, DCT, CD PCT: H comes from intracellular dissociation of H2CO3 (formation of this cataylsed by carbonic anhydrase drugs that inhibit this enzyme decr secretion of acid in PCT) 1 H secreted via Na-H exchanger (1H out, 1Na in - gradient for Na maintained by Na-K ATPase) 1 HCO3 reabsorbed via diffusion into interstitial fluid Buffer: H reacts with HCO3 ( H2CO3 ( CO2 and H20; CA in brush border facilitates this ( CO2 re-enters tubular cells to form more H2CO3 For each mol HCO3 removed from urine in this reaction, 1mol HCO3 enters blood and hence is reabsorbed Most H has no effect on pH of urine due to formation of CO2 and H20 DCT H secretion independent of Na and CD: ATP-driven H pump in intercalated cells (in acidosis, action increased by deposition of more of these pumps in membranes); increased activity by aldosterone Also a H-K ATPase Cl-HCO3 exchanger transports HCO3 into interstitial fluid Buffer (PCT and DCT): NH3 is lipid soluble and diffuses down conc gradient into interstitial fluid and urine via nonionic diffusion ( reacts with H ( NH4 which remains in urine Priniciple reaction producing NH4 in cells is glutamine ( glutamate + NH4 (enzyme glutaminase); glutamate may ( -ketoglutarate + NH4 (enzyme glutamic dehydrogenase);  ketoglutarate metabolized using 2H and freeing 2HCO3 Incr secretion of NH3 and excretion via NH4 in chronic acidosis (adaptation) Buffer (DCT and CD): H reacts with HPO4 ( H2PO4 as PO4 is highly concentrated here due to reabsorption of H20 DCT has less ability to secrete H than PCT, but secretion has more effect on pH Limiting pH of urine is 4.5 (can go from 4.5 8.0) below this secretion stops (ie. in CDs); buffers important; H cause urinary titratable acidity (amount of alkali that must be added to urine to return pH to 7.4 this doesnt account for H2CO3 which has been converted to H20 and CO2) Secretion limited by changes in: Intracellular pCO2 (incr pCO2 ( incr H2CO3 available to buffer, H secretion enhanced) K (decr K ( enhanced H secretion) CA (CA inhibition ( decr H secretion as less formation of H2CO3) Aldosterone (incr aldosterone ( incr transport of Na ( incr secretion of H and K) HCO3 Excretion HCO3 reabsorption is proportionate to amount filtered over wide range When high plasma HCO3 ( HCO3 appears in urine, urine becomes alkaline When low plasma HCO3 ( secreted H no longer used to reabsorb HCO3 ( H must combine with buffers ( acidic urine, with higher NH4 content Na Excretion Normally 96-99% filtered Na is reabsorbed; urinary Na output can change a lot depending of diet. Determined by: GFR: affected by tubuloglomerular feedback etc Reabsorption: governed by Aldosterone (adrenal mineralocorticoid): incr reabsorption Na acting primarily on CDs by incr number of active ENaCs; also incr Cl reabsorption and incr K and H secretion; eventually kidneys escape effect of steroid (escape phenomenon) preventing oedema, this phenomenon is absent in nephrosis, cirrhosis, heart failure PGE2: inhibits Na-K ATPase and ENaCs ( excretion of Na Endothelin and IL-1 incr formation of PGE2 ( excretion of Na Ouabain ( inhibits Na-K ATPase ( excretion of Na Angiotensin II ( action of PCT ( incr reabsorption of Na and HCO3 K Excretion Much is reabsorbed in PCT THEN secreted by DCT and CD (much of K movement is passive, so rate of secretion proportionate to rate of flow); amount secreted equal to K intake; secretion of K in CD related to reabsorption of Na (which is related to excretion of H), so decr K excretion when decr Na reaching distal tubule or when incr H secretion Renal Disease ( proteinuria usually albuminaemia ( hypoproteinaemia ( decr oncotic p, decr plasma vol, oedema ( loss of conc and diluting ability ( polyuria/nocturia; in advanced renal disease loss of countercurrent mechanism and loss of functioning nephrons ( nephrons compensate by producing osmotic diuresis ( damages nephron ( oliguria and anuria ( uraemia ( anaemia ( 2Y hyperparathyroidism (due to 1,25-dihydroxycholecalciferol) ( acidosis urine is maximally acidified and decr renal tubular production of NH4 so decr H secretion ( abnormal Na metabolism Na retention due to decr filtration (GN) / incr aldosterone (nephrotic syndrome, due to decr plasma proteins ( decr plasma vol due to interstitial oedema ( trigger RAA) / heart failure The Bladder Filling: walls of ureters contain SM in spiral, longitudinal and circular bundles; regular peristalsis; oblique passage through bladder wall prevents reflux Emptying: also spiral, longitudinal and circular (detrusor) muscle; internal urethral sphincter doesnt encircle; external urethral sphincter is skeletal muscle; intravesical p not raised until bladder well filled (as radius increases; law of Laplace pressure = 2x wall tension / radius); plasticity when bladder stretched, tension initially produced not maintained; sharp rise in p as micturition reflex produced first urge to void felt at 150ml, marked sense of fullness at 400ml Micturition: contraction of detrusor ( emptying; micturition is sacral spinal reflex (initiated by stretch receptors in bladder wall) initiated at 300-400ml facilitated and inhibited by higher brain centres which alter threshold for voiding reflex; afferent limb of reflex travels in pelvic nerves, paraS efferent limb also travel in pelvic nerves Facilitatory area in pontine region Inhibitory area in midbrain Transection above pons ( threshold for voiding lowered Transection at top of midbrain ( reflex normal Effect of deafferentation all reflex contractions stop; bladder becomes distended and hypotonic; some contraction maintained due to intrinsic response of SM to stretch Effect of deafferent- and deefferentation flaccid and distended, but later becomes shrunken with hypertrophied wall and many contractions due to denervation hypersensitisation Effect of SC transaction during spinal shock flaccid and unresponsive ( overfilled with overflow incontinence ( voiding reflex returns but without voluntary control; voiding reflex may become hyperactive Regulation of ECF Volume and Composition Tonicity Plasma osmolality 280-295mosm/kg Total blood osmolality  total body Na + total body K / total body H20 ( changes occur when disproportion between amount of electrolytes and amound of H20 Incr osmolalilty ( release of vasopressin and stimulation of thirst Volume Determined by amount of osmotically active solute in ECF; Na most important factor Decr vol ( incr aldosterone, vasopressin, AII (also causes thirst and constricts BVs); incr vol ( incr ANP and BNP from heart ( natiuresis and diuresis; volume overrides osmotic regulation Buffers (Henderson-Hasselbach Equation) NB. ANION (-) If acid is added: eq shifts to L ( levels of buffer anions (A-) drop as they react with added H ( less effect on pH Anions of added acid excreted by renal tubules with a covering cation (usually Na) to maintain electrochemical neutrality 2NaHCO3 + H2SO4 ( Na2SO4 + 2H2CO3 Kidney then replaces Na with by H, so reabsorbing Na and HCO3 (effectively reversing the above) Na2SO4 + 2H2CO3 ( 2NaHCO3 + 2H+ + SO42- H+ and SO4 excreted If base added: eq shifts to R; H ions bind OH, but more H ions released so less effect on pH Buffering capacity greatest when amount of free anion = amount of undissociated acid (when A/HA = 1 ( log[A][HA] = 0 ( pH = pK); K applies to infinitely diluate solutions in which interionic forces are negligible HA ( H+ + A- ( [H+] x [A-] = K ( pH = pK + log [A-] HA [HA] Regulation of H Conc Note a decr in pH by 1 unit is a 10-fold incr in H conc; pH of blood is pH of true plasma that has been in equilibrium with RBC (as RBC contain Hb which is an important buffer); normal arterial pH is 7.4 (venous slightly lower; acidosis <7.4, alkalosis >7.4) H load comes from: Aa metabolism: H load of 50meq/day Aa in liver for gluconeogenesis ( NH4 + HCO3 ( NH4 incorporated into urea and protons produced bufferered by HCO3, so little NH4/HCO3 enter circulation Metabolism of other aa ( H2SO4, H3PO4 (strong acids) ( major H load CO2 metabolism: usually hydrated to H2CO3 and excreted by lungs/kidneys; H load of 12,500meq/day Exercise ( lactic acid Diabetic ketosis ( acetoacetic acid and -hydroxybutyric acid Renal failure Buffers in blood: Plasma proteins: free carboxyl and amino groups dissociate HProt ( Prot- + H+ eg. RCOOH ( RCOO- + H+ ( pH = pK(RCOOH) + log [RCOO-] [RCOOH] eg. RNH3+ ( RNH2 + H+ ( pH = pK(RNH3+) + log [RNH2] [RNH3+] Haemoglobin: dissociation of imidazole groups of histadine residues; also has free carboxyl and amino groups; present in large amounts so 6x buffering capacity of p proteins HHb ( H+ + Hb Carbonic acid bicarbonate system: first system is difficult to measure as low H2CO3 and low pH; however H2CO3 is in equilibrium with CO2 ( 2nd system (in clinical practice, [CO2] is x by 0.301 as this is solubility coefficient) this system still has low pK, but is most effective buffer system as amount of dissolved CO2 can be controlled by respiration and HCO3 can be controlled by kidneys When H added: H2CO3 formed, HCO3 declines; extra H2CO3 converted to CO2 (excreted by lungs effectively as incr H causes incr RR) and H2O so H2CO3 conc doesnt rise and pH isnt altered much NB. CA inhibited by cyanide, azide, sulfide, sulfonamides 1) H2CO3 ( H+ + HCO3- ( pH = pK (3) + log [HCO3] [H2CO3] 2) H2CO3 ( CO2 + H20 (CA catalyst) ( pH = pK (6.1) + log [HCO3-] [CO2] Buffers in interstitial fluid: carbonic acid bicarbonate system as abov Buffers in intracellular fluid: proteins as shown above Also H2PO4 ( H+ + HPO42- Buffers in CSF and urine: bicarbonate and phosphate systems Acidotic/Alkalotic States Resp acidosis: retained CO2 is in equilibrium with H2CO3, which is in equilibrium with HCO3- ( incr HCO3-; most buffering is intracellular; renal compensation Resp alkalosis: decr pCO2; most buffering is intracellular; renal compensation Metabolic acidosis: when acids stronger than buffers are added to blood; only 15-20% acid load will be buffered in ECF, the rest dealt with intracellularily; incr H ( incr RR (resp compensation), renal compensation causes excretion of H Metabolic alkalosis: when alkali added to blood; incr plasma HCO3 and pH; 30-35% OH load buffered intracellularily; resp compensation with decr RR; renal compensation as below Renal compensation: HCO3 reabsorption depends on filtered load of HCO3 (affected by GFR and plasma HCO3 level) rate of H secretion by renal tubular cells (as HCO3 is reabsorbed in exchange for H) which is  pCO2 In resp acidosis ( incr renal tubular H secretion, incr HCO3 reabsorption ( incr plasma HCO3 ( incr pH In resp alkalosis ( decr renal H secretion, decr HCO3 reabsorption ( decr plasma HCO3 ( decr pH In metabolic acidosis ( anions(-) are filtered (each with a cation, Na) in renal tubules ( tubules then secrete H in exchange for 1Na and 1HCO3 ( urinary buffers then tie up H so this can continue; when acid load v large, cations are lost with anions ( diuresis; glutamine synthesis by kidneys increased ( incr supply of NH4 to kidney, can also be converted to -ketoglutarate which produces HCO3 to help buffer In metabolic alkalosis ( ABG s Can measured pCO2 and pH then calculate HCO3 Venous gas: has pCO2 7-8mmHg higher, pH 0.03-0.04 unit lower, HCO3 2mmol/L lower Anion gap: difference between conc of cations (+) other than Na and conc of anions (-) other than Cl and HCO3 in plasma. Consists mainly of proteins in anionic form and organic acids Increased (eg. ketoacidosis, lactic acidosis) decr plasma conc of K, Ca, Mg incr conc/charge of/on plasma proteins incr organic anions in blood (eg. lactate, aspirin) Decreased: incr cations (+) decr plasma albumin Normal (eg. hyperchloraemic acidosis eg. due to CA inhibitors) DO LAST BIT WITH SIGGAARD-ANDERSON CURVE NOMOGRAM METABOLISM Metabolism: chemical and E transformations occurring in body ( produce CO2 and H20 Catabolism: oxidation liberating small amounts of E Anabolism: formation of substances taking UP energy Energy Metabolism Metabolic Rate: Amount of E liberated per unit time Amount of energy liberated by catabolism of food in body = amount liberated when food burned outside of body Energy output = external work + E storage (0 or ive if fasting) + heat Efficiency = work done / total E expended (eg. 50% for isotonic muscle contractions) Factors: Muscular exertion: O2 consumption incr for long time afterwards 2Y to O2 debt Recently ingested food: assimilation of food into body produces specific dynamic action (SDA) Environmental temp: U-shaped; when lower than body, shivering etc; when higher metabolic processes elevate 14% for every degree elevation; MR @ rest in comfy temp 12-14hrs after last meal = BMR (decr by 10% during sleep, by 40% with prolonged starvation) = 2000kcal/day in normal man Others: height, weight (BMR = 3.52W0.75), sex, age, growth, reproduction, lactation, emotional state, thyroid hormones, E and NE Calories (gram/small/standard): Amount of heat E needed to raise temp of 1g H20 by 1 degree 1kcal = 1000cal Calorimetry burn foodstuffs outside body and measure heat produced Indirect calorimetry measure O2 consumption per unit time (as O2 isnt stored) which is  metabolism Carbohydrate = 4.1 kcal/g Fat = 9.3 kcal/g Protein = 5.3 kcal/g (in body, incomplete so 4.1) Respiratory Quotient (RQ): SS vol of C02 produced : vol O2 consumed per unit time Work out O2 consumed = blood flow per unit time x AV difference between O2 concs Respiratory Exchange Ratio (R): CO2 : O2 at any given time whether or not equilibrium reached RQ carbohydrate = 1 (as H and O present in same amount as H20) (RQ brain 0.97-0.99 so primary E source is carbohydrate) RQ fat = 0.7 (as extra O2 needed for formation of H20) RQ protein = 0.82 During exercise: incr R as lactic acid converted to C02 during anaerobic glycolysis Metabolic acidosis: incr R as incr CO2 being expired Metabolic alkalosis: decr R Intermediary Metabolism E stored in high/low-energy phosphate compounds which have bonds between phosphoric acid residues and organic compounds ( released when bond hydrolysed Eg. ATP (( ADP releasing E, AMP releasing E) formed by oxidative phosphorylation which takes up 80% basal E consumption; 27% used for protein synthesis, 24% Na-K ATPase, 9% gluconeogenesis, 6% Ca ATPase, 5% myosin ATPase, 3% ureagenesis Eg. Creatine phosphate (phosphorylcreatine, CrP) found in muscle Eg. Thioesters (eg. Coenzyme A) Digestion ( aa, fat derivatives, fructose, galactose, glucose ( absorbed ( metabolized to short-chain fragments (common metabolic pool, intermediates ie. High/low E phosphate compounds) ( carbohydrates, proteins and fats made ( enter citric acid cycle ( hydrolysis ( E and H and CO2 ( H20 Oxidation: combination of a substance with O2 / loss of H / loss of electrons Catalysed by co-enzymes (organic, non-protein) and co-factors (simple ions) which act as carriers for products of reaction (eg. Accept H) Eg. Nicotinamide adenine dinucleotide (NAD) ( NADH Eg. Dihydronicotinamide adenine dinucleotide (NADP) ( NADPH Eg. Flavin adenine dinucleotide (FAD) ( FADH) H from NADH and NADPH then transferred to Flavo-protein- cytochrome system (in mitochondria) a chain of enzymes which