ࡱ>  ]7 6bjbjUU " 7|7|2l8@t<n|$ X+Glp ࡒt0*  0<""THE CIRCULATORY SYSTEM: BLOOD General Concepts The circulatory system is composed of: the blood (the circulating material) the heart (pump) blood vessels (conduit) The blood circulates continuously inside the pipeline composed of blood vessels and heart. The blood circulation is driven by rhythmic contraction and relaxation of the heart. Blood vessels are distributed into every parts of a human body. The walls of blood vessels at special portions, namely, capillaries, are permeable to small molecules. Thus, small molecules in the blood and interstitium can cross the walls of blood vessels very efficiently, allowing exchange between blood and interstitium. Primary Functions of the Circulatory System Include: Transportation Deliver life-supporting materials, i.e., O2, glucose, amino acid, fatty acids, vitamins, minerals, etc. These nutrients enter into the blood from special sources (organs) and are distributed to whole body by the blood. Deliver regulating signals, i.e., hormones to tissue cells Collect waste products from tissue cells and deliver to special organs (kidney, lung) for disposal Distribute heat throughout the body 2) Protection Special components of the blood patrol whole body and fight against invaded microorganisms and cancerous cells. Why is a circulatory system needed? External environment External environment is the environment outside human body. Human beings obtain oxygen and nutrients from external environment, and excret waste products into external environment. However, most cells in a human body do not have direct contact with the environment. Internal environment The majority of human cells are bathed in tissue fluid or interstitium. The interstitium is considered as an internal environment for human cells. The physiochemical properties of interstitium are strictly controlled to maintain ideal living conditions for human cells (homeostasis). These conditions include: presence of oxygen, glucose, amino acids, lipids to convert energy and maintain cellular structures strict extracellular concentrations of electrolyte including Na, Cl, K, Ca, and Mg, etc. optimal osmolarity of 280-300 mOsm pH 7.35-7.45 37-38( C The optimal internal environment is strikingly similar to the ancient sea. The internal environment is determined by, which is the medium around all cells. If cells were isolated from human body, and then left in the air or tap water, they would die in a few minutes. A system is needed to connect internal environment to external environment. This system is circulatory system THE BLOOD General Properties of Whole Blood Fraction of body weight 8% Volume of the adult body Female: 4-5 L; Male: 5-6 L Mean temperature 38( C (100.4( F) pH 7.35 - 7.45 Viscosity (relative to water) Whole blood: 4.5-5.5; plasma: 2.0 Osmolarity 280-300 mOsm/L Mean salinity (mainly NaCl) 0.85% Hematocrit Female: 37%-48%; male: 45%-52% (percent RBCs by volume; Fig 18.2) Hemoglobin Female: 12-16 g/100 ml; male: 13-18 g/100 ml Mean RBC count Female: 4.8 million/(l; male: 5.4 million/(l Platelet counts 130,000-360,000/(l Total WBC counts 4,000-10,000/(l Composition of the Blood The blood is composed of formed elements (cells and cell fragments) and plasma (extracellular fluid). Formed elements Erythrocytes (red blood cells, RBCs) Platelets Leukocytes (white blood cells, WBCs) Granulocytes Neutrophils Eosinophils Basophils Agranulocytes Lymphocytes Monocytes Composition of Plasma Water 92% by weight Proteins Total 6-9 g/100 ml Albumin 60% of total plasma protein Globulin 36% of total plasma protein Fibrinogen 4% of total plasma protein Enzymes of diagnostic value trace Glucose (dextrose) 70-110 mg/100 ml Amino acid 33-51 mg/100 ml Lactic acid 6-16 mg/100 ml Total lipid 450-850 mg/100 ml Cholesterol 120-220 mg/100 ml Fatty acids 190-420 mg/100 ml High-density lipoprotein (HDL) 30-80 mg/100 ml Low-density lipoprotein (LDL) 62-185 mg/100 ml Neutral Fats (triglycerides) 40-150 mg/100 ml Phospholipids 6-12 mg/100 ml Iron 50-150 (g/100 ml Vitamins Trace Electrolytes Sodium 135-145 mEq/L Potassium 3.5-5.0 mEq/L Magnesium 1.3-2.1 mEq/L Calcium 9.2-10.4 mEq/L Chloride 100-106 mEq/L Bicarbonate 23.1-26.7 mEq/L Phosphate 1.4-2.7 mEq/L Sulfate 0.6-1.2 mEq/L Nitrogenous Wastes Ammonia 0.02-0.09 mg/100 ml Urea 8-25 mg/100 ml Creatine 0.2-0.8 mg/100 ml Creatinine 0.6-1.5 mg/100 ml Uric acid 1.5-8.0 mg/100 ml Bilirubin 0-1.0 mg/100 ml Respiratory gases (O2, CO2, and N2) Serum is the fluid that remains after blood clots and the solids are removed. Serum is identical to plasma except for the absence of clotting proteins. Erythrocytes (Red Blood Cells, RBCs) Function: Primary -- transport oxygen from the lung to tissue cells, and carbon dioxide from