are reduced then reoxidised ( final enzyme cytochrome c oxidase which transfers H to O2 ( H20 Reduction: reverse of above Carbohydrate Metabolism Made up of glucose, galactose and fructose; principle product of carbohydrate digestion is glucose Fasting plasma glu = 70-110 mg/dL (3.9-6.1mmol/L); 15-30mg/dL higher in arterial blood Normal 70kg man has 2500kcal stored in 400g muscle glycogen, 100g liver glycogen, 20g glu; 112,00kcal stored in fat (80%) Glu load: 50% ( CO2 and H20 5% ( glycogen 30-40% ( fat Factors affecting glu level: Dietary intake Rate of entry of glu into cells Glucostatic activity of liver 5% converted into glycogen, 30-40% converted into fat Renal handling of glucose: renal threshold is 180mg/dL ( glycosuria Exercise: during exercise plasma glu raised by hepatic glycogenolysis; muscles use glycogenolysis with incr uptake glu; incr gluconeogenesis; decr insulin; incr glucagon and E @ rest: brain uses 70-80% glu, rest by RBC; muscles use fas for metabolism 1) Glucose ( enters cells ( phosphorylated to glucose 6-phosphate Catalysed by hexokinase; in liver catalysed by glucokinase which has greater affinity for glu and incr by insulin, decr by diabetes/starvation 1 mol ATP used for conversion of glu to G6P 2) ( G6P ( polymerized to glycogen (glycogenesis; G6P ( G1P ( uridine diphosphoglucose (UDPG) ( glycogen catalysed by glycogen synthase (dephosphorylated form active, phosphorylated form inactive); a protein primer named glycogenin is required, and its availability limits reaction) ( stored in liver and skeletal muscle or ( catabolised (glycolysis) ( pyruvate and lactate via 2 pathways Embden-Meyerhof pathway: via cleavage through fructose to triose 1 mol ATP used for converstion of fructose 6-phosphate to fructose 1,6-diphosphate Direct oxidative pathway (hexose monophosphate shunt): oxidation and decarboxylation to pentoses 3) ( phosphoglyceraldehyde ( phosphoglycerate (this reaction ANAEROBICALLY releases 1 mol ATP; requires NAD+ and produces NADH) 4) ( phosphoglycerate ( phosphoenolpyruvate 5) ( phosphoenolpyruvate ( pyruvate (this reaction ANAEROBICALLY releases 1 mol ATP) NB. Via EM pathway, 2 phosphoglyceraldehyde produced, so 4 ATP produced ANAEROBICALLY per mol glu, but 1 mol ATP used ( net production of 3 ATP per mol G6P (this figure is 2 ATP if made from glu)) 6) ( pyruvate ( lactate (in this reaction pyruvate accepts H from NADH (when needed under anaerobic conditions) produced in 3) thereby reforming NAD+ needed for above reaction; lactate produced converted back to pyruvate when O2 restored as H then accepted by flavoprotein-cytochrome chain) ( proteins (gluconeogenesis regulated by PGC-1, a transcriptional coactivator, induced by fasting) ( acetyl-CoA (this is IRREVERSIBLE; this reaction requires NAD+ and produces NADH) 7) Acetyl-CoA enters citric acid/Krebs/tricarboxylic acid cycle with oxidation of carbohydrate/fat/protein to CO2 and H20; AEROBIC) ( joins oxaloacetate ( forms citrate ( 7 subsequent reactions ( release 2 CO2 ( 4 H transferred to flavoprotein-cytochrome chain (2 from NADH from step 3, 2 from NADH from step 6) ( overall producing 12 ATP and 4 H20 (2 H20 used in cycle) ( 24 ATP formed by subsequenct 2 turns of cycle So, net production by EM pathway and CA cycle = 38 ATP If hexose monophosphate shunt used, amount ATP released depends on amount of NADPH convered to NADH then oxidized. Aas ( intermediates in reactions; hence non-glucose protein molecules converted to glu NB. Glu makes fat through acetyl-CoA but since this is a one-way reaction there is very little conversion of fat to carbohydrate, but there can be conversion of glycerol (from fat) ( dihydroxyacetone phosphate (muscle uses fas for metabolism) Directional flow valves: when enzymes can make reactions unidirectional hence effect metabolism Glycogenolysis: catalysed by phosphorylase which is activated by: E working on beta-2 receptors in liver (incr cAMP ( activation of PKA ( phosphorylase kinase activated ( phosphorylates phosphorylase activating it phosphorylated form active (a), dephosphorylated inactive (b)) E working on alpha-1 receptors in liver ( intracellular Ca ( activation of phosphoylase kinase independent of cAMP Glycogen ( G6P ( glucose (via glucose-6-phosphatase which is present in liver; other tissues dont have this enzyme to G6P follows route above ( incr lactate) Glucagon: only stimulates phosphorylase in liver so will cause incr plasma glu E: stimulates phosphorylase in liver and skeletal muscle, so will cause incr plasma glu and lactate McArdles syndrome: deficiency of muscle phosphorylase Other hexoses: Galactose ( phosphorylated ( reacts with UDPG to form uridine diphosphogalactose (can be used for formation of glycolipids and mucoproteins) ( converted to UDPG ( glycogen synthesis; utilization of galactose requires insulin Fructose ( F6P (catalysed by hexokinase or fructokinase) ( F1,6P ( split into dihydroxyacetone phosphate (which enters pathway for glu metabolism) and glyceraldehydes (which is phosphorylated); these reactions are independent of insulin; F6P can also form F2,6DP (regulates gluconeogenesis; high F2,6DP level ( incr breakdown of F6P to F1,6P ( so incr pyruvate; low F2,6DP level ( incr gluconeogenesis; glucagons ( decr F2,6DP) Protein Metabolism 2-10 aa = peptides; 10-100 aa = polypeptides; >100 aa = proteins 1g/kg body weight / day desirable for needs Supplies 9.3 kcal/g Essential aa = must be obtained from diet; Aa pool = supplies needs of body; hormones made from aas Protein Formation: Proteins made of aas linked by peptide bonds joining amino to carboxyl group; aas are acidic/neutral/basic in reaction; Glycoproteins contain carbs, lipoproteins contain lipids; Body s own proteins being constantly broken down and reformed; turnover rate 80-100g/day; during growth synthesis > breakdown Order of aa in peptide chain = 1Y structure; twisting and folding = 2Y structure (eg. -helix; -sheet); arrangement of twisted chains into layers, crystals or fibres = 3Y structure; arrangement of subunits = 4Y structure Use of protein: Formation of hormones (eg. Thyroid, catecholamines, histamine, serotonin, melatonin Formation of urinary sulfates: via oxidation of cysteine; SO4 will be excreted accompanied by Na/K/NH4/H; ethereal sulfates are fromed in liver from oestrogens, steroids, indoles and drugs Interconversions Transamination (an interconversion): conversion of aa ( keto acid with simultaneous conversion of another keto acid ( aa; catalysed by transaminases; occurs in many tissues Eg. Alanine + alpha-ketoglutarate ( pyruvate + glutamate Oxidative deamination (an interconversion): aa undergo dehydrogenation ( imino acid ( hydrolysed to keto acid with production of NH4; occurs in liver Eg. Aa + NAD+ ( imino acid + NADH + H Imino acid + H20 ( Keto acid + NH4 Ketogenic: leucine, isoleucine, phenylalanine, tyrosine; converted to ketone body acetoacetate Glucogenic: alanine and other aas; converted to compounds that can form glucose Urea cycle: much NH4 produced by deamination in liver enters urea cycle ( carbamoyl phosphate ( citrulline in mitochondria ( arginine ( urea (formed in liver; so in liver disease decr BUN and incr NH3) ( excreted in urine NB. Aa can also react with NH4 ( amide; or can convert NH4 ( NH3 (eg. In urine, NH3 reacts with H permitting it to be secreted) Formation of creatine: made in liver from methionine, glycine and arginine; in skeletal muscle creatine reacts with ATP formed by glycolysis and oxidative phosphorylation ( ADP and phosphorylcreatine (which is important store of ATP, reversed during exercise); creatine shouldnt be excreted in urine in normal men marker of extensive muscle breakdown Formation of creatinine: formed from phosphorylcreatine Formation of purines and pyrimidines: made in liver; combine with ribose to form nucleosides; found in co-enzymes, DNA, RNA Protein loss: Proteins lost: hair, menstruation, urine, stools Protein degradation: removal of abnormal/old protein Conjugation of protein to ubiquitin tickets them for degradation (ubiquinitination) ( degraded in proteasomes / lysosomes; or tickets them for various destinations in cell Uric acid formed by breakdown of purines ( excreted in urine via filtration ( 98% reabsorbed ( 80% secreted Starvation: Low protein / normal calorie diet ( decr excretion urea and sulfates ( normal excretion creatine (wear-and-tear, not affected by diet) Low protein / low calorie diet ( insulin ( glucose attempts to spare protein (enough glycogen stores for 1/7 starvation; ie. 0.1kg in liver, 0.4kg in muscles) ( fats ( ketoacids attempt to spare protein ( ketosis (12kg fat) ( protein catabolism (from liver, spleen, muscles) ( incr urea nitrogen excretion (urea and nitrogen formed) Fat Metabolism Fas (can be saturated have double bonds; unsaturated no double bonds), triglyceraides (3x fas bound to glycerol), phospholipids, sterols Essential fas: linolenic, linoleic and arachidonic acids; polyunsaturated; arachidonic acid formed from tissue phospholipids by phospholipase A2 These are precursors of eicosanoids (PGs, prostacyclin, TX, lipoxins, leukotrienes); formation inhibited by glucocorticoids which inhibit phospholipase A2, NSAIDs which inhibit COXs; have short HLs made via enzymes COX: makes PG, prostacyclin, TX LOX: makes 5-HETE, 12-HETE, 15-HETE, lipoxins, LT CYP monooxygenases: make 12-HETE, EETs, DHTs PG: PGH2 is precursor for PGs, TXs and prostacyclin (converted by tissue isomerases); made from arachidonic acid by prostaglandin G/H synthases 1 and 2 (COX 1 and 2); COX1 constitutive, COX2 induced by GFs, cytokines and tumour promoters; work via G proteins TX: TXA2 made by plts ( promotes vasoC and plt aggregation Prostacyclin: produced in endothelium ( promotes vasoD Leukotrienes: arachidonic acid converted to 5-hydroperoxyeicosatertraenoic acid (5-HPETE) by 5-lipoygenase ( leukotrienes (eg. Aminolipids LTC4, LTD4, LTE4, LTF4); ( bronchoC, arterioC, incr vasc perm, chemotaxis; work via CysLT1 receptor ( broncoC, chemotaxis, incr vasc perm, CysLT2 ( pul vasc SM constriction; BLT ( chemotaxis Lipoxin: A dilates microvasculature, B inhibits cytotoxic effects of NKCs Cellular lipids: Structural lipids part of membranes Neutral fat stored in adipose cells; mobilized during starvation; make up 15% body weight in men, 21% in women; adenylyl cyclase in adipose tissue activated by glucagons, NE + E via beta-3 receptor Brown fat more in infants; between scapulas, at nape of neck, along gt vessels; extensive SNS supply (( release of NE ( beta3-adrenergic receptors ( incr lipolysis, fa oxidation ( varies efficiency with which E produced and food utilized; incr nerve output when eating ( heat production); contain many droplets of fat and many mitochondria; normal oxidative phosphorylation occurs but also uncoupling of metabolism and generation of ATP so more heat produced (via uncoupling protein UCP1) Plasma lipids: major lipids are insoluble in aqueous solutions hence arent free Free fatty acids: bound to albumin Lipoprotein complexes: cholesterol, triglycerides, phospholipids; complexes incr solubility of lipids; generally contain hydrophobic core of triglycerides surrounded by phospholipids and protein (apoproteins APO E,C,B) Exogenous pathway: transports lipids from intestine to liver Chylomicrons: formed in intestinal mucosa during absorption of products of fat digestion; very large lipoprotein complexes containing APO C; enter circ via lymphatics; cleared from circ by lipoprotein lipase in capillary endothelium (catalysed breakdown of triglyceride ( fa and glycerol (enter adipose cells or enter circ bound to albumin) ( become chylomicron remnants which go to liver ( internalized by receptor-mediated endocytosis ( degraded in lysosomes Endogenous pathway: transports lipids to and from tissues Very low density lipoproteins (VLDL): contain APO C; formed in liver; transport triG formed in liver to other tissues Intermediate density lipoprotein (IDL): lipoprotein lipase removes triG from VLDL ( IDL; give up phospholipids; pick up cholesteryl esters via lecithin-cholesterol acyltransferase Low density lipoprotein (LDL): when more triG lost; provide cholesterol to tissues (LDL taken up by receptor-mediated endocytosis in clathrin coated pits ( endosome ( proton pumps in endosome decr pH inside endosome ( LDL receptor released and recycled ( endosome fuses with lysosome ( cholesterol made available ( inhibits production of intracellular chol by HMG-CoA reductase, stimulates esterification of XS chol, inhibits synthesis of new LDL receptors); LDL also taken up by macrophages (via scavenger receptor) esp LDL that has been modified by oxidation ( when become overloaded become foam cells High density lipoprotein (HDL): take up chol from cells; made in liver and intestinal cells; transfer chol to liver where is excreted into bile Metabolism TriG broken down by lipoprotein lipase as shown above (feeding INCREASES activity, fasting DECREASES activity), or hormone-sensitive lipase found intracellularily in adipose tissue (activity slowly INCREASED by GH, steroids and thyroid hormones and starvation via incr activity of cAMP; DECREASED activity by insulin and PGE and feeding by inhibiting formation of cAMP) ( fa ( enter cell or mobilize bound to albumin (provided to cell by chylomicrons and VLDL (used extensively in heart), or synthesized in depots) ( acetyl-CoA ( citric acid cycle (in mitochondria by beta-oxidation serial removal of 2 C from fa with high yield of ATP compared to glu; medium and short chain fa can enter mitochondria easily, long-chain must be bound to carnithine to cross inner mitochondrial membrane the linked pair then moved into matrix space by a translocase ( ester hydrolyse and carnithine recycled) Formation Acetyl-CoA ( fa occurs in many tissues; occurs principally outside mitochondria Ketone Body Formation Normal level 1mg/dL Acetyl-CoA ( acetoacetyl-CoA in many tissues ( acetoacetate in liver (a -keto acid, a ketone body) ( -hydroxybutyrate and acetone (ketone bodies; anions) ( enter circulation. Ketones normally metabolized as fast as formed: acetoacetate metabolized with CoA (from succinyl-CoA; and via other pathways) ( form CO2 and H20 via citric acid cycle (occurs in tissues other than liver) If incr acetyl-CoA or decr supply of products of glu metabolism (eg. Starvation, DM, high-fat low carb diet, less can enter citric acid cycle ( acetoacetate accumulates ( ability of tissues to oxidize ketones exceeded ( ketosis ( anions so metabolic acidosis ( abolished by giving glu (hence carbs are antiketogenic) Cholesterol Metabolism Normal level 120-200mg/dL Precursor of steroid hormones and bile acids, important in cell membranes Chol synthesis: shown in diagram; negative feedback by inhibiting HMG-CoA reductase; so when dietary intake high, hepatic synthesis inhibited Chol absorption: absorbed via chylomicrons ( after chylomicrons give up triG in adipose tissue ( chylomicron remnants bring chol to liver ( most incorporated in VLDL ( circulates Chol excretion: excreted in bile in free form and as bile acids ( some reabsorbed from intestine Decr chol: thyroid hormones, oestrogens ( incr LDL receptors in liver, incr HDL levels Incr chol: biliary obstruction, untreated DM Trace Elements: essential for life; arsenic, chromium, cobalt, copper, fluorine, iodine, iron, manganese, molybdenum, nickel, selenium, silicon, vanadium, zinc Vitamin: organic dietary constituent necessary for life, health and growth that doesnt supply E; vit E is bound to chylomicrons ( transferred to VLDL in liver B1 (thiamine, B complex) ( beriberi, neuritis B2 (riboflavin) ( glossitis, cheilosis Niacin ( pellagra Pyridoxine ( convulsions, hyperirritability Pantothenic acid ( dermatitis, enteritis, alopecia, adrenal insufficiency Biotin ( dermatitis, enteritis Folates ( sprue, anaemia, NTD B12 (cycobalamin) ( pernicious anaemia C ( scurvy D ( rickets E ( ataxia K ( haemorrhagic phenomena ENDOCRINOLOGY Thyroid Gland Effect ( stimulates O2 consumption; regulate lipid and carbohydrate metabolism XS ( body wasting, nervousness, incr HR, tremor, XS heat production Lack ( mental and physical slowing, poor cold resistance T3 = triiodothyronine; 25mcg daily production; 60% turnover per day; HL 1/7; 4x more potent; VOD 40L T4 = tetraiodothyronine / thyroxine; 75mcg/day daily production; 10% turnover per day; HL 7/7; VOD 10L Anatomy: comes from evagination of floor of pharynx; 2 lobes connected by thyroid isthmus, occasional pyramidal lobe; high rate blood flow; made of multiple acini; follicles filled with colloid Iodine: Normal plasma level 0.3g/dL Ingested iodine (500g; min 150 needed; def when <50g ingested) ( iodide ( absorbed (distributed in 25L) ( thyroid (120g/day) ( T3 and T4 (uses 80g/day) ( secreted ( metabolized in liver and other tissues ( some secreted into bile ( some undergoes enterohepatic circulation, 20 g/day lost in faeces ( somes enters ECF (60 g/day) ( enters ECF (40 g/day) ( kidney ( excreted in urine Enters thyroid via Na/I symporter (2Y AT) which transports into cells against electrochemical gradient for I; E provided from Na-K ATPase; a 2nd transport enzyme pendrin controls passage of I across membrane Deficiency: inhibits thyroid function, get goiter due to high TSH XS: inhibits thyroid function via Wolff-Chaikoff effect, inhibits binding of iodide transiently, reduces effect of TSH on thyroid by decr cAMP response, inhibits proteolysis of TG Thyroid Hormone: Naturally occurring form is L-isomers Thyroid cells: collected and transport iodine Make thyroglobulin (glycoprotein; made in thyroid cells; secreted into colloid by exocytosis of granules that contain thyroid peroxidase (catalyses oxidation of iodide and its binding; can be blocked by v high I levels)) Remove thyroid hormones from TG (H bonds hydrolysed) Iodide oxidized to iodine in thyroid ( bound to tyrosine residues of thyroglobulin forming MIT and DIT (iodide organification) ( thyroid hormones remain bound to TG until secretion into colloid Thyroid hormone synthesis: monoiodotyrosine (MIT) ( iodinated to diiodotyrosine (DIT) ( 2 DITs + TG (oxidative condensation (coupling reaction) involing thyroid peroxidase) ( T4 ( 1 DIT and 1 MIT ( T3 or RT3 Thyroid hormone secretion: 80g T4, 4g T3, 2g RT3 secerted; MIT and DIT NOT secreted Thyroid cells ingest colloid by endocytosis ( merge with lysosomes ( proteases break bonds between iodinated residues and TG ( T3, T4, DIT, MIT liberated into cytoplasm of cell ( MIT and DIT deiodinated by iodotyrosine deiodinase ( free I reutilized by gland ( T3 and T4 enter circ (ratio of T4:T3 5:1) Thyroid hormone transport: T4 = 8g/dL (free 2; HL 6-7/7; VOD 10L) T3 = 0.15g/dL (shorter HL, more rapid action) Both bound to p proteins (99.98% T4 in plasma is bound mostly to TBG; T3 99.8% bound 46% to TBG, rest to albumin) Albumin (has largest capacity to bind T4; 13/7) Transthyretin (HL 2/7) Tyroxine binding globulin (TBG; has smallest capacity to bind T4 and yet most T4 bound to this; HL 5/7; incr by pregnancy and certain drugs; decr by glucocorticoids, androgens) Thyroid hormone metabolism: T4 and T3 deiodinated (by deiodinases D1,2,3) in liver, kidney, other tissues; some T3 and 4 further deiodinated to deiodotyrosines ( conjugated in liver to sulfates and glucuronides ( bile (some enterohepatic circ) ( stool ( 4% daily I loss T4: 1/3 converted to T3, 45% converted to RT3 (metabolically inactive) D1: in liver, kidneys, thyroid, pituitary; responsible for T3(4 in periphery D2: in brain, pituitary, brown fat; responsible for T3(4 in those organs D3: in brain and reproductive tissues; main source of RT3 Illnesses may suppress deiodinases (( incr RT3, decr T3) eg. Burns, trauma, Ca, cirrhosis, renal failure, MI, fasting, amiodarone, beta blockers, corticosteroids Triiodothyronin (T3): 13% release from thyroid, 87% formed from deiodination of T4; more active than T4 more rapid, 3-4x more potent as less tightly bound to plasma proteins and more acid binding to TR Reverse triiodothyronine (3,3,5-triiodothyronine, RT3): inactive; 5% secreted by thyroid, 95% by deiodination of T4; more prominent in fetus Mechanism of Action: TSH works via GPCR Enter cells via AT (affinity for T4 receptor less than T3, explaining potency) ( T4 deiodinated to T3 ( T3 binds thyroid receptors (TR1 and 2; TR1 and 2) in nuclei ( hormone-receptor complex binds DNA ( alter gene expression Can get mutation of TR ( T hormone resistance; clinically euthyroid as TR OK, but high TSH Regulation of Release: TRH: from hypothalamus; secreted into capillaries of pituitary portal venous system ( pituitary gland ( mediates incr secretion due to cold; inhibited by stress TSH: glycoprotein; from APG; made of subunit  and ; HL 60mins; degraded in liver and kidneys; peak secretion at midnight; ave level 2U/mL ( incr iodide binding; synthesis of T3, T4, MIT, DIT; secretion of TG into colloid; endocytosis of colloid; incr blood flow; chronic causes cell hypertrophy and goiter - inhibited by dopamine, somatostatin, glucocorticoids TSH receptor: on thyroid cells; serpentine; activates Gs ( adenylyl cyclase and PLC \ NB. Thyroid cells also have receptors for IGF-1, EGF and other GFs Homeostasis: when sudden incr bind proteins ( decr free hormone ( incr TSH ( incr release hormone Thyroid also regulates own uptake of iodide independent of TSH Effects of Thyroid Hormones: Metabolism ( incr O2 consumption (calorigenic action) (EXCEPT in brain, testes, uterus, LN, spleen, APG); will cause vitamin def ( incr DPG (incr dissociation of O2 from Hb) ( incr activity of Na-K ATPases ( decr circulating chol levels Heart ( chonotropic, inotropic; incr no  receptors, enhanced response to E+NE ( incr HR and PP ( generation of heat ( decr PVR as heat dissipating mech ( renal Na and H20 retention ( altered expression of myosin heavy chain (more , which has higher ATPase activity) ( incr speed of cardiac contraction Adipose tissue ( catabolic (incr lipolysis) Muscle ( catabolic (incr protein breakdown) ( will cause K release which is excreted in urine; also thyrotoxic myopathy, muscle weakness, cramps, stiffness Bone ( incr growth and skeletal development CNS ( incr brain development ( rapid mentation, irritability, restlessness; incr responsiveness to E+NE ( activated RAS ( hyperreflexia Gut ( incr carb absorption Lipoprotein ( incr formation of LDL receptors Symptoms: HypoT: hypoT: no response to TSH pituitary hypoT: thyroid responds to TSH Hypothalamic hypoT: thyroid responds to TSH; incr TSH following dose of TRH ( myxoedema (skin contains polysaccharide, hyaluronic acid, chondroitin sulfuric acid which accumulate) ( decr BMR ( coarse sparse hair ( Yellow skin: carotenemia due to accum of carotene in skin (as T needed for hepatic conversion of carotene to vit A) ( poor cold tolerance ( slow husky voice ( slow mentation, poor memory ( incr plasma chol ( cretinism (dwarf, mental retardation, potbellies, large tongue, deaf mute, rigidity HyperT: Graves disease (60-80%; autoimmune; antibodies to TSH receptor ( stimulate receptor; TSH Low; also ab to TG and thyroid peroxidase) Hashimotos thyroiditis (ab destroy thyroid, but during early inflamm XS secretion) Toxic adenoma / multinodular goiter, TSH-secreting APG tumour, mutations of TSH receptor, ectopic thyroid tissue ( nervous ( weight loss ( hyperphagia ( heat intolerance ( incr PP ( fine tremor ( warm soft skin ( sweating ( incr BMR ( exophthalmos (adipocytes in orbits have TSH receptor ( release cytokines ( inflammation and oedema) Pancreas Glucose: Enters cells by facilitated diffusion GLUT 1: in placenta, BBB, brain, RBC, kidneys, colon; basal uptake; transport across BBB GLUT 2: B cell glu sensor; in B cells, liver, SI, kidneys; transport OUT of intestine and renal epithelial cells; regulation of insulin release GLUT 3: in brain, placenta, kidneys; basal uptake inc into neurons GLUT 4: in skeletal and cardaic muscle, adipose tissue; insulin-sensitive uptake of glu GLUT 5: in jejunum and sperm; fructose transport GLUT 6: GLUT 7: in liver; G6P transporter in ER 2Y AT with Na SGLT 1 in small intestine and renal tubules SGLT 2 - in renal tubules On entering cell, glu phosphorylated Anatomy: Islets of Langerhans: in pancreas, more in tail; make up 2% of gland; 1-2 million islets; blood drains into hepatic portal vein; involved in paracrine regulation A cells: secrete glucagon from granules; make up 20% of cells; surround B; stimulates release of insulin and somatostatin B cells: secrete insulin from granules; account for 60-75% of cells; in centre of islet; inhibits release of glucagon Respond to stimulation via hypertrophy Prolonged stimulation (eg. XS GH or T hormone) ( B cell exhaustion ( transient then permanent diabetes D cells: secrete somatostatin from granules; inhibits release of insulin, glucagon and PP F cells: secrete pancreatic polypeptide Insulin: Glycogenesis, antigluconeogenesis, antilipolysis, antiketotic IGF-I and IGF-II responsible for nonsuppressible insulin-like activity - weak Synthesis: preproinsulin has peptide removed as enters RER of B cells, molecule folded and disulfide bonds formed ( proinsulin containing A and B chain, connected by connecting (C) peptide ( transported to GA ( packaged into granules ( transport of granules via microtubules, during which C peptide removed, proteases involved in processing ( insulin formed (Polypeptide 2 chains of aa linked by disulfide bridges) ( exocytosis of 90-97% insulin, some C peptide, rest proinsulin into blood Metabolism: HL 5 mins; binds to insulin receptors; destroyed by proteases in endosomes formed by endocytosis in liver (60%) and kidney (35-40%) (this ratio is reversed in diabetics receiving insulin, where renal metabolism is more important) Mechanism of action: Insulin receptor: found on most tissues; made of 2 (extracellular, bind insulin) and 2 (intracellular portions have tyrosine kinase activity) glycoprotein subunits bound by disulfide bonds; on binding to receptor, complex undergoes endocytosis ( complex enters lysosome ( recycled; HL 7hrs Insulin binds receptor ( triggers tyrosine kinase activity of  subunits ( autophosphorylation of  subunits (ie. They come close together and phosphorylate eachother) ( phosphorylation/desphosphorylation of cytoplasmic proteins Activated phosphoinositol-3 kinase ( vesicles containing GLUT 4 fuse with cell membrane; incr glycogen synthase activity, incr glycogen formation, enhanced cell growth and division, other metabolisc effects Activated glucokinase (in liver) ( incr phosphorylation of intracellular glu ( decr free glu conc intracellularily ( incr glu influx Causes K to enter cells due to incr activity of Na-K ATPase ( decr extracellular K Regulation of secretion: Normal insulin 0-70U/mL (basal - 1U/hr) Fast response: Glu ( enters B cells by GLUT 2 transporter ( phosphorlyated to glucokinase ( metabolized to pyruvate in cytoplasm ( enters mitochondria and Kreb s cycle ( release of ATP which enters cytoplasm ( inhibition of ATP-sensitive K channels ( decr K efflux ( depolarization of B cell ( Ca influx through voltage-gated Ca channels ( exocytosis of insulin-containing granules ( initial insulin spike Slow response: pyruvate from above ( Krebs cycle ( incr intracellular glutamate ( commits another pool of granules to release ( prolonged 2nd phase Insulin release stimulated: Glu, mannose aas (eg. Arginine, leucine) - amplify glu-induced insulin release -ketoacids (eg. Acetoacetate) ( these release ATP which inhibit K channels mentioned above Beta-agonists, glucagon, theophylline ( incr cAMP in B cells ( incr Ca (amplify glu-induced insulin release) Vagal stimulation and Ach ( M4 receptors ( incr Ca Glucagon, secretin, CCK, gastrin, GIP  amplify glu-induced insulin release Sulphonylureas Incr affinity of insulin for receptor: GH, GC Inhibited insulin release: SNS ( NE acting on 2-receptors K depletion (eg. Thiazide diuretics) Somatostatin Phenytoin, diazoxide, vinblastin, colchicine Effects: Anabolic; incr storage of glu, fa, aa ( incr no glu transporters in cell membrane Rapid (sec): incr transport of glu, aa and K into insulin-sensitive cells Intermediate (min): stimulation of protein synthesis Inhibition of protein degradation Activation of glycolytic enzymes and glycogen synthase Inhibition of phosphorylase and gluconeogenic enzymes Delayed (hrs): incr mRNAs for lipogenic and other enzymes Adipose tissue: Incr glu entry Incr fa synthesis and triG deposition Incr glycerol phosphate synthesis Activation of lipoprotein lipase (responsible for uptake from plasma) Inhibition of hormone-sensitive lipase (responsible for catabolism) Incr K uptake Muscle: Incr glu entry Incr glycogen synthesis (induces glycogen synthase and glucokinase) Incr aa uptake and protein synthesis in ribosomes Decr protein catabolism and release of gluconeogenic aa Incr ketone uptake Incr K uptake Liver: Decr ketogenesis / glycogenolysis / gluconeogenesis ( decr glu output Incr protein synthesis Incr lipid synthesis Incr glycogenesis (induces glucokinase and glycogen synthase) Defiency: decr peri utilization decr entry of glu into cells (except in brain and RBC where OK) deranged glucostatic function of liver with incr release decr glycogen synthesis, incr glu output ( EXTRACELLULAR GLU XS ( polyuria (osmotic diuresis) ( polydipsia (dehydration) ( weight loss ( glycosuria ( incr HbA1c (when prolonged hyperG, HbA glycated) ( INTRACELLULAR GLU DEF ( incr lipolysis (to supply E needs of cell) ( incr action of hormone-sensitive lipase ( incr free fas and triGs ( decr lipogenesis: due to intraC glu def; decr removal of triG, fa and chylomicrons from blood due to decr activity of lipoprotein lipase ( incr fa and triG ( catabolised to AcoA ( some enters Krebs cycle ( CO2 + H20 ( rest cannot enter Krebs cycle for conversion to fa as depleted AcoA carboxylase ( XS AcoA ( converted to acetoacetyl-CoA ( acetoacetate, acetone, - hydroxybutyrate (ketone bodies; source of E) formed in liver ( anions of strong acids ( buffering capacity exceeded ( ketosis, acidosis NB. Cations lost with anions in urine ( hypoNa and K ( incr protein catabolism to C02 and H20 and glu via incr gluconeogenesis ( decr entry of aa into muscle (decr protein synthesis so