tissue cells to the lung. Other-- Buffer blood pH. Structure: biconcave disc shape, which is suited for gas exchange. The shape is flexible so that RBCs can pass though the smallest blood vessels, i.e., capillaries. no organelles or nucleus. Primary cell content is hemoglobin, the protein that binds oxygen and carbon dioxide. Hemoglobin consists of two components, globin and heme pigment. Globin is composed of four peptides two ( and two ( -- each bind to a ringlike heme group. Each heme group bears an atom of iron, which binds reversibly with one molecule of oxygen. Thus, each hemoglobin can carry four molecules of oxygen. Hemoglobin bound with oxygen is called oxyhemoglobin, which is red. Hemoglobin free of oxygen is called deoxyhemoglobin, which becomes dark red. 20% of carbon dioxide in the blood binds to globin part of hemoglobin, which is called carbaminohemoglobin. Regulation Production of Erythrocytes Terms: Hematopoiesis refers to whole blood cell production. Erythropoiesis refers to red blood cell production. All of blood cells including red and white arise from the same type of stem cell, the hematopoietic stem cell or hemocytoblast in red bone marrow. The red bone marrow is a network of reticular connective tissue that borders on wide blood capillaries called blood sinusoids. As hemocytoblast mature, they migrate through the thin walls of the sinusoids to enter the blood. Erythrocytes are produced throughout whole life of a human being to replace dead cells. The average life span of erythrocytes is 120 days. Feedback Regulation of Erythropoiesis regulated based on renal oxygen content erythropoietin, a glycoprotein hormone, is produced by renal cells in response to a decreased renal blood O2 content erythropoietin stimulates erythrocyte production in the red bone marrow A drop in renal blood oxygen level can result from: reduced numbers of red blood cells due to hemorrhage or excess RBC destruction reduced availability of oxygen to the blood, as might occur at high altitudes or during pneumonia increased demands for oxygen (common in those who engage in aerobic exercise) Dietary Requirements for Erythropoiesis Iron and vitamin B12 and folic acid are essential for hemoglobin synthesis. Erythrocyte Disorders Anemia is a condition in which the blood has an abnormally low oxygen-carrying capacity. Common causes of anemia include: 1) an insufficient number of red blood cells 2) decreased hemoglobin content 3) abnormal hemoglobin Two such examples are Thalassemias and Sickle-cell anemia, which are caused by genetic defects. Polycythemia is an abnormal excess of erythrocytes that increases the viscosity of the blood, causing it to sludge or flow sluggishly. Common causes of Polycythemia include: 1) Bone marrow cancer 2) A response to reduced availability of oxygen as at high altitudes Human Blood Groups Agglutinogens specific glycoproteins on red blood cell membranes determine blood type all RBCs in a person carry the same type of agglutinogens. Agglutinins are preformed antibodies in plasma bind to agglutinogens that are not carried by host RBCs cause agglutination --- aggregation and lysis of incompatible RBCs. ABO Blood Groups Type A: RBCs carry type A agglutinogens. Plasma contains preformed antibodies, agglutinin, against B agglutinogens. The person can accept type A or type O blood transfusion. Type B: RBCs carry type B agglutinogens. Plasma contains agglutinin against A agglutinogens. The person can accept type B or type O blood transfusion. Type O: RBCs carry neither type A nor type B agglutinogens. Plasma contains agglutinin against both A and B agglutinogens. The person can accept only type O blood transfusion. Type AB: RBCs carry type A and B agglutinogens. The person can accept type AB, A, B or O blood transfusion. Rh Blood Groups Rh positive RBCs contain Rh agglutinogens. The majority of human beings is Rh positive. Rh negative RBCs contain no Rh agglutinogens. Agglutinins against Rh-positive RBCs are produced when Rh-negative. Human beings receive Rh-positive RBCs for the second time. Leukocytes (White Cells) Leukocytes include neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Function: defense against diseases Leukocytes form a mobile army that helps protect the body from damage by bacteria, viruses, parasites, toxins and tumor cells. Circulating in the blood for various length of time The majority have a life span of several hours to several days while a few memory cells can live for many years. Margination: slow down by cell adhesion molecules secreted by endothelial cells Diapedesis: Leukocytes slip out of the capillary blood vessels. Chemotaxis: Gather in large numbers at areas of tissue damage and infection by following the chemical trail