maintained supply of aa for gluconeogenesis) ( incr activity of various enzymes in Krebs cycle / glycolysis (ie. Phosphoenolpyruvate carboxykinase, F1,6-DPase, G6Pase, pyruvate carboxylase) ( glycogen depletion ( hyperphagia due to decr glu in satiety area of hypothalamus ( coma (may be due to acidosis / dehydration; may be hyperosmolar) ( CHRONIC EFFECTS: intracellular hyperG ( activation of enzyme aldose reductase ( incr formation of sorbitol in cells ( decr Na-K ATPase; intracellular glu converted to advanced glycosylation end products (AGEs) ( crosslink matrix proteins ( damage BVs XS: hypoG; glu only source of fuel for brain, which has poor carbo reserves ( Complete inhibition of insulin secretion at 80mg/dL glu ( Incr secretion of glucagon and E ( incr glycogenolysis by liver ( Incr secretion of GH and cortisol ( decr glu utilization peripherally Palpitations, nervous, sweating (due to autonomic discharge; if not present hypoglycaeamia unawareness) ( hunger, confusion ( lethargy, coma, convulsions, death Insulin resistance; incr BMI; decr lipogenesis and muscle genesis, incr gluconeogenesis; hyperinsulinaemia and dyslipidaemia = metabolic syndrome / syndrome X Glucagon Glycogenolysis, gluconeogenesis, lipolysis, ketogenesis Normal insulin:glucagon is 2.3; catabolic; mobilizes glu, fa, aa Synthesis: preproglucagon found in A cells, L cells in lower GI tract and brain ( in A cells ( processed to glucagon and major proglucagon fragment (MPGF) ( secreted into portal vein ( in L cells ( processed to glicentin has some glucagon activity glucagon-like polypeptides 1 and 2 (GLP-1 and 2) have no activity but processed to GLP-1 (7-36) which stimulates insulin secretion and glucose use oxyntomodulin inhibits gastric acid secretion ( in A and L cells ( residual glicentin-related polypeptide (GRPP) is left (has no activity) Metabolism: HL 5-10mins; degraded by liver (which is reaches 1st via portal vein so low systemic levels) Regulation of Secretion: Stimulators: low glu, aas (eg. High protein meal prevents hypoG while insulin allows storage of glu), CCK, gastrin, cortisol, exercise, infections, stress, beta-agonists (beta-receptors mediators of SNS supply), theophylline, Ach Inhibitors: glu, somatostatin, secretin, fa, ketones, insulin, phenytoin, alpha-agonists, GABA effect on A cells (via GABAa receptors which are Cl channels and allow Cl influx that hyperpolarize A cells) Effects: Incr blood sugar level Acts on serpentine receptors ( incr plasma glu In liver: via Gs ( adenylyl cylase ( incr intracellular cAMP ( PKA ( activation of phosphorylase ( glycogenolysis ( inhibit conversion of phosphoenolpyruvate to pyruvate ( inhibit conversion of F6P to F1,6DP via different receptor ( activation of PLC ( incr cytoplasmic Ca ( glycogenolysis Also: incr gluconeogenesis Incr ketone body formation by decr malonyl-CoA levels in liver Lipolysis No glycogenolysis in muscle Incr secretion of GH, insulin, pancreatic somatostatin +ive inotropic effect on heart due to incr cAMP Somatostatin: Found in D cells Release stimulated by: glu, aa, CCK Action: inhibit secretion of insulin, glucagon, and pancreatic polypeptide in a paracrine fashion Effect: ( hyperG and (due to low CCK) slowed gastric emptying, decr gastric acid secretion, gallstones Pancreatic Polypeptide: Release stimulated by: fasting, exercise, acute hypoG Release inhibited by: somatostatin, IV glu Effect: slowed absorption of food Exercise: Incr GLUT 4 transporters in muscle cell membranes (insulin independent) ( incr entry glu into skeletal muscle ( can cause hypoG Catecholamines: 1) Initial glycogenolysis: activation of phosphorylase in liver via beta-receptors ( incr intracellular cAMP Via alpha-receptors ( incr intracellular Ca ( incr hepatic glu output ( hyperG 2) Then glyocgenesis: activation of phosphorylase in muscle via actions above ( incr formation G6P ( incr pyruvate ( converted to lactate ( enters circ ( oxidized in liver to pyruvate ( converted to glycogen 3) Other effects: incr fa Thyroid Hormone: exacerbates diabetes as incr absorption of glu from SI and enhance glycogenolytic effect of catecholamines Glucocorticoids: exacerbate diabetes via causing gluconeogenesis in liver, incr hepatic glycogenesis and ketogenesis, decr peri glu utilization GH: exacerbates diabetes via mobilization of fa from adipose tissue, decr glu uptake into tissues, inr hepatic glu output, decr tissue binding of insulin Adrenal Glands Anatomy Blood supply from renal, phrenic and aortic arteries large blood flow Medulla: 28% mass; granule-containing cells near venous sinuses; densely innervated; 2 cells types: E-secreting type: larger, less dense granules; 90% NE-secreting type: smaller, dense granules; 10% Secretes E (more important in humans), NE, D; secretion stimulated by preganglionic nerve fibres via splanchnic nerves Cortex: cells contain large amount of SER; secretes steroid hormones; secretion contolle by ACTH (G) and AII (M) glucocorticoids (metabolism of carbs and protein), mineralocorticoids (maintenance of Na balance and ECF vol) and sex hormones Outer zona glomerulosa (15% overall mass) secrete corticosterone and aldosterone; also important in formation of new cortical cells which replenish the inner layers Inner Zona fasciculata (50%) columns of cells; secrete corticosterone, cortisol > sex hormones Inner zona reticularis (7%) continuous with inner ZF; secrete corticosterone, cortisol < sex Hormones Catecholamines Synthesis: NE: formed by hydroxylation and decarboxylation of tyrosine E: formed by methylation of NE (catalysed by phenylethanolamine-N-methyltransferase (PNMT), induced by glucocorticoids which are in high conc in adrenal vein) D: 50% comes from medulla, 50% from ANS Stored in granules with ATP and chromogranin A Also made in adrenal medulla: metenkephalin, adrenomedullin Regulation of secretion: Ach from preganglionic neurons ( opens cation channels ( Ca influx from ECF ( exocytosis of granules Incr release: incr SNS; familiar stree ( incr NE, unexpected stress ( incr E Decr release: sleep Metabolism: ( enter plasma ( 95% dopamine, 70% E and NE conjugated to sulphate (inactive) ( HL 2mins ( methoxylated ( 50% occurs in urine as free/conjugated metanephrine and normetanephrine ( 35% occur in urine as 3-methoxy-5-hydroxymandelic (vanillymandelic) acid (VMA) (700 g/day) ( small amount of free E (6 g/day) or NE (30 g/day) Mechanism of Action: work of alpha and beta receptors Effects: Mostly mediated through E in physiological circumstances Most of effects of NE are through local release from postganglionic sym neurons Metabolic: glycogenolysis in liver and skeletal muscle (via beta-receptor ( cAMP and phosphorylase) (via alpha-receptor ( Ca) Incr secretion isulin and glucagons (via beta-receptor; decr secretion via alpha-receptor) Lipolysis ( fa Incr plasma lactate Incr BMR (may be due to cut vasoC ( incr temp; incr muscle activity; oxidation of lactate in liver) Cardiac: positive inotrope and chonotrope (via beta1-receptor) Incr myocardial excitability NE ( VasoC in most organs (via alpha1-receptor) E ( vasoD in skeletal muscle and liver (via beta-2 receptor) ( net decr PVR NE alone ( incr BP but reflex bradycardia with decr CO E alone ( widened PP, incr HR and incr CO (due to insufficient reflex) CNS: incr alertness; anxiety and fear Other: incr K due to release from liver ( then prolonged decr K due to incr entry into skeletal muscle Dopamine: ( renal vasoD; vasoD in mesentry; vasoC elsewere via release of NE; +ive inotrope via beta1-receptors; natiuresis by inhibition of renal Na-K ATPase; net incr SBP Cortical Hormones Made from chol C19 steroids: androgenic dehydroepiandrosterone (DHEA), androstenedione (most oestrogens made from this) C21 steroids: mineralocorticoids aldosterone, deoxycorticosterone (on 3% activity of aldosterone); 9- fluorocortisol has mineralocorticoid activity Glucocorticoids  cortisol (10-20mg/day in normal adult), corticosterone (7:1 ratio); prednisone and dexamethasone have glucocorticoid activity Synthesis: 1) Acetate / uptake from LDL in body ( cholesterol ( esterified and stored in lipid droplets ( transported to mitochondria by sterol carrier protein 2) In mitochondria converted to pregnenolone (catalysed by cholesterol desmolase / side-chain cleavage enzyme / P450scc / CYP11A1 CP450 member) ( Pregnenolone ( 17-hydroxypregnenolone (catalysed by 17-hydroxylase / p450c17 / CYP17 CP450 member) 3) Pregnenolone ( moves to SER ( dehydrogenated to progesterone (catalysed by 3-hydroxysteroid dehydrogenase  NOT a CP450 member; this enzyme more active in ZF) ( Progesterone ( 17-hydroxyprogesterone (catalysed by 17-hydroxylase) NB. 17-hydroxypregnenolone can be converted to 17-hydroxyprogesterone (catalysed by 3- hydroxysteroid dehydrogenase) 4) In SER: Progesterone ( hydroxylated to 11-deoxycorticosterone (catalysed by 21-hydroxylase / P450c21 / CYP21A2  a CP450) 17-hydroxyprogesterone ( hydroxylated to 11-deoxycortisol (catalysed by 21-hydroxylase) 5) 11-deoxycorticosterone and 11-deoxycortisol move back to mitochondria IN ZONA FASCICULATA/RETICULARIS ( hydroxylated to corticosterone and cortisol (catalysed by 11-hydroxylase / P450c11 / CYP11B1  a CP450) IN ZONA GLOMERULOSA ( catalyst aldosterone synthase / p450c11AS / CYP11B2 is present ( aldosterone formed (no 11-hydroxylase or 17-hydroxylase in ZG) NB. 17-pregnenolone and 17-progesterone ( C19 steroids dehydroepiandrosterone and androstenedione (catalysed by 17,20-lyase; this enzyme more active in ZR therefore makes more androgens) ( androstenedione converted to testosterone and oestrogens in fat and other peri tissues (important in postmenopausal women) Deficiencies: 17-hydroxylase  rare; no sex hormones produced so female genitalia; can still make mineralocorticoids so get hyperT and hypoK; def cortisol but can still make corticosterone and aldosterone 21-hydroxylase  common; decr production cortisol and aldosterone ( incr ACTH; steroids converted to androgens ( virilisation; def in aldosterone ( hypoNa and hypoV 11-hydroxylase virilisation, but hyperT Regulation of release: Glucocorticoid: ACTH (HL 10mins) binds to receptors on adrenocortical cells ( Gs ( adenylyl cyclase ( incr formation pregnenolone and derivatives ( release of hormones (inc androgens); ACTH increases sensitivity of adrenal to further release of ACTH ACTH released in circadian rhythm (peak in morning); governed by biologic clock in suprachiasmatic nuclei of hypothalamus Decr ACTH release: free GCs (also decr adrenal responsiveness to ACTH) inhibition at pituitary and hypothalamic level Incr ACTH release: stress (there is a ceiling at which incr ACTH no longer incr release of GC); incr due to incr CRH from paraventricular nuclei in hypothalamus ( transported through portal-hypophysial vessels to APG; multiple inputs to hypothalamus from emotional stress / pain etc Mineralocorticoid: ACTH can stimulate MC release, but effect is transient Renin (from JG cells surrounding renal afferent arterioles which notes drop in ECF vol) ( activates angiotensinogen ( conversion of angiotensin I to II ( AII binds to AT1 receptors in ZG ( G protein ( activation of PLC ( incr PKC ( incr chol converted to pregnenolone ( incr conversion of corticosterone to aldosterone (helps action of aldosterone synthase) K ( stimulates conversion of chol to pregnenolone, and of deoxycorticosterone to aldosterone Works via depolarizing cell ( opens voltage-gated Ca channel ( incr intracellular Ca Hence low K diet decr sensitivity of ZG to AII ANP inhibits renin secretion ( decr responsiveness of ZG to AII Conc of dehydroepiandrosterone sulphate higher in young men than old, due to altered activity of lyase activity Incr release GC and MC: surgery, anxiety, physical trauma, haemorrhage Incr release MC only: hyperK (small incr needed), hypoNa (large drop needed), constriction of IVC in thorax (decr intrarenal p), standing Plasma Binding: bound steroids are inactive; bound acts as reservoir Cortisol: 90% bound to transcortin / corticosteroid-binding globulin (CBG) (synthesized in liver; production increased by oestrogen incr in pregnancy and hyperthyroidism; decr in cirrhosis, nephrosis; if incr ( more cortisol incr ACTH ( incr cortisol secretion until normal free level, so high total level without symptoms of XS) Albumin (minor; 5%; large capacity but low affinity); 5% free Stronger bound than corticosterone so longer HL (60-90mins); very little free; binding saturated at 20g/dL; total amount 13.5g/dL Corticosterone: similar to above, but lesser extent HL 50mins Aldosterone: slight protein binding; HL 20mins (short); total level 0.006g/dL Metabolism: Cortisol: in liver (similar for cortisone except not step 3); rate decreased in liver disease and stress Cortisol reduced ( dihydrocortisol ( tetrahydrocortisol ( conjugated to glucuronic acid 20% Cortisol ( cortisone (catalysed by 11-hydroxysteroid dehydrogenase type 1 and 2) ( this is active but promptly reduced and conjugated to tetrahydrocortisone glucuronide 1/3 Cortisol ( 17-ketosteroid version ( conjugated to sulphate ( conjugates freely soluble ( enter circ and bind to p proteins ( excreted in urine, by tubular secretion (only 1% excreted unchanged) ( 15% excreted in stool (may under enterohepatic circ) Aldosterone: Converted in liver to tetrehydroglucuronide derivative Converted in liver and kidneys to 18-glucornide derivative (will be converted to free aldosterone in v acidic pH) ( excreted in urine 1% free form, 5% form 2, 40% form 3 Mechanism of action: Glucocorticoids: bind to glucocorticoid receptors (which when not bound are complexed with Hsp90 ( binding causes dissociation of Hsp) ( AT to nucleus ( complexes act as transcription factors (binds to GC receptors elements (GRE) in genes) ( synthesis of enzymes which alter cell function; hGR is active receptor; hGR is inactive form capable of inhibiting GC s; proteins called coregulators / corepressors help/inhibit interaction of GRE s with receptor Mineralocorticoids: bind to cytoplasm receptor (eg. Principle cell in renal tubules) ( complex moves to nucleus ( altered transcription of mRNAs ( incr protein production ( incr activity of epithelial Na channel (ENaC) via incr insertion of channel in cell membranes, incr synthesis of channel, incr serum and glucocorticoid-regulated kinase ( incr activity of Na-K ATPase NB. GCs can bind to MCs receptors; hence MC-sensitive tissues contain enzyme 11-hydroxysteroid dehydrogenase type 2 which converts cortisol ( cortisone ( 11-oxy derivative which is not active at receptor; if this enzyme is absent, GC have MC effects Effects: Androgens: adrenal androgens only have 20% effect of testosterone ( masculinising effects (little effect unless in XS amount) ( promote protein anabolism and growth Glucocorticoids: overall catabolic incr protein catabolism ( incr aa Incr hepatic glycogenesis and gluconeogenesis Incr G6Pase activity Incr plasma glu level ( incr insulin release (which stimulates lipogenesis, so net deposition of fat with incr fa and glycerol in circ) Incr lipid levels (lipolysis) and ketone body formation Permissive action: small amounts vital for certain reactions to occur (ie. Needed for metabolic action of glucagon and NE+E, vascular reactions of NE+E Needed for effective H20 excretion Encourage sequestration of eosinophils in spleen and lungs; decr basophils; incr neutrophils, plts and RBCs; decr lymphocyte count; decr secretion of cytokines; inhibit inflamm response; inhibit macrophages and APCs; decr PG, LT and PAF synthesis, and COX2; suppress mast cell degranulation; decr histamine release from basophils and mast cells ( decr cap permeability; no effect on abs at mod doses Deficiency ( altered H20, carb, protein, and fat metabolism; fasting ( hypoG XS ( Cushings syndrome; will be protein depleted; thin skin, poor muscles, poor wound healing, easy bruising, thin hair, central fat distribution, buffalo hump, striae, hyperG, hyperlipidasemia, ketosis; may get mineralocorticoid action from v high GC ( salt and H20 retention ( moon face, K depletion, weakness; may get hyperT; bone dissolution ( OP; incr appetite, insomnia, psychosis; chronic XS ( decr ACTH, GH, TSH, LH; antagonize effect of Vit D on Ca absorption NB. Corticosterone exerts minor MC effect Mineralocorticoids: incr reabsorption of Na from urine (via action on principal cells in CD ( K diuresis), sweat, saliva, colon ( Na retention (takes 10-30min to develop); Na exchanged for K and H Deficiency ( hypoNa, hypoV, hyperK XS (eg. Conns; 2Y due to cirrhosis, heat failure, nephrosis) ( hyperNa but also hyperH20 so Na level normal, hyperV ( incr BP, hypoK; H lost in urine; weakness, tetany, polyuria, hypokalaemic alkalosis Escape phenomenon: still get urinary loss of Na due to incr secretion of ANP; this prevents Oedema NB. Deoxycorticosterone is precursor of aldosterone; HL 70mins; control of secretion related to ACTH Calcium Metabolism Calcium Normal plasma level 10mg/dL; 2.5mmol/L Normally ingest 600-1000mg/day (absorb 100-250mg/day) Absorption: Active tranposrt out of SI via Ca-dependent ATPase (increased by 1,25dihydroxycholecalciferol; incr Ca ( decr 1,25DHCC so absorption indirectly proportionate to dietary intake Some passive diffusion Distribution 99% Ca sequestered in skeleton Readily exchangeable reservoir small; 500mmol/day moves in and out Slowly exchangeable reservoir large; involves bone resorption and deposition; only 7.5mmol/day moves in and out 1% Ca free important for 2nd messenger, coagulation, muscle contraction, nerve function some bound to p protein (proportionate to p protein level; incr binding at high pH) is filtered by kidneys but 98-99% reabsorbed (60% in PCT, rest in aLOH and DCT; DCT regulated by PTH) Deficiency: ( hypocalcaemic tetany via excitatory effect on nerve and muscle cells; may cause fatal laryngospasm \98% filtered Ca reabsorbed by kidney Phosphate Normal plasma level 12mg/dL Found in ATP, 2,3-DPG, proteins Absorption: absorbed in duodenum and SI by AT and passive diffusion; absorption proportionate to dietary intake; incr absorption by 1,25dihydroxycholecalciferol Distribution 85-90% in skeleton Rest free is filtered in glomeruli ( 85-90% reabsorbed (2Y to AT in PCT; this AT is inhibited by PTH) 2/3 is in organic compounds; 1/3 in PO4, HPO4, H2PO4 85% filtered phosphate reabsorbed by kidney Vitamin D Are secosteroids Synthesis: 7-dehydrocholesterol ( sun ( previtamin D3 (rapid) ( slow development of Vit D3 (cholecalciferol) (can also be ingested in diet)( transported in plasma bound to vitamin D-binding protein (DBP) (has lower affinity for 1,25 (hence more rapid clearance) than for 25, and 24,25 Metabolism: In liver, cholecalciferol converted to 25-hydroxycholecalciferol (calcidiol, 25-OHD3) (normal level 30ng/mL) ( in PCT of kidneys converted to 1,25-dihydroxycholecalciferol (calcitriol, 1,25-(OH)2D3 (catalysed by 1-hydroxylase; normal level 0.03ng/mL; also made in keratinocytes in skin, placenta, macrophages) ( in kidneys 24,25-dihydroxycholecalciferol also formed Regulation of synthesis: of 1,25-dihydroxycholecalciferol Incr formation: caused by PTH (low Ca ( incr PTH); low PO4 Decr formation: decr PTH (high Ca ( negative feedback on PTH); high PO4 (inhibits 1-hydroxylase); 1,25-dihydroxycholecalciferol (which also inhibits 1-hydroxylase, encourages formation of 24,25-dihydroxycholecalciferol, inhibits formation of PTH) ( 24,25-dihydroxycholecalciferol formed instead Mechanism of Action: 1,25-dihydroxycholecalciferol ( binds receptor ( exposes DNA-binding region ( altered transcription ( formation of calbindin-D proteins (calbindin-D9k and D28k) ( incr Ca transport ( incr no Ca-H ATPase molecules in intestinal cells ( incr Ca transport Effects: of 1,25-dihydroxycholecalciferol Incr Ca and phos for formation of bone ( incr Ca absorption in SI ( incr reabsorption of Ca in kidneys (25 more potent) ( incr synthetic activity of osteoblasts (with 2Y incr activity of osteoclasts) ( regulates PTH release, insulin release, cytokine production by macrophages and T cells Deficiency: rickets / osteomalacia; bowed bones, dental defects, hypoCa PTH Normal plasma level 10-55pg/mL HL 10mins Anatomy: 4 glands embedded in thyroid; chief cells make and secrete PTH; also contain oxyphil cells function of which unknown Synthesis: preproPTH made ( enters ER ( aa removed ( proPTH ( removal of more aa in Golgi apparatus ( PTH ( packaged into secretory granules and released from chief cells Metabolism: rapidly cleaved by Kupffer cells in liver into biologically inactive fragments ( cleared by kidney; HL few mins Mechanism of action: 1) hPTH/PTHrP receptor: binds PTH and PTH-related protein (PTHrP; marked effect on growth and development of cartilage in utero; involved in Ca transport in placenta); serpentine receptor coupled to Gs ( adenylyl cyclase ( incr cAMP; also activated PLC via Gq ( incr intracellular Ca ( PKC 2) PTH2 receptor: in brain, placenta and pancreas; binds PTH; serpentine receptor coupled to Gs ( adenylyl cyclase ( incr cAMP 3) CPTH receptor: binds PTH Regulation of Secretion: Ca binds calcium sensing receptor (CaR); incr phos ( binds free Ca ( decr level of free Ca ( incr PTH Incr secretion: low Ca; incr phosphate (which causes low Ca and inhibits formation of 1,25DHCC) Decr secretion: incr Ca (cell membrane serpentine Ca receptor coupled via G protein to phosphoinositide turnover ( inhibits PTH secretion); 1,25DHCC decreases preproPTH via decr gene transcription; ow Mg; low PTH ( Ca deposited in bones Effects: Incr Ca level by bone resorption Decr plasma phosphate ( incr bone resorption (incr activity and no of osteoclasts) ( incr phosphate excretion in urine (decr reabsorption phosphate at PCT) ( incr Ca reabsorption in DCT (decr reabsoprtion of phos, aa, HCO3, Na, Cl, SO4) ( incr formation of 1,25DHCC ( incr absorption Ca at SI ( stimulates osteoclasts and osteoblasts in longterm ( suppresses further formation of PTH Deficiency: low Ca ( NM hyperexcitability ( hypoCa tetany (Chvosteks sign, Trousseaus sign); high phosphate XS: hyperCa, hypophosphataemia; may get kidney stones Calcitonin Secreted from parafollicular cells of thyroid; HL 10mins Regulation of secretion: incr release by beta-agonists, dopamine, oestrogens, gastrin, CCK, glucagons, secretin Mechanism of action: serpentine receptors in bone and kidney Effect Decr Ca and phos as all entering bone: ( Inhibits bone resorption (inhibits activity of osteoclasts) ( decr Ca and decr phos ( increases Ca and phos (and Na, K, Mg) excretion by kidney ( incr secretion of Na, K, Cl and H20 into gut; decr release of gastrin May protect pregnant bone, prevent postprandial hyperCa, have role in skeletal maturation Others Oestrogen: inhibit secretion of cytokines (eg. IL-1, IL-6, TNF) which aid development of osteoclasts ( decr breakdown of bone; inhibit bone resorbing effects of PTH GC s: lower Ca by inhibiting osteoclast formation and activity, but cause OP over longterm (decr bone formation by inhibiting osteoblasts, incr bone resorption); decr absorption of Ca and phos from SI; incr renal excretion of Ca and phos GH: incr Ca ecretion in urine; incr intestinal absorption of Ca; resultant incr Ca IGF-1: incr protein synthesis in bone Thyroid: incr Ca Insulin: incr bone formation Pituitary Gland Anatomy PPG: endings of axons from supraoptic and paraventricular nuclei of hypothalamus on BVs; contains pituicytes APG: connected to brain via portal hypophysial vessels; made up of interlacing cells (containing granules of stored hormone) and network of sinusoidal fenestrated capillaries Contain chromophilic cells  can be acidophils / basophils; secretory Somatotropes  secrete GH Lactotropes  secrete prolactin Corticotropes  secrete ACTH; POMC is hydrolysed in there cells for from ACTH and -LPH and -endorphin which are secreted Thyrotropes  secrete TSH Gonadotropes  secrete FSH and LH chromophobic cells  secretory; inactive with few granules IPG: proopiomelanocortin (POMC) further hydrolysed to corticotropin-like intermediate-lobe peptide (CLIP; function unknown), -LPH (function unknown) and -endorphin Deficiency: decr adrenal GC s and sex hormones (still some secretion); decr stress-induced incr aldosterone, but still some secretion so no H20 retention; decr growth; decr thyroid function; decr 2Y sex characteristics; tendancy to hypoG when fasted; decr ACTH ( decr protein catabolism ( decr osmotically active substrate in urine ( decr urine production (despite decr ADH); GH 0.2-1.0mg/day output; basal level 0-3ng/mL in adults Distribution: bound to p protein which is produced by cleavage of GH receptors; 50% bound Metabolism: rapid, partly in liver; HL 6-20mins Mechanism of action: large receptor has 2 binding sites for receptors (JAK/STAT cytokine receptor) binds 1 subunit, attracts another subunit ( homodimer ( receptor activation ( activates intracellular enzyme cascades (eg. JAK2-STAT pathway); possibly acts on cartilage to make stem cells that respond to IGF-I Regulation of secretion: feedback control Incr release: GHRH from hypothalamus; ghrelin from hypothalamus Def of E substrate (eg. hypoG, exercise, fasting), incr aa (eg. Protein meal), glucagon, stress, goint to sleep, L-dopa, apomorphine, oestrogens and androgens (peak at puberty has protein anabolic effect ( growth; cause incr size of spikes of GH ( incr release IGF-I ( growth); thyroid hormones needed for proper release of GH Decr release: somatostatin (GH release-inhibiting factor; inhibits release of GH, glucagons, insulin, and gastrin); IGF-I (via direct negative feedback on APG and incr relase of somatostatin) REM sleep, hyperG, cortisol, fa, GH Effects: ( stimulate growth (eg. Incr chondrogenesis ( giganticism if growth plates not fused; if GPs fused ( acromegaly incr size organs, incr protein content, decr fat content); higher spikes during puberty with higher mean plasma level over 24hrs Works via incr secretion of somatomedins (eg. IGF-I (somatomedin C), IGF-II) synthesized in liver, cartilage and other tissues IGF-I secretion independent of GH in utero, but after birth dependent on GH; peaks at puberty then decr thereafter IGF-II secretion independent of GH; role in growth of fetus; constant level ( incr plasma phosporus ( decr plasma urea nitrogen and aa ( incr lean body mass ( decr body fat and chol ( incr fa (ketogenic, catabolic) ( incr BMR ( incr GI absorption of Ca ( decr renal excretion of Na and K (probably cos redirected to growing tissues) ( incr GFR and renal blood flow ( incr hepatic glu output (def causes hypoG) ( incr ability of B cells to respond to insulinogenic stimuli FSH Made of  and  subunits which must be combined for max physiologic activity; act via GPCR LH Made of  and  subunits which must be combined for max physiologic activity; act via GPCR TSH Made of  and  subunits which must be combined for max physiologic activity Renal Endocrine Function Renin-Angiotensin System Renin: acid aspartyl protease; made as preprorenin ( converted to prorenin ( some secreted (very little converted in circulation) ( some converted to renin in kidneys (in secretory granules of JG cells located in media of afferent arterioles) HL 80mins Angiotensinogen: made in liver; incr lvel by GC, thyroid, oestrogens, cytokines, AII ACE: form AII from AI; inactivates bradykinin (hence cough on ACEi); found in endothelial cells; conversion of AI ( AII occurs in lungs Angiotensin: AI (no physiological activity) ( AII (physiological activity) metabolized rapidly by peptidases (in RBCs, and many tissues for local effect uterus, placenta, eyes, pancreas, heart, fat, adrenal cortex, testis, ovary, pituitary, brain) ( AIII (has 40% pressor activity, 100% aldosterone-stimulating activity) ( further metabolism to AIV (also has some physiogical activity); also removed from circ by trapping mechanism in vascular beds of various tissues; HL 1-2mins Mechanism of action of AII: AT1 receptors: serpentine; coupled to Gq ( PLC ( incr cytosolic free Ca level; responsible for most effects of AII found in arterioles and adrenal cortex; XS AII downregulates receptors in arterioles, but upregulates receptors in cortex AT2 receptors: via G protein ( activate phosphatases ( antagonize growth effects, open K channels ( incr production of NO ( incr cGMP Regulation of secretion of renin: Incr release: incr SNS; incr NE+E (act on beta1-receptors on JG cells); PGs; Na depletion; diuretics; hypotension; haemorrhage; upright posture; dehydration; heart failure; cirrhosis; RAS (( decr afferent arteriole p) Decr release: incr Na and Cl reabsorption across macula densa (renin release inversely proportional to amount of Na and Cl entering DCT from LOH; Na and Cl enter macula densa cells cia Na-K-2Cl transporter); incr afferent arteriolar p; AII (negative feedback); ADH Na-depleted people and cirrhosis circulating AII increased ( downregulation of receptors in vascular SM ( decr response Effects of AII: ( arteriolar constriction ( incr SBP and DBP ( incr aldosterone secretion from adrenal cortex ( helps release of NE from postganglionic sym neurons ( contraction of mesangial cells ( decr GFR ( incr Na reabsorption in renal tubules ( decr sensitivity of baroreflex in brain (helps pressor effect) via action on circumventricular organs (area postrema) ( incr H20 intake via action of circumventricular organs (subfornical organ and organum vasculosum of lamina terminalis) ( incr secretion of ADH and ACTH via action on circumventricular organs Erythropoietin Synthesis: 85% from kidneys (produced by interstitial cells in peritubular capillary bed), 15% from liver (produced by perivenous hepatocytes) Metabolism: metabolized in liver; HL 5hrs Mechanism of action: receptor has tyrosine kinase activity ( inhibits apoptosis of RBCs and incr growth Effect: Incr no of erthyropoietin-sensitive committed stem cells in BM ( converted to RBC precursors ( erthyrocytes; takes 2-3days for incr RBCs Regulation of release: incr release: hypoxia, androgens, helped by E+NE GI Physiology Carbohydrates Polysaccharides (eg. Starches - glycogen, amylopectin, amylose), disaccharides (eg. Lactose, sucrose), monosaccharides (eg. Fructose, glucose) Digestion Mouth: salivary -amylase digests starch ( -dextrins, maltotriose and