of molecules released by damaged cells or other leukocytes Destroy foreign substances or dead cells by Phagocytosis or other means Structure Leukocytes are grouped into two major categories on the basis of structural and chemical characteristics: Granulocytes -- contain specialized membrane-bound cytoplasmic granules, including neutrophils, eosinophils, and basophils. Agranulocytes -- lack obvious granules, including lymphocytes and monocytes Summary of Leukocytes Cell typeDescriptionNumber of Cells/(l of blood and percent of WRCs (%)Duration of development (D) and life span (LS) FunctionLeukocytes (WRCs)Spherical, nucleated cells 4,000-10,000Neutrophils Nucleus multilobed; inconspicuous cytoplasmic granules; diameter 10-14 (m 3000-7000 40%-70% WRCsD: 6-9 days LS: 6 hours to a few daysPhagocytize bacteriaEosinophils Nucleus bilobed; red cytoplasmic granules; diameter 10-14 (m100-400 1%-4% WRCsD:6-9 days LS: 8-12 daysKill parasitic worms; destroy antigen-antibody complexes; inactivate some inflammatory chemical of allergy Basophils Nucleus lobed; large blue-purple cytoplasmic granules; diameter 10-12 (m 20-50 0.5% WRCsD: 3-7 days LS: a few hours to a few daysRelease histamine and other mediators of inflammation; contain heparin, an anticoagulantLymphocytes T cells B cellsNucleus spherical or indented; pale blue cytoplasm; diameter 5-17 (m1,500-3,000 20%-45% WRCsD: days to weeks LS: hours to yearsMount immune response by direct cell attack (T cells) or via antibodies (B cells) Monocytes Nucleus U- or kidney-shaped; gray-blue cytoplasm; diameter 14-24 (m100-700 4%-8% WRCsD: 2-3 days LS: monthsPhagocytosis; develop into macrophages in tissues Leukocyte Disorders Normal Leukocyte Count: 4,000 10,000/(l Leukopenia: < 4,000/(l normal leukocytes Leukocytosis: > 10,000/(l normal leukocytes Leukemia Leukemia refers to a group of cancerous conditions of white blood cells. Descendants of a single stem cell in red bone marrow tend to remain unspecialized and mitotic, and suppress or impair normal bone marrow function. extraordinarily high number of abnormal (cancerous) leukocytes Platelets Platelets are not cells but cytoplasmic fragments of extraordinarily large (up to 60 (m in diameter) cells called megakaryocytes. Normal Platelet Count: 130,000 400,000/(l Function Secrete vasoconstrictors that cause vascular spasms in broken vessels Form temporary platelet plugs to stop bleeding Secrete chemicals that attract neutrophils and monocytes to sites of inflammation Dissolve blood clots that have ourlasted their usefulness Secrete growth factors that stimulate mitosis in fibroblasts and smooth muscle and help to maintain the linings of blood vessels HEMOSTASIS Hemostasis refers to stoppage of bleeding. During hemostasis, three phases occur in rapid sequence: vascular spasms platelet plug formation coagulation, or blood clotting. Blood clotting requires the involvement of thirteen coagulation factors. including fibrinogen, prothrombin, calcium ion, antihemophilic factor (AHF), etc. Coagulation = clot formation Clot formation requires involvement of many clotting factors. These factors are normally present in the blood in an inactive form. The factors are activated when blood vessel is broken or blood leaves blood vessel. The sequential activation (reaction cascade) of the clotting factors finally leads to the formation of fibrin meshwork. Blood cells are trapped in fibrin meshwork to form a hard clot. Coagulation Disorders Thrombosis is the abnormal clotting of blood in an unbroken vessel. Thrombus is a clot that attaches to the wall of blood vessel. Embolus is a clot that comes off the wall of blood vessel and travel in the blood stream. Embolism is the blockage of blood flow by an embolus that lodges in a small blood vessel. Infarction refers to cell death that results from embolism. Infarction is responsible for most strokes and heart attacks. Bleeding Disorders Thrombocytopenia a condition in which the number of circulating platelets is deficient ( <50,000/(l ) causes spontaneous bleeding from small blood vessels all over the body Deficiency of clotting factors due to impaired liver function Hemophilias hereditary bleeding disorders due to deficiency of clotting factors THE HEART Anatomy of the Heart Location The heart is located in the mediastinum of the thorax (chest), superior to diaphragm, posterior to chestbone, anterior to esophagus, and medial to left and right lungs. Size: about the size of a fist. Coverings of the Heart The heart is enclosed in a double-walled sac called the pericardium. Layers of the Heart Wall The heart wall is composed of three layers: Epicardium (superficial) Myocardium (middle) Endocardium (deep) Chambers of the Heart The heart has four chambers, left atrium, left ventricle, right atrium, and right ventricle. The left atrium and ventricle are separated from the right atrium and ventricle by the septum through which the blood cannot pass. The left atrium receive oxygenated blood from the lungs empty oxygenated blood into the left ventricle The left ventricle receive oxygenated blood from the left atrium eject oxygenated blood into the aorta The right atrium receive deoxygenated blood from the vena cava empty deoxygenated blood to the right ventricle The right ventricle receive deoxygenated blood from the right atrium eject deoxygenated blood into the pulmonary artery Valves of the Heart The four heart valves ensure the unidirectional pumping of blood by the heart: bicuspid, aortic, tricuspid, and pulmonary valve. Bicuspid, or mitral, valve located at the opening between the left atrium and left ventricle opens only when pressure inside the left atrium is higher that that inside the left ventricle, and closes when the pressure gradient is opposite ensures unidirectional blood flow from the left atrium to the left ventricle Aortic valve located at the opening between the left ventricle and the aorta opens only when pressure inside the left ventricle is higher that that inside the aorta, and closes when the pressure gradient is opposite ensures unidirectional blood flow from the left ventricle to the aorta Tricuspid valve located at the opening between the right atrium and right ventricle opens only when pressure inside the right atrium is higher that that inside the right ventricle, and closes when the pressure gradient is opposite ensures unidirectional blood flow from the right atrium to the right ventricle Pulmonary valve located at the opening between the right ventricle and the pulmonary artery opens only when pressure inside the right ventricle is higher that that inside the pulmonary artery, and closes when the pressure gradient is opposite ensures unidirectional blood flow from the right ventricle to the pulmonary artery Aortic and pulmonary valves are also called semilunar valves; bicuspid and tricuspid valves are also called atrioventricular valves. FUNCTION OF THE HEART The Cardiac Cycle Throughout ones lifetime, the heart contracts and relaxes rhythmically. The term systole refers to contraction; diastole refers to relaxation. Each heart beat, or cardiac cycle consists of one systole and one diastole. Each cardiac cycle can be further divided into the following sequential phases: Ventricular systole - isovolumic contraction - ejection Ventricular diastole - isovolumic relaxation - rapid filling - atrial contraction Isovolumetric ventricular contraction: follows atrial contraction Both ventricles start to contract. The ventricular pressures exceed atrial pressures. The bicuspid and tricuspid valves close. Both aortic and pulmonary valves remain closed. The ventricular pressures continue to increase up to the same level as aortic pressure or pulmonary arterial pressure. During this phase, ventricular pressures increase but volumes do not change because all heart valves are closed. Isovolumetric means no change in volume. Ventricular ejection: follows isovolumetric ventricular contraction Both ventricles continue to contract. The ventricular pressures exceed aortic and pulmonary arterial pressure. The aortic valve and pulmonary valve open. Blood is ejected into aorta and pulmonary artery. Isovolumetric ventricular relaxation: follows ventricular ejection, when ventricles start to relax The ventricular pressures drop quickly below aortic and pulmonary pressures. Both aortic and pulmonary valves close; bicuspid and tricuspid valves remain closed. The ventricular pressures continue to drop to the same level as atrial pressures. The ventricular volumes do not change because all heart valves are closed. Ventricular filling: The left and right ventricles relax. Ventricular pressure drops below atrial pressure. Bicuspid and tricuspid valves open. Blood flows from left atrium into left ventricle, and from right atrium into right ventricle. The volume of ventricles are increasing.  