maltose Stomach: -amylase inhibited by acidic gastric juice SI: salivary and pancreatic -amylase active as above Oligosaccharidases present in brush border \ -dextrinase  breaks down -dextrins, maltotriose and maltose Maltase  breaks down -dextrins, maltotriose and maltose Sucrase  breaks down sucrose, maltotriose and maltose Disaccharidases present in BB Lactase  breaks down lactose Trehalase  breaks down trehalose Sucrase ( 1 glu + 1 fru Lactose ( glu and galactose Trehalose ( 2 glu Def in enzymes ( osmotic diarrhoea, bloating + flatulence (due to production of CO2 and H2 from disaccharies in lower SI and LI) Def lactase ( lactose intolerance Absorption Glucose: rapid absorption in all SI (no absorption in LI) via Na-dependent glu transporter (SGLUT) a Na-glu cotransporter (incr absorption if incr Na conc on mucosal surface of cells); same mechanism for galactose Na moves along conc gradient Na undergoes AT into lateral intercellular spaces (maintaining conc grad) Glu transported by GLUT2 into interstitum and capillaries Fructose: facilitated diffusion by GLUT5 in enterocytes, then via GLUT2 into intersitium; independent of Na Pentoses: simple diffusion Proteins Digestion Endopeptidases (eg. Trypsin, chymotrypsin, elastase) - digest interior peptide bonds Exopeptidases (eg. Carboxypeptidase A and B) - digest aa at carboxyl ends Stomach: pepsinogen I (in acid secreting regions) and pepsinogen II (in pyloric region) activated by HCl ( pepsin ( digest proteins and polypeptides (cleave peptide linkages) Work in acidic enviro so decr activity when gastric contents mixed with alkaline pancreatic juice in duodenum and jejunum SI: occurs in 3 sites 1) Enzymes from pancreas act in lumen Enteropeptidase stimulates trypsin (endo) ( digests proteins and polypeptides Trypsin stimulates Chymotrypsin (endo) digests proteins and polypeptides Elastase (endo) digests elastin and other protesin Carboxypeptidase A and B (exo) digest proteins and polypeptides Nucleases digest nucleic acids ( nucleotides 2) Enzymes from SI mucosa act in brush border Enteropeptidase: digests trypsinogen ( trypsin Aminopeptidase digests polypeptides Carboxypeptidase digests polypeptides Endopeptidases digests polypeptides Dipeptidase digests dipeptides ( 2aa Enzymes split nucleotides ( nucleosides and phosphoric acid ( sugars and purine and pyrimidine bases 3) Intracellular mucosal enzymes: Peptidases digest di- and tripeptides which are AT into intestinal cells Absorption Rapid in duodenum and jejunum, slow in ileum, none in LI; 50% from food, 25% from digestive juices, 25% from desquamated cells Multiple systems into enterocytes: 3 systems require Na, 2 require Na and Cl, 2 dont need Na Into blood: 3 system require Na, 2 dont need Na 2-5% not absorbed ( digested by bacteria in LI ( excreted Protein absorption indicated in food allergies; absorption of protein Ags occurs in microfold cells overlying Peyers patches ( Ag presented to lymphoid cells Lipids Digestion Mouth: lingual lipase from Ebners glands on dorsal surface of tongue digests up to 30% triGs ( fa + 1,2-diacylglycerols; still active in stomach SI: most occurs in duodenum; emulsified by bile salts, lecithin and monoglycerides ( form micelles which contain fa, monoglycerides and chol in hydrophobic centres ( these can pass to BB for digestion Pancreatic lipase digests triGs ( 2 monoglycerides and fa; action inhibited by acid, but OK as pancreatic juice is alkaline Colipase binds to pancreatic lipase, increasing action; released in prohormone form which is activated by trypsin Bile salt-acid lipase (lipase activated by bile salt) digests cholesteryl esters ( chol; also digests esters of fat-soluble vitamins and phospholipids Cholesteryl ester hydrolase digests cholesteryl esters ( chol Absorption mostly in upper SI; 95% absorbed Passive diffusion / carriers into enterocytes ( rapidly esterified in enterocytes so conc grad maintained ( small fas are H20-soluble so can be ATed into blood and circulate as free fas ( larger fas are reeesterfied to triG in SER ( chol is esterified ( esters coated in protein, cholesterol and phospholipid ( chylomicron ( enter lymphatics via exocytosis NB. Colonic bacteria ( short-chain fas via action on carbs and fibre ( absorbed and metabolized, have trophic effect on colonic epithelial cells, combat inflamm, help maintain acid-base equilibrium, promote absorption of Na H20 and Electrolytes 2000ml ingested + 7000ml secreted ( 98% reabsorbed, 200ml lost in stools Na: Na moves either way depending on conc grad Na-K ATPase in BL membrane ( some Na active absorbed in SI and esp in LI 2Y AT of Na with glu and aa Cl: from IF ( enterocyte via N-K-2Cl cotransporter ( Cl secreted into lumen via channels (activated by incr cAMP) H20: move according to osmotic p usually equals out at the jejunum then maintained thereafter; much absorption in LI 2Y to AT of Na K: some secreted into lumen (eg. As part of mucus) and some passively enters lumen down conc grad H-K-ATPase in distal LI causes AT of K into enterocytes Vitamins and Minerals Vitamins: ADEK fat soluble; mostly in upper SI; B12 in ileum (bound to intrinsic factor from stomach); B12 and folate Na-independent, but others co-transported with Na Ca: 30-80% absorbed; incr absorption is defiency, decr if XS Fe: Fe3+ ingested ( Fe3+ reductase in BB converts to Fe2+ (aided by gastric secretions which dissolve Fe3+ making reduction easier) ( Fe2+ absorbed in duodenum via DMT1 ( stored as ferritin in enterocytes; may aggregate as haemosiderin ( transported into IF via ferroportin 1 (facilitated by hephaestin) ( Fe2+ converted back to Fe3+ in plasma ( bound to transport protein transferrin (has 2 binding sites; usually 35% saturated) 70% Fe in Hb, 3% in myoglobin, 27% in ferritin; XS Fe ( accum of haemosiderin which causes damaged ( haemachromatosis Regulation of GI function Layers: Muscosa Submucosa: contains SM fibres (circular) Muscularis: contains 2 layers of SM (inner circular, outer longitudinal) Serosa: continues on to mesentery Nervous Supply: Myenteric (Auerbachs) plexus: between 2 muscle layers in muscularis; innervates these muscles, involved in motor control Submucous (Meissners) plexus: between mucosa and submucosa; innervates glands, endocrine cells and BVs PNS: preganglionic paraS efferents end on cholinergic nerve cells in plexuses ( incr Ach secretion SNS: postganglionic sym efferents end on cholinergic nerve cells in plexuses ( NE inhibits Ach secretion via alpha-2 receptors; some end directly on SM cells or on BVs Basic electrical activity: (not in oesophagus and prox stomach) SM has spontaneous rhythmic fluctuations in membrane potential (-65 - -45mV); initiated by interstitial cells of Cajal located near myenteric plexus in stomach and SI, near submucous plexus in colon; rarely causes contraction but cause muscle tension; depolarization due to Ca influx, repolarisation due to K efflux; Ach incr tension, E decr; co-ordinates motor activity contraction only occurs during depolarizing part of wave Migrating motor complex: quiescent period (I) ( irregular electrical and mechanical activity (II) ( bursts of regular activity (III); occur every 90mins with cycles migrating from stomach to distal ileum; stopped by ingestion of food, only during fasting state Peristalsis: reflex response inititated when wall stretched ( release of 5-HT ( activates sensory neurons ( activates myenteric plexus ( release of substance P and Ach ( SM contraction behind bolus ( release of NO, VIP and ATP ( SM relaxation ahead of bolus Moves at 2-25cm/sec; occurs intrinsically, but influenced by extrinsic input GI hormones: Enteroendocrine cells: are hormone secreting; called enterochromaffin cells if also secreted 5-HT; called APUD/neuroendocrine cells if also secrete amines Gastrin: Synthesis: Preprogastrin processed into multiple gastrins of multiple lengths (G17 is principle form causing gastrin secretion); produced by G cells antral portion of gastric mucosa; contain many gastrin granules; some gastrin also found in pancreas, APG, IPG, hypothalamus, medulla, vagus and sciatic nerves Regulation of secretion: G cells have microvilli at luminal border ( detect changes in gastric contents Incr secretion: luminal peptides and aa; luminal distension; incr vagal discharge (release gastrin-releasing polypeptide (GRP) at G cells); Ca and E in blood (Xab> ? 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form; inactivated in kidney and SI Effects: stimulation of gastric acid and pepsin secretion trophic action of mucosa of SI, LI and stomach stimulates gastric motility stimulates insulin secretion (after protein meal) incr glucagons secretion Cholecystokinin-Pancreozymin (CCK-PZ / CCK) Sythesis: secreted by I cells in mucosa of upper SI, nerves in distal SI and LI (also found in brain); preproCCK processed into many fragments; CCK 8 and 12 are most active Metabolism: 5mins Regulation of secretion: Incr secretion: contact of intestinal mucosa with products of digestion (peptides and aa and fa); digestion caused by release of pancreatic juice causes +ve feedback loop Decr secretion: Mechanism of action: CCK receptors activate PLC ( incr production IP3 and DAG Effects: contraction of GB Secretion of pancreatic juice Helps action of secretin in causing secretion of pancreatic juice Inhibits gastric emptying (augments contraction of pyloric sphincter) Trophic effect on pancreas Incr secretion of enterokinase Incr motility of SI and LI Incr glucagon secretion Stimulates insulin secretion Secretin Synthesis: secreted by S cells in mucosa of upper SI Metabolism: HL 5mins Regulation of secretion: Incr secretion: products of protein digestion; acidic contents of SI Decr secretion: Mechanism of action: works via cAMP Effects: incr secretion of HCO3 by duct cells of pancrease and biliary tract ( secretion of waterly, alkaline pancreas juice augments actions of CCK in causing secretion of pancreatic juice decr gastric acid secretion contraction of pyloric sphincter stimulates insulin secretion GIP Synthesis: made by K cells in muscosa of duodenum and jejunum Regulation of secretion: inc by glu and fat in duodenum Effects: inhibits gastric secretion and motility in high doses; stimulates insulin secretion VIP Synthesis: preproVIP Metabolism: HL 2mins Effects: stimulates intestinal secretion of electrolytes and H20; relaxation of intestinal SM; dilation of peri BVs; inhibition of gastric acid secretion; potentiates action of Ach at salivary glands Peptide YY Inhibits gastric acid secretion and motility; release from jejunum stimulated by fat Ghrelin Secreted in stomach; stimulates GH secretion; central control of food intake Motiliin Secreted by enterochromaffin cells and Mo cells in stomach, SI and colon; acts on GPCRs in duodenum and colon ( contraction of SM in stomach, SI and LI; regulator of MICs Somatostatin Secreted by D cells in pancreatic islets and GI mucosa; inhibits secretion of gastrin, VIP, GIP, secretin and motilin, pancreatic exocrine secretion, gastric acid secretion, gastric motility, GB contraction, absorption of glu, aa and triGs; stimulates acid in lumen Neurotensin: from mucosa of ileum; stimulate by fa; inhibits GI motility and incr ileal blood flow Substance P: incr motility GRP: in vagal nerve ending terminating on G cells; incr gastric secretion Guanylin: from intestinal mucosa; ( incr conc of intracellular cGMP ( incr secretion of Cl into lumen Mouth Mastication: wet, smaller particles Saliva: 1500ml/day; helps swallowing, keeps moist, solvent for molecules, neutralize gastric acid when regurgitated into oesophagus; hypotonic, slightly acidic, rich in K, low in Na and Cl (when salivary flow rapid, less time for removal of Na and Cl and addition of K and HCO3 in ducts ( saliva more isotonic) Glands: Parotid: ( serous, watery; 20% Submandibular: ( mixed, moderately viscous; 70% Sublingual: ( mucous, viscous; 5% Salivary glands contain zymogen granules containing salivary enzymes ( discharged from acinar cells into ducts; contains: Lingual lipase: by glands on tongue -amylase: by salivary glands Mucins: glycoproteins that lubricate food, bind bacteria, protect oral mucosa Immune globulin IgA\ Lysozyme: attacks walls of bacteria Lactoferrin: binds Fe, bacteriostatic Proline-rich proteins: protect tooth enamel, bind toxic tannins Regulation of secretion: PNS ( incr secretion of watery saliva, vasoD in gland due to VIP Atropine and anticholingergics ( decr saliva SNS ( vasoC in gland, decr saliva Swallowing: afferent impulse: trigeminal, GP and vagus nerves ( nucleus of tractus solitarius and nucleus ambiguous efferent impulse: trigeminal, facial and hypoglossal nerves Voluntary stage: tongue pushes backwards Involuntary stage: contraction of pharyngeal muscles, inhibition of resp and glottic closure, peristalsis at 4cm/sec Oesophagus Lower oesophageal sphincter: tonically active (prevents reflux) but relaxes on swallowing; vagal input causes contraction; release of NO and VIP from interneurons causes relaxation; achalasia due to incr tone due to deficiency of myenteric plexus ( decr release NO and VIP Intrinsic sphincter: more prominent SM Extrinsic sphincter: fibres of diaphragm surrounding oesophagus Oblique fibres of stomach wall create flap valve that helps prevent regurg when intraG p rises Stomach Secrete gastric juice (2500ml) Cardia and pyloric region: neck cells of gastric glands and mucosa secrete mucus (with HCO3, made of glycoproteins called mucins) ( alkaline pH at luminal surface; incr by PG Body: several glands open onto gastric pit Contains parietal (oxyntic) cells: secrete HCl and IF HCl: kills bacteria, necessary pH for digestion, stimulates flow of bile stimulated by histamine via H2 (( incr cAMP via Gs), Ach via M3 (( incr intracellular Ca), gastrin (incr intracellular Ca)) and IF Inhibited by PG but activating Gi H-K ATPase pumps H (from CO2 + H20 ( H2CO3 (catalysed by CA) ( H + HCO3) against conc grad and IF; at rest cell contains tubulovesicular structures in walls ( on activation, structures move to apical membrane inserting more H-K ATPase into it Cl channels activated by cAMP transport Cl down electrochemical grad into lumen; Cl \ enters parietal cell from blood via countertransport with HCO3 from above (after meal, may get postprandial alkaline tide as blood becomes alkaline) IF: binds to cyanocobalamin (B12) ( complex taken up by cubilin in receptors in distal ileum ( absorption of complex by endocytosis ( B12 transferred to transcobalamin II which transports B12 in plasma Chief (zymogen / peptic) cells: contain zymogen granules ( secrete pepsinogens Enterochromaffin-like (ECL) cells: secrete histamine; stimulated by gastrin; inhibited by Somtostatin Dumping syndrome: in gastrectomised pt; rapidly absorption of glu ( incr insulin ( hypoG ( weakness, dizziness, sweating; hypertonic meals rapidly entering intestine ( movement of H20 into gut ( hypoV Gastric Motility Mechanism: food enters stomach ( upper part relaxes (receptive relaxation; vagal; triggered by mvmt of oesophagus) ( peristalsis in lower, mixing (contraction in distal part is