EMBED PowerPoint.Slide.8   Atrial contraction: follows ventricular filling The left and right atria contract to push more blood into the ventricles. Bicuspid and tricuspid valves are still open. The volume of ventricles is further increasing. Electrical Control of Cardiac Cycle TERMINOLOGY Excitation - definition: generation of action potentials - different from contraction Contraction - definition: shortening of muscle cells triggered by excitation Excitation-Contraction coupling - events mediate excitation and contraction Autorhythm Autorhythm means the heart can beat on its own without the need for exogenous commands. Original Impulses from S-A Node Contraction of cardiac muscles is triggered by endogenous electrical impulses. The electrical impulses are normally generated by a group of specialized pacemaker cells at sinoatrial (SA) node, which is located in the right atrial wall, just inferior to the entrance of the superior vena cava. Action potential of SA nodal cells Pacemaker potential Upstroke fast calcium influx Repolarization fast potassium efflux Conduction in Atria The electrical impulses from SA node spread through the entire right and left atrial muscle mass, triggering contraction of the right and left atrium. Delay at A-V Node In the mean time, the impulses from S-A node travel to atrioventricular (A-V) node, a group of specialized cells in the lower end of the interatrial septum near the tricuspid valve, and are delayed at A-V node. This delay allows time for the atria to finish contraction and empty their contents into the ventricles before ventricles start to contract. A-V node is the only route that impulses from SA node are transmitted into ventricles. Rapid Conduction in Ventricles via Purkinje Fibers After the delay at A-V node, the impulses rapidly spread to the ventricles via specialized fibers, Purkinje fibers. The Purkinje fibers can transmit the impulses at a speed 6 times faster than regular ventricular muscle fibers. The transmission is so fast that the impulses spread throughout the entire ventricular muscle mass almost immediately, which triggers simultaneous (synchronous) contraction of all the ventricular muscle fibers. Functional syncytium. Note: Each electrical impulse can trigger cardiac muscle contraction normally only once. A normal heart generates 60 to 100 impulses in 1 minute at resting state. Properties of cardiac muscles Excitation of the cardiac muscles is triggered by electrical impulse rather than neural transmitters. Contraction of the cardiac muscles is triggered by elevation of intracellular calcium. Excitation is transmitted from one myocyte to adjacent myocytes via intercalated discs (functional syncytium) Myocytes depend heavily on oxygen and blood supply. Not fatigue Long refractory period Refractory Period last from the onset of action potential until repolarization to -50 mV in atrial/ventricular myocytes or full repolarization in SA and AV nodes. during which myocytes do NOT respond to any electrical impulse prevent ventricles from contracting at too high rates so that enough time is allowed for refill of the ventricles prevent repeatitive (retrograde) excitation of the heart by a single impulse Electrocardiograms (ECG or EKG) ECG is the recording of electrical impulse transmission in the heart via electrodes placed on skin. Applications of ECG 1) measure automaticity: HR, rhythmicity, pacemaker 2) measure conductivity: pathway, reentry, block 3) reveal hypertrophy 4) reveal ischemic damages: location, size, and progress ECG Deflection Waves P wave - corresponds to depolarization of atria (impulse transmission through atria) -just precedes atrial contraction QRS complex - corresponds to depolarization of ventricles (impulse transmission through ventricles) -precedes ventricular contraction T wave - corresponds to repolarization of ventricles P-R interval - indicates time needed for depolarization of atria PLUS time for impulse to travel through A-V node NOTE: Repolarization of atria occurs during QRS but since atria have smaller mass, any deflection this would cause is masked by events in the ventricles. Disorders of Cardiac Conduction System ---- Arrhythmias - refers to abnormal initiation or conduction of electrical impulses in the heart - caused by ischemia, fibrosis, inflammation, or drugs Bradycardia : slow ( < 60 beats/min) Tachycardia : fast ( > 100 beats/min) Flutter and Fibrillation - contract uncoordinatedly and extremely rapidly - ineffective heart beat => death Premature contraction the heart beat triggered by ectopic pacemakers (cells other than SA node) Conduction Block A-V block: First degree delayed at A-V node (prolonged P-R interval), but all impulses transmitted into ventricles Second degree some but not all impulses transmitted into ventricles Third degree no impulse is transmitted into ventricles. fatal if not correct using artificial pacemaker. Stokes-Adams Attacks --- ventricular asystole ( cerebral ischemia (loss of consciousness, convulsion, and sudden death) Ventricular branch block: block of ventricular conduction system slow conduction via regular cardiac muscle fibers an asynchronous contraction, and heart pump deficiency Artificial Pacemaker - Application: slow sinus rhythm, complete AV or ventricular block - Generator of electric pulses - Installation Heart Sounds Four sounds are normally produced by the heart, but only