antral systole; 3-4 waves/min) ( contraction of pyloric region and duodenum; liquid food enters duodenum (pyloric contraction prevents regurg due to CCK and secretin Regulation: cephalic (CNS; presence of food in mouth incr vagus output ( incr gastrin via GRP, incr Ach to incr acid and pepsin; incr by anger, decr by fear and depression) gastric (local reflex responses to gastrin; stretch and chemical stimuli esp aa; receptors ( submucosal plexus synapsing on postganglionic paraS neurons ( parietal cells ( gastrin) intestinal (reflex and hormonal feedback; fats, carbs and acid in duodenum inhibit gastric aicd and pepsin secretion and gastric motility via peptide YY) alcohol and caffeine act directly on mucosa Osmolarity of contents: duodenal osmoreceptors sense hyperosmolarity ( decr gastric emptying Empting fastest for carbs > protein > fat Pancreas Zymogen granules contain digestive enzymes ( exocytosis into lumens of pancreatic ducts ( pancreatic duct of Wirsung joins CBD ( ampulla of Vater opening in duodenal papilla, encircled by sphincter of Oddi Pancreatic juice: 1500ml/day high HC03 ( neutralize gastric acid also contain Na, K, Ca, Mg, Cl, SO4, HPO4 enzymes secreted as proenzymes Trypsinogen ( converted to trypsin by enteropeptidase (from BB; NOT activated in pancreas as this would cause autodigestion), also activated by trypsin itself (+ive feedback loop; pancreas contains a trypsin inhibitor) Trypsin: converts chymotrypsinogens ( chymotrypsin Proenzymes ( active enzymes Regulation of secretion: secretin acts on ducts ( juice rich in alkaline (high HCO3, low Cl), low in enzymes (due to incr cAMP) ( incr bile secretion CCK acts on acinar cells ( juice high in enzymes, low in volume (via PLC) Ach acts on acinar cells ( jucie high in enzymes, low in volume (via PLC) Liver and Biliary System Blood extensively modified on passage through liver (portal vein ( sinusoids ( central veins ( hepatic veins ( IVC) acini, at one side portal vein, hepatic artery, bile duct, this area has best oxygenation Bile formation: intralobular BD ( interlobular BD ( R+L hepatic ducts ( CHD ( unites with CD ( CBD Functions: formation and secretion of bile Metabolism of glu, aa, lipids, fat and water soluble vits Inactivation of toxins, steroids and other hormones Synthesis of acute phase proteins, albumin, CFs, steroid and hormone-binding proteins Kuppfer cells for immunity Bile: Alkaline; 500ml/day Made of bile salts (Na and K salts of bile acids; conjugated to glycine and taurine; made from chol) Cholic and chenodeoxycholic acid formed in liver 2Y bile acids: Cholic ( deoxycholic acid by bacteria in LI Chenodeoxycholic ( lithocholic acid by bacteria in LI Reduce surface tension; emulsification of fat (amphipathic so can form micelles hydrophilic out, hydrophobic in) 90-95% absorbed from SI via Na-bile salt cotransporter powered by basolateral Na-K ATPase ( portal vein ( reexcreted in bile 5-10% enter colon ( converted as above ( lithocholic acid excreted, deoxycholic acid absorbed and H20 soluble bile pigments (glucuronides are bilirubin and bilverdin breakdown products of heme) Bilirubin: formed by breakdown of Hb ( bound to albumin ( enters liver cells ( bound to cytoplasmic proteins ( conjugated to glucuronic acid by glucuronyl transferase (activity incr by barbs, antihistamines, anticonvulsants) in SER ( bilirubin diglucuronide (more H20 soluble) ( AT into bile canaliculi ( SI which is impermeable to conjugated bilirubin, most of which excreted but colon bacteria can form urobilinogen which can be reabsorbed into general circ or enterohepatic circ ( excreted in urine ( small (conjugated) amount enters blood ( excreted in urine Jaundice can be due to XS production of bilirubun, decr uptake of bilirubin into hepatic cells, disturbed intracellular protein binding/conjugation ( incr free bilirubin disturbed secretion of conjugated bilirubin, intr/extrahepatic bile duct obstruction ( incr conjugated bilirubin If bile doesnt enter faeces ( white acholic stools Also secreted in bile: chol (supersaturation ( gallstones; not able to form micelles if too much), ALP Gallbladder: absorption of water in stored bile Cholagogues: cause contraction of GB; CCK Choleretics: cause incr secretion of bile; vagus nerve, secretin Small Intestine Duodenum becomes jejunum at ligament of Treitz ( upper 40% jejunum, lower 60% ileum ( ends at ileocaecal valve Contains solitary lymphatic nodules aggregated lymphatic nodules (Peyers patches) intestinal glands (crypts of Lueberkuhn) throughout - enterocytes formed from undifferentiated cells here which migrate to tips of villi; ave lifespan 2-5/7 as rapidly sloughed; secrete isotonic fluid; contain Paneth cells in bottom which secrete defensins natural ABs duodenal (Brunners glands) secrete mucus various enteroendocrine cells valvulae conniventes m membrane covered in villi covered by single layer of columnar epithelium containing network of capillaries and lymphatic vessel (lacteal), with submucosa running to tip of villus; free edges of cells in villi form microvilli covered in glycocalyx (layer rich in amino sugars) which make up brush border epithelial cells secrete mucus goblet cells secrete mucus in SI and LI Cells connected by tight junctions Mucus secretion incr by cholinergic stimulation, chemical and physical irritation Motility: MMCs present; replaced by peristalsis controlled by BER; 12 BER cycles/min in prox jejunum ( 8 in distal ileum; Peristaltic rushes are intense waves occurring when obstruction present; mvmt below slow transit time Segmental contractions move chime to and fro, incr exposure to mucosal surface, initiated by focal incr Ca influx Tonic contractions prolonged contractions which separate regions of SI from eachother Intestinal adaption: when some bowel removed, hyperplasia and hypertrophy of remaining bowel; still malabsorption if >50% bowel removed (decr enterohepatic circ ( decr fa absorption, osmotic effect of unabsorbed bile salts ( enter colon where incr intestinal secretion; jejunum worse at adapting so worse if distal ileum removed Paralytic ileus: due to activation of opioid receptors / incr discharge from NA fibres in splanchnic nerves; lasts 6-8hrs in intestine, 2-3/7 in colon Colon 4hrs to get to cecum, 6 hrs to hepatic flexure, 9hrs to splenic flexure, 12hr to pelvis For absorption of H20, Na and minerals; external muscle layer collected into 3 longitudinal bands (teniae coli) ( haustra; no villi; short glands; solitary lymph follicles; ileum progects into cecum so incr colonic p closes ileocaecal valve, but incr ileal p opens it; gastroileal reflex causes relaxation of cecum, SNS causes contraction of valve Na AT out, H20 along osmotic grad; net secretion of HCO3 and K Segmentation contraction and peristalsis in colon, also mass action contraction with large contraction of SM ( move material ( defecation reflex; BER 2/min at ileocaecal valve, 6/min at sigmoid Intestinal bacteria: eg. E coli, enterobacter aerogenes, bacteroides fragilis; may use nutrients (eg. Aas), but also make nutrients (eg. Folic acid, B vits, vit K, fas); role in cholesterol metabolism; 3 types: Pathogens: cause disease Symbionts: benefit host Commensals: no effect on host or vice versa Dietary fibre: cellulose, hemicellulose, lignin, gums, algal polysaccharides, pectic substances; poorly digested; forms bulk Defecation: a spinal reflex that can be inhibited or facilitated voluntarily SNS to internal anal sphincter ( contraction (involuntary); relaxes on distension with reflex muscular contractions external anal sphincter nerve supply from pudendal nerve; tonic contraction ( relaxes when p 55mmHg in rectum / voluntary defecation due to straining (abdo muscles contract, pelvic floor lower 1-3cm, relaxation of puborectalis, decr anorectal angle to 15 deg Gastrocolic reflex: distension of stomach ( contractions in rectum BLOOD Plasma Composition Circulating Body Fluids  Blood: normal circulating vol is 8% body weight, 5600mL; 55% of vol is plasma Bone marrow: extramedullary haematopoiesis occurs BM disease; in children occurs in all bones, by 20yrs only in long bones; active cellular marrow is red marrow, inactive is infiltrated with fat yellow marrow; 75% is WBC, 25% is RBC as average life span of WBC is short; HSCs best derived from blasocytes of embryos in umbilical cord blood Granuloctye and Macrophage Colony-Stimulating Factors: stimulate growth of certain cell lines; also sustain mature cells; some crossing-over of action of factors; usually acting locally in BM; Stem cell factor needed from prolif and maturation of HSCs CytokineSourceCell Line StimulatedIL-1Multiple cell typesErythrocyte, granulocyte, megakaryocyte, monocyteIL-3T cellsErythrocyte, granulocyte, megakaryocyte, monocyteIL-4T cellsBasophilIL-5T cellsEosinophilIL-6Endothelial cells, fibroblasts, macrophagesErythrocyte, granulocyte, megakaryocyte, monocyteIL-11Fibroblasts, osteoblastsErythrocyte, granulocyte, megakaryocyteErythropoietinKidney, Kupffer cellsErythrocyteSCFMultiple cell typesErythrocyte, granulocyte, megakaryocyte, monocyteG-CSF (granulocyte)Endothelial cells, fibroblasts, monocytesGranulocyteGM-CSF (granulocyte-macrophage)Endothelial cells, fibroblasts, monocytes, T cellsErythrocyte, granulocyte, megakaryocyteM-CSF (macrophage)Endothelial cells, fibroblasts, monocytesMonocyteThrombopoietinLiver, kidneyMegakaryocyte WBC s: 4000-11000cells/ L Granulocytes/polymorphonuclear leukocytes: horseshoe nuclei, become lobed as older; contain cytoplasmic granules that contain substances involved in inflamm/allergic reactions Neutrophils: 3000-6000cells/L; 50-70% of WBC; halflife 6hrs; attracted to endothelial cell surfaces by selectins ( roll along it ( bind to neutrophil adhesion molecules of integrin family ( pass through wall of capillaries between endothelial cells by diapedesis Eosinophils: 150-300cells/ L; 1-4% of WBC; halflife short; also undergo diapedesis; maturation and activation induced by IL3 and 5, GM-CSF Basophils: 0-100cells/ L; 0.4% of WBC Lymphocytes: large round nuclei and scanty cytoplasm; 1500-4000cells/ L; 20-40% of WBC Monocytes: much agranular cytoplasm and kidney-shaped nucleus; 300-600cells/ L; 2-8% of WBC Mast cells: heavily granulated wandering cells found in areas rich in CT; contain heparin, histamine and proteases; have IgE receptors and degranulate when IgE coated antigens bind them Monocytes: circulate for 72hrs then enter tissues and become tissue macrophages (eg. Kupffer cells in liver, pul alveolar macrophages, microglia in brain) where they persist for 3/12 Lymphocytes: enter blood stream via lymphatics; only 2% usually found in blood, rest in lymphoid organs Lymphocyte precursors come from BM ( thymus to be transformed into T cells ( to LNs ( to body T cells ( cytotoxic (CD8) destroy foreign cells; development aided by helper T cells; divided into  and  types ( helper 1 (CD4)  secrete IL-2 and IF, important in cellular immunity ( helper 2 (CD4) secrete IL-4 and 5, interact with B cells for humoral immunity ( memory T cells ( bursal equivalents (eg. fetal liver, BM, spleen) to be transformed into B cells ( to LNs ( to body B cells ( plasma cells secrete Ig from Ag-binding receptors ( memory B cells Antibodies: 1) Bind and neutralize protein toxins 2) Block attachment of viruses and bacteria to cells 3) Osponise bacteria 4) Activate complement Natural Killer Cells: are cytotoxic lymphocytes, but are not T cells Cytokines: hormone-like molecules that act in paracrine fashion to regulate immune responses; a superfamily are chemokines which attract WBCs to areas (receptors are G proteins) CytokineSourceActivityRelevanceIL-1MacrophagesActivate T cells and macrophages; causes fever; incr slow wave sleep and decr appetiteSeptic shock, RA, atherosclerosisIL-2TH1 cellsActivate lymphocytes, NKCs and macrophagesTrt of metastatic RCC, melanoma, tumoursIL-4TH2 cells, mast cells, basophils, eosinophilsActivate lymphocytes (esp TH2), monocytes, IgE class switchingAllergyIL-5TH2 cells, mast cells, eosinophilsDifferentiation of eosinophilsAllergyIL-6TH2 cells, macrophagesActivation of lymphocytes, differentiation of B cells, stimulate production of acute-phase proteins; causes feverActs as GF in myelomaIL-8T cells and macrophagesChemotaxis of neutrophils, basophils, T cellsMarker of disease activityIL-11BM stromal cellsSimulate production of acute-phase proteinsDecr chemotherapy-induced thrombocytopaeniaIL-12Macrophages and B cellsStimulate production of IF by TH1 cells and NKC s; induce TH1 cellsVaccinesTNFMacrophages, NKC s, T and B cells, mast cellsInflammation; causes feverRALymphotoxin (TNF)TH1 cells and B cellsInflammationMS and IDDMTGFT cells, B cells, mast cells and macrophagesImmunosuppressionMS and MGGM-CSFT cells, B cells, NKC s and macrophagesPromote growth of granulocytes and monocytesDecr neutropenia after chemo; stimulate cell production after BM transplantIFVirally infected cellsInduce resistence of cells to viral infectionAIDS, melanoma, chronic hepatitis B and CIFVirally infected cellsInduce resistence of cells to viral infectionDecr relapse of MSIFTH1 cells and NKCsActivate macrophages, inhibit TH2 cellsHelp chronic granulomatous disease Complement system: 3 pathways activate system 1) Classic pathway: triggered by immune complexes 2) Mannose-binding lectin pathway: triggered when lectin binds mannose groups in bacteria 3) Alternative/properdin pathway: triggered by contact with pathogen Pathways work in various manners; 1) Opsonisation ( chemotaxis ( lysis by inserting perforins into cell membranes ( disrupt membrane polarity 2) Activate B cells and aid immune memory 3) Dispose of waste products after apoptosis Inflamm response: may kill bacteria / damage host tissue (eg. RA) Incr production of neutrophils Bacteria interacts with factors and cells to cause chemotaxis of neutrophils to infected area via chemokines (C5a, leukotrienes, mast cells, basophils); this movement + phagocytosis require microfilaments and microtubules, interaction of actin and myosin-I Plasma factors cause opsonisation of bacteria usually IgG and complement proteins added so can bind easily to neutrophil ( G-protein mediated response ( incr motor activity of cell ( ingestion of bacteria by phagocytosis (exocytosis (neutrophil granules discharge contents into phagocytic vacuoles, and into interstitial space degranulation) Granules contain defensins (antimicrobial proteins) proteases elastases metalloproteinases (attack collagen) Respiratory burst: cell membrane enzyme NADPH oxidase activated ( toxic oxygen metabolites to help kill; this requires incr O2 uptake and metabolism of neutrophil NADPH + H+ + 2O2 ( NADP + 2H+ + 2O2- (free radical) O2- + O2- + H+ + H+ ( H2O2 + O2 (catalysed by superoxide dismutase) (both are bactericidal) H2O2 ( H2O + O2 (catalysed by catalase) Myeloperoxidase: released by neutrophils, catalyses conversion of Cl, Br, I, and SCN to acids (HOCl, HOBr etc) which are oxidants Incr activity of eosinophils Release proteins, cytokines and chemokines that produce inflammation; esp abundant in GI, RS and GU tract mucosa; incr in