two, the first and second heart sounds, are audible through a stethoscope. First Heart Sound - occurs when the atrioventricular (AV) valves close at the beginning of ventricular contraction. - generated by the vibration of the blood and the ventricular wall - is louder, longer, more resonant than second heart sound. Mitral valve closes slightly before tricuspid valve Second Heart Sound occurs when aortic and pulmonary semilunar valves close at the beginning of ventricular dilation generated by the vibration of the blood and the aorta Aortic valve closes slightly before pulmonary valve. Abnormal Heart Sounds (murmurs) - often heard in valvular disease Insufficiency -- Valve(s) can not close completely, causing backflow. Stenosis -- Valves can open only partially (narrowed opening), restricting forward blood flow. - Systolic murmurs: mitral stenosis or aortic insufficiency. - Diastolic murmurs: aortic stenosis or mitral insufficiency. MECHANICAL PROPERTIES OF THE HEART Heart Rate is the number of heart beat in 1 minute. Normal value: 60-100/min Stroke volume is the volume of blood pumped out by each ventricle with each contraction. Cardiac Output (CO) is the amount of blood pumped out by each ventricle in 1 minute. Cardiac output = stroke volume x heart rate Ejection Fraction = stroke volume/end-diastolic ventricular volume Preload is the degree of stretch of the ventricular muscle cells just before they contract. is determined by ventricular filling. within normal range, the greater a preload, the stronger the following contraction, i.e., the greater stroke volume. --- Frank-Starling Law. Afterload is the pressure that must be overcome for the ventricles to eject blood into aorta or pulmonary artery. is determined by arterial pressure. is greater to the left heart than the right heart. Contractility is the intrinsic strength of cardiac muscles. Factors on Cardiac Output 1) Preload: ( Preload ( ( cardiac output Frank-Starling law of the heart: ( venous return ( ( stroke volume (venous return ( (end diastolic volume ( (preload ( ( overlap of thick filaments and thin filaments ( (number of interacting cross-bridges ( ( force of contraction ( ( stroke volume 2) Afterload: ( afterload ( (cardiac output 3) Contractility: ( contractility ( ( cardiac output 4) Heart Rate: dual effects on cardiac output REGULATION OF THE HEART FUNCTION Regulation by Autonomic Nervous System Sympathetic Nervous System (SNS) innervates all components of the heart. release Norepinephrine (NE) stimulates (1-adrenergic receptors in cardiac cell membranes. increases heart rate (positive chronotropic) and contractility (positive inotropic) Parasympathetic Nervous System (PNS) innervates SA node and AV node. releases Acetylcholine (Ach). acts on m-cholinergic receptors. decreases heart rate (negative chronotropic). prolongs delay at AV node. has little effect on contractility. Control by Higher Centers - Medulla Oblongata Sympathetic: distinct accelerator and augmentor sites in medulla Parasympathetic: Nucleus vagus and nucleus ambiguus - Hypothalamus, Thalamus, Cerebral cortex Involved in the cardiac response to environmental temperature changes, exercise, or during excitement, anxiety, and other emotional states Control by reflexes Baroreceptor Reflex - Stimulated by increase in arterial pressure (sensitive to stretch) - Effect: negative chronotropic and inotropic - regulates the heart when arterial pressure increases or drops - sensitive to abrupt changes in arterial pressure -- short term regulator Chemoreceptor Reflex - Stimulated by decrease in blood oxygen, and pH, and increase in CO2 - Effects: 1) Hypoxemia has dual effects Direct effect: decreases heart rate Indirect effect: positive choronotropic and inotropic via hypercapnia 2) Hypercapnia and low pH has positive choronotropic and inotropic effects. Proprioceptor Reflex - Stimulated by muscle and joint movement - Effects: increase heart rate Regulation by Hormones Epinephrine released from adrenal gland increasing heart rate and contractility Thyroxin released from thyroid gland increasing heart rate Autoregulation Stroke volume is autoregulated by ventricular filling (Frank-Starling law). Other Factors Blood level of ionic calcium, sodium, and potassium Hypercalcemia (high plasma Ca++): positive inotropic Hypernatremia (high plasma Na+): negative chronotropic Hyperkalemia (high plasma K+): negative chronotropic, used in lethal injection Age, gender, exercise, and body temperature Blood Supply to Cardiac Muscles The blood in heart chambers can hardly nourish any cardiac muscles. Surprising! Most of myocytes get nutrients from coronary circulation. Coronary Circulation Coronary arteries (originated from aorta) bring blood to cardiac muscles. is rich in arterial anastomosis to secure blood supply to myocytes Venous blood is emptied into the right atrium through cardiac veins and coronary sinus. is regulated primarily by local metabolic products such as adenosine (Autoregulation). Blockade of coronary artery causes myocardial infarction, or heart attack. Coronary Atherosclerosis Typical lesion dull white and slightly elevated fibrous plaque (atheroma) on coronary arterial lumen. Histology of the plaque composed of lipid, smooth muscle, macrophages, and connective tissues. occur often at arterial branching points cause stenosis of coronary arteries occlude arterial lumen when combined with internal hemorrhage, thrombosis, and arterial spasm Risk Factors in the Development of Atherosclearosis include hyperlipidemia, hypercholesterolemia , abnormality of lipoproteins, hypertension, diabetes mellitus, family history, cigarette smoking, and elevated blood homocysteine CARDIOVASCULAR SYSTEM III - BLOOD VESSELS Route of Blood Flow 1) typical route: Heart ( Arteries ( Capillaries ( Veins ( Heart 2) special route: Anastomoses - arterial anastomoses-collateral channels - arteriovenous anastomoses, example: metarterioles - venous anastomoses: Postal system: Consists of two capillary beds, found in intestine-liver, hypothalamus-pituitary, and kidneys. Pulmonary Circulation Right ventricle pumps deoxygenated blood to the lungs via the two pulmonary arteries. [Note: All other arteries in the body carry oxygenated blood.] Oxygenated blood from the lungs returns to the left atrium via four pulmonary veins. [Note: All other veins in the body carry deoxygenated blood.] Systemic Circulation Left ventricle pumps oxygenated blood to the rest of the body. This blood leaves the heart via the aorta. Deoxygenated blood returns from the body tissues via the superior vena cava and the inferior vena cava Comparison of the two circuits Amount of blood pumped into both pulmonary and systemic circulation by right and left ventricles is the same but the work of the left ventricle is greater because left ventricle has to overcome greater resistance. This is reflected in the thicker myocardium of the left ventricle. Pulmonary circuit is shorter with low pressure. Systemic circuit is longer, faces 5 times the resistance. General Structure of Blood Vessel Walls 1.Tunica Intima - inner layer; surrounds lumen of vessel -endothelium - simple squamous; continuous with endocardium; slick surface -loose connective tissue sub-endothelial layer 2.Tunica Media - middle layer -circularly arranged SMOOTH MUSCLE cells - SYMPATHETIC NS innervation allows VASOCONSTRICTION and VASODILATION -sheets of ELASTIN 3.Tunica Adventitia - outermost layer -loosely woven collagen fibers -may have its own blood supply from VASA VASORUM ARTERIES carry blood away from the heart; carry oxygenated blood in the systemic system; carry deoxygenated blood in the pulmonary system branch and descend like trees, diameter decreases as descending vary in structure at different portions in arterial trees classified into 3 major portions from proximal to distal, i.e., elastic arteries, muscular arteries, and arterioles. 1.Elastic (conducting) Arteries - largest diameter arteries, i.e., aorta and its branches - most elastin in tunica media - help maintain continuous blood as ventricle relaxes - lessened elasticity occurs with old age and arteriosclerosis 2. Muscular (distributing) Arteries - lumen diameter 1cm to 0.3mm; distal to elastic arteries; serve specific body organs - have more smooth muscle and less elastic fiber, thickest tunica media active in vasoconstriction highly innervated by autonomic nervous system 3. Arterioles (resistance arteries) - lumen diameter 0.3mm to 10um; smallest arteries - eventually lead to capillary beds tunica media gets progressively thinner, down to single layer of smooth muscle cells constrict slightly at resting state --- vascular tone relaxation or contraction determines blood flow through capillary bed highly innervated by autonomic nervous system CAPILLARIES interweaving network of blood vessels between arterioles and venules leaky to water, O2, CO2, and small solutes in all capillaries, leaky to larger molecules from proteins to blood cells in specific regions like liver, bone marrow, and lymphoid organs Capillary walls consist of tunica intima only VEINS - continuous with capillaries, collect blood from capillaries, and deliver it to the heart - have thinner walls and larger lumens than arteries - tunica media is thin - tunica adventitia is thickest layer; in vena cava contains longitudinal smooth muscle - act as blood reservoirs - contain ~60% of bodys blood, thus, called capacitance vessels lower blood pressure travel in parallel with arteries to