allergic disorders and other RS/GI diseases; more selective than neutrophils Incr activity of basophils Release proteins and cytokines; contain histamine and heparin which are all released when activated by histamine-releasing factor secreted by T cells; for immediate hypersensitivity Incr activity of mast cells Involved in inflamm reactions initiated by IgE and IgG; release TNF- by ab-independent mechanism ( non-specific natural immunity; involved in allergic reactions Incr activity of macrophages Activated by lymphokines from T cells ( migrate via chemotaxis ( phagocytosis similar to neutrophils; secrete substances that affect lymphocytes, PGE and CFs Phagocytic disorders: Neutrophil hypomotility: poorly polymerized actin ( slow neutrophils Chronic granulomatous disease: failure to make O2 in neutrophils and monocytes G6PD def: failure to make NADPH and hence decr O2 production Immunity: Innate immunity: found in invertebrates and 1st line defense in vertebrates Receptors bind sequences of sugars/fats/aa found in common bacteria / urate crystals secreted by bacteria activate immune response ( defense mechanisms via NKCs, neutrophils, macrophages ( release of IFs, phagocytosis, antibacterial peptides, complement system, proteolysis ( activate acquired immune system Eg. TLR4 (toll receptor) binds bacterial lipopolysaccharide protein CD14 (important in production of septic shock in G-ive bacteria) ( cascade of immune events Eg. TLR2 for microbial lipoproteins, TLR6 for peptidoglycans, TLR9 for DNA Acquired immunity: specific Ags activate T and B cells ( production of abs Humoral immunity: mediated by ab s (in  globulin fraction of plasma proteins) produced by B cells ( activate complement system and neutralize ag s; important in bacterial infection Cellular immunity: mediated by T cells ( insert perforins; important in viral/fungal infections, delayed allergy, rejection of transplants, fighting tumours Antigens: Ag taken up by APC can be dendritic cells in LNs, spleen and skin macrophages B cells Ag partially digested in APC ( peptide fragment coupled to HLA (human leukocyte Ags) - protein products of MHC (major histocompatibility complex) genes on C6 Class I  heavy chain assoc noncovalently with 2-microglobulin; found on all nucleated cells; mainly coupled to peptide fragments generated from proteins (in proteasomes) from WITHIN cells Class II  lighter chain assoc noncovalently with lighter  chain; present in APC s (inc B cells and activated T cells); mainly couped to peptide fragments from EXTRACELLULAR proteins that enter cell by endocytosis (eg. bacteria) HLA-Ag complex put on cell surface ( presented to  T cell receptors (made up of  and  units) Cytotoxic (CD8) T cells bind MHC-I ( kill target directly Helper (CD4) T cells bind MHC-II ( T cells secretes cytokines that activate other lymphocytes For T cell activation 2 signals needed - there is also binding of adhesion molecules to complementary proteins in APC B cells can binds Ags directly ( contact TH2 cell for activation and ab formation ( memory B and plasma cells (secrete abs) Immunoglobulins Bind and neutralize protein toxins; block attachment of viruses and bacteria to cells; opsonise bacteria; activate complement Made of 4 polypeptide chains 2 heavy chains, 2 light chains joined by disulphide bridges that permit mobility; heavy chains flexible at hinge; contain C constant segment, and variable segments (J joining, D diversity, V variable); V are Ag binding sites; Fc portion is effector portion IgG: complement activation IgA: localized protection in external secretions (secretory immunoglobulins) IgM: complement activation IgD: Ag recognition by B cells IgE: reagin activity; releases histamine from basophils and mast cells Platelets: Small granulated bodies that accumulate at sites of vascular injury; no nuclei; HL 4/7; formed from megakaryocytes in BM by pinching off bits of cytoplasm; 60-75% in blood, rest in spleen; membranes have receptors for collagen, ADP, vWF and fibrinogen Cytoplasm contains dense granules (containing substances secreted on plt activations 5-HT, ADP, adenine nucleotides) -granules (contains proteins in lysosome  CF s, PDGF (stimulates wound healing, mitogen for vascular SM)) Production regulated by CSF s from megakaryocytes and thrombopoietin (from liver and kidneys) BV wall injury ( exposed collagen and von Willebrand factor in wall ( plts adhere via receptors ( plt activation ( release contents of granules ( ADP stimulates more plt aggregation (aided by platelet activating factor from neutrophils and monocytes which acts via GPCR ( incr arachidonic acid derivatives (eg. TXA2)) Red Blood Cells: Biconcave discs made in BM; no nuclei; last 120days; shrink/swell depending on osmotic p (haemolyse in hypotonic saline); spleen removes abnormal RBCs Hb: O2 carrying pigment; globular molecule made of 4 subunits each containing heme (Fe containing porphyrin derivative) and polypeptides (2 pairs per Hb molecule) which form globin portion; binds O2 ( oxyHb (O2 attaches to Fe in heme; H and 2,3BPG compete with O2 ( decr affinity of Hb for O2); drugs may cause Fe2+ to be converted to Fe3+ ( methemoglobin; CO reacts with Hb ( COHb (has much higher affinity for Hb than O2) HbA: 22; normal adult Hb HbA2 (2.5%): 22 HbF: 22; bind less avidly to 2,3-BPG so higher affinity for O2 Gower 1 Hb: 22 (in embryo) Gower 2 Hb: 22 (in embryo) Catabolism: RBC s destroyed in tissue macrophage system ( heme converted to bilverdin (CO formed in process) ( converted to bilirubin and excreted in bile Plasma: Normal plasma vol is 5% body weight (3500ml); contains CFs If whole blood allowed to clot, and clot removed ( remaining is serum (same as plasma but minus fibrinogen, CF II, V, VIII) Plasma proteins: albumin, globulin, fibrinogen, CFs, abs; capillary walls impermeable to these ( exert 25mmHg oncotic pressure across capillary wall pulling H20 into blood; also responsible for 15% buffering capacity of blood; mostly anionic; most made in liver except abs Low in liver disease, starvation, malabsorption Lymph: Tissue fluid that enter lymphatic vessels ( enters venous blood via thoracic and R lymphatic ducts; contains CFs; lower protein content than plasma; involved in absorption of H20-insoluble fats; lymphocytes enter blood through lymph Haemostasis: Damage to blood vessel wall ( constriction (due to 5-HT) and formation of haemostatic plug of plts as they bind to collagen and aggregate ( bound together by insoluble fibrin as fibrin monomer polymerises and has covalent cross-linkages, catalysed by XIII and requiring Ca (formed from soluble fibrinogen in clotting cascade) ( definitive clot Thrombin: activates plts, endothelial cells, leukocytes SEE DIAGRAMS 03 3263242 A = when AVN activated H = transmission through His bundle V = V depol PA interval = time from 1st appearance of atrial depolarization to A wave = conduction time from SAN to AVN AH interval = AVN conduction time HV interval = from start of H to start of QRS = conduction in BOH and BBs Late diastole: MV and TV open; AV and PV closed; MV and TV drift closed towards end blood flows into A and V (70% of V filling); r of filling decr as Vs become distended End-diastolic V vol = 130ml Atrial systole: R systole occurs before L MV and TV open propels more blood (30%) into V via incr Ap contraction of atrial muscle around IVC, SVC and pul veins but still some regurg into veins ( a wave in JVP Ventricular systole: L systole occurs before R (but ejection in R occurs 1st as pul art p p in aorta (80mmHg) and pul art (10mmHg)) ( AV and PV open; AV valves bulge into atria causing small rise in IAp ( c wave in JVP ventricular ejection (rapid then slow ejection; IVp (L @ 120mmHg, R @ 25mmHg) reaches max then decr so late in systole Ap > Vp but momentum keeps blood going; contraction causes MV and TV to be pulled down causing decr Ap; 70-90ml ejected per V overall) End-systolic V vol = 50ml EF (% end-diastolic vol ejected per stroke) = 65%; reflects V function Early diastole: protodiastole (when V muscle fully contracted and Vp drops; 0.04s) Ends when momentum of blood overcome ( AV and PV close (during expiration occurs @ same time, during inspiration AV closes before PV due to lower impedance of pul vasc tree) isovolumetric ventricular relaxation (IVp drops rapidly; blood enters A causing incr Ap ( v wave on JVP) Ends when Vp < Ap ( MV and TV open Vs fill rapidly then slower, causing decr Ap O2 + Hb ( HbO2 (oxyhaemoglobin) Amount of O2 bound to Hb increases rapidly until 500mmHg then levels out thereafter Max amount O2 that can bind Hb is O2 capacity when all available binding sites occupied expose blood to v high pO2 and subtract dissolved O2 1g Hb can bind 1.39ml O2 Normal blood has 15g Hb/100ml so capacity 20.8ml/100ml O2 saturation: % of available binding sites that have O2 attached; 97.5% if 100mmHg O2 (arterial), 75% if 40mmHg (venous) O2 combined with Hb X 100 O2 capacity Normal value of pO2 at 50% sat is 27mmHg which is P50 More linear than O2 dissociation curve The lower the sat of Hb with O2, the larger the CO2 conc for given pCO2 (Haldane effect better ability of reduced Hb to mop up H+ produced when carbonic acid dissociates, greater ability of reduced Hb to form carbaminohaemoglobin More steep than O2 dissociation curve Between 40-50mmHg CO2 conc changes more that O2 so pO2 diff between arterial and venous blood is large, but pCO2 diff is small ~  ׯ ǰ Ұ  / : E ^ ʱ ٱ ڱ ( ) ٲ  9 Q q y ϳ ӳ ݳ  Ǵ Ҵ ( 0 ~ 4 꽴ߴߴƩƏƘƘƏƏƏƁ jhq@hq@CJaJhq@6CJaJhq@>*CJaJhMWCJaJh9Nlhq@CJaJh9Nl>*CJaJh9Nl6CJaJhq@CJaJhUSCJaJhUS>*CJaJh9Nlh9NlCJaJh9NlCJaJ jh9Nlh9NlCJaJ2N ׯ  a } Ұ / D E ^ ڱ A [ ٲ `gd9NlgdPY 9 q γ ϳ ӳ ƴ Ǵ Ҵ ' ( 0 } ~ 4 5 B M N ̷  | } gdPY4 5 B N Z ̷ з   8 9 Z [ } ǹ ȹ  , . 0 p @ B ʻ 4 B Ҽ  H ` ½ ŷŮŷŮŷŮŷţŮŮŮŮŮŮŮh1>*CJaJhthtCJaJht>*CJaJ jhthtCJaJhtCJaJht6CJaJh16>*CJaJ jh1h1CJaJh16CJaJh1CJaJ< ߹  p 2 м F f ; 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'? K? w? ? ? ? ? ? ? ? ? @ Ǿᘌ~ᾘ~ jhp!hzCJaJhp!hz>*CJaJhp!hzCJaJh hz6CJaJ jhp!hz6CJaJhz6CJaJhp!hz6CJaJ jh hzCJaJhzCJaJh hz>*CJaJh hzCJaJ0? ? ? @ @ @ %@ y@ z@ A $A [A \A A A B B :B ;B bB LC MC sC C C # $ gdK7gd<`gd @ @ @ @ @ @ \A jA A A 9B :B ;B B B C " # $      ݭ{phK7hzCJaJh\EhzCJaJh96hzCJaJ jh96hzCJaJ jh\EhzCJaJh\Ehz6CJaJh<hzCJaJUhC-hzCJaJhC-hz>*CJaJhz6CJaJ jhhzCJaJhzCJaJhz,CO2 curve shifted to R by incr SO2 As long as ratio of HCO3 : pCO2 x 0.03 remains 20, pH will remain same; HCO3 detemined by kidney, pCO2 by lung Davenport diagram: shows relationship between HCO3, pCO2 and pH; A is normal plasma; line CAB (buffer line) is effect as carbonic acid is added to whole blood presence of Hb makes line steeper, displaced upwards if more HCO3 from kidneys (incr base excess defined by distance between new buffer line and old), vice versa Respiratory Acidosis Incr pCO2 ( decr HCO2/pCO2 ratio ( decr pH ( move towards B as HCO3 must incr due to dissociation of carbonic acid, but ratio of HCO3:pCO2 decr; if persists, kidney conserves HCO3 and secretes H+ as H2PO4 and NH4 so ratio HCO3:pCO2 returns to normal (moves from B to D ( compensated resp acidosis which is usually not complete so pH not completely normalized, amount detemined by base XS (vertical difference between BA and DE) Resp alkalosis Decr pCO2 ( incr HCO3:pCO2 ratio ( incr pH (A(C); renal compensation excretes HCO3 ( return ratio to normal (C(F) which may be nearly complete ( base deficit Metabolic acidosis Decr ratio HCO3:pCO2 ( decr pH (A(G); resp compensation lowering pCO2 ( incr HCO3:pCO2 due to H+ ions detected by chemoreceptors (G(F) ( base defecit P-V curve is non-linear; becomes stiffer at high vols Hysteresis: lung vol at any p during deflation is larger than during inflation Note lung without any expanding p still has air inside it; even if p is above atmospheric p (0 on horizontal axis) airways will collapse trapping air inside (this occurs at higher vols in lung disease) p in airways and alveoli = atmospheric; change in pressure occurs outside lung ( transpulmonary pressure (p outside lung is subatmospheric due to elastic recoil of lung Compliance = slope of p-v curve (ie. vol change per unit p change); compliance is 200ml/cm water; at higher expanding pressures Decr compliance (slope of curve flattens): lung disease, alveolar oedema, incr pul venous p and if lung unventilated for long period due to atelectasis and incr surface tension Incr compliance: pul emphysema, normal aging lung, asthma attack Elasticity: tendancy of lung to return to resting vol after distension due tp fibres of elastic and collagen in alveolar walls and around vessels and bronchi Shape of intrapleural p curve different to vol curve due to changes in lung compliance Before inspiration: Intrapleural p = -5cm due to elastic recoil of lung Alveolar p = 0cm (atmospheric); with no airflow there is no p difference along airways On inspiration: Lung expands ( elastic recoil increases ( intrapleural p drops from A(B on black line; intrapleural p decreased even more by airway resistance (80%) (hatched area, A(B on blue line) Part of hatched area is due to tissue resistance (20%) p required to overcome viscous forces of tissue as they slide over eachother Tissue + airway resistance = pulmonary resistance On expiration: Note airway resistance causes intrapleural p to be LESS negative (follow blue line) Inspiration: intrapleural p A(B(C Work done = 0ABCD0 Work done to overcome elastic forces = 0AECD0 Work to overcome airway+tissue resistance = ABCEA; the more airway resistance, the more negative intrapleural p needs to become The faster RR, faster flow rate, larger this area ABCEA is, but also 0AECD0 Expiration: intrapleural p C(F(A Work done = 0AECD0 Work to overcome airway+tissue resistance = AECFA (this lies within 0AECD0 so is done by energy stored in elastic structures (ie. passive) ( O2 consumption incr linearly; above certain limit VO2 becomes constant (VO2max) incr work above here needs anaerobic glycolysis ( Ventilation incr linearly ( at high VO2 values, due to lactic acid release, more incr ventilation due to ventilatory stimulus; change occurs at anaerobic threshold ( incr diffusing capacity of lung (incr diffusing capacity of membrane and vol of blood in pul capillaries due to recruitment and distension of capillaries due to incr CO and hence high pul art and venous p) ( incr CO linearly with work level due to incr HR and SV; change in CO is only that of change in ventilation ( decr ventilation-perfusion inequality due to more uniform distribution of blood flow ( O2 dissociation curve moves to R due to incr pCO2, H+ and temp ( easier O2 unloading ( decr PVR as caps open ( decr diffusion distance to tissues Flow-volume curve: remember after small amount gas exhaled, flow limited by airway compression and determined by elastic recoil force of lung and resistance of airways upstream of collapse point Restrictive: max flow rate decreased, total vol exhaled decreased; flow rate unnaturally high during latter part of expiration due to incr lung recoil Obstructive: max flow rate decreased, total vol exhaled decreased; 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