each organ or tissue; in limbs, veins are located more superficially while arteries are more deeply, which is good for protecting arteries. Venules - smaller than veins, lumen diameter 8-100um; collect blood from capillaries -tunica media and tunica adventitia are sparse; absent in postcapillary venules, which are porous Venous Valves - prevent backflow of blood - similar to semilunar valves of heart - esp. in veins of limbs - formed from folds of tunica intima - incompetent venous valves cause varicose veins & hemorrhoids Distribution of blood Pulmonary circulation: ~18%, Heart: ~12%, System circulation: ~70% (in which, 11% in arteries, 5% in capillaries, and 54% in veins) PRESSURE THAT DRIVES BLOOD FLOW General Concepts Blood Pressure: pressure inside a blood vessel Blood flows from high pressure to low pressure (aorta to vena cava) Aorta ( arteries ( arteriole ( capillaries ( venules ( veins ( vena cava (100) (100-80) (80-40) (40-20) (20-10) (10-0) (0) mmHg Arterial blood pressure has to be maintained within certain range 60-140 mmHg Arterial blood pressure fluctuates (pulsatile) during cardiac cycle; the peak value is called systolic pressure, and the lowest value is called diastolic pressure Systolic pressure (Ps) Occurs during ventricular ejection Normal range: 90-140 mmHg Diastolic pressure (Pd) Occurs right before aortic valve opens Normal range: 60-90 mmHg Pulse pressure Difference between systolic and diastolic pressures Pulse decreases with distance from heart - eliminated completely in arterioles Mean arterial pressure (Pa) The mean arterial pressure is the pressure in the arteries, averaged over time. Mean Arterial Pressure = diastolic pressure + 1/3 pulse pressure - Indirect measurement of arterial pressures using sphygmomanometer BLOOD FLOW Definition: volume of blood moving through a structure in a given time (ml/min) Law: Blood Flow = difference in blood pressure /peripheral resistance Peripheral Resistance opposition to blood flow due to friction determined by: blood viscosity (thickness), stable blood vessel length, stable blood vessel diameter under physiological control Poiseuiles law (( ( r4 F: blood flow F = --------- ((: pressure difference 8(L r4: fourth power of the vessel radius (: blood viscosity L: vessel length Total Body Blood Flow Equal to cardiac output (CO) affected by: stroke volume heart rate total peripheral resistance Arterial Blood Flow fast velocity (small total cross-section area) primarily regulated by diameters of small arteries and arterioles rich in smooth muscles in vascular walls strictly controlled by nervous, hormonal, and auto regulation mechanisms determines the total peripheral resistance and blood flow to each individual organ. Capillary Blood Flow Called microcirculation Slow velocity (large cross-section area) regulated by constriction/dilation of arterioles and precapillary sphincters exchange of nutrients, wastes, and gases across capillary wall; it is at nowhere but capillaries, that the blood load and unload its cargo. Vascular Shunt: consists of metarteriole and thoroughfare channel, and allows blood to bypass true capillaries Capillary Exchange: Permeability of Capillary Wall: Permeable to: O2, CO2, ions, H2O, glucose, amino acids, fatty acids, vitamins, and hormones Impermeable to: most proteins and blood cells Three routes Through intercellular cleft Through endothelial cells Through fenestration Three mechanisms Simple diffusion: determined by concentration gradient of individual chemicals across capillary wall and permeability of capillary walls to each individual substance Ficks law J = -PS(Co Ci) Where J = quantity of a substance moved per unit time (t), P = capillary permeability of the substance, S = capillary surface area, Ci = concentration of the substance inside the capillary, Co = concentration of the substance outside the capillary Filtration and reabsorption Filtration refers to net fluid movement from plasma to tissue (out) Reabsorption refers to net fluid movement from tissue back to plasma (in) Filtration/reabsorption is determined by the difference between hydrostatic pressure and colloid osmotic pressure in plasma and tissue fluid Net filtration occurs at arterial end of capillaries. Net reabsorption occurs at venous end of capillaries. Colloid osmotic (oncotic) pressure is generated by large molecules like proteins that are impermeable to capillary wall. Starling hypothesis Qf = k [(Pc + (i) (Pi + (p)] Where Qf = fluid movement via filtration k = filtration constant Pc = capillary hydrostatic pressure (i = interstitial fluid colloid osmotic pressure Pi = interstitial fluid hydrostatic pressure (p = plasma colloid osmotic pressure Transcytosis Large molecules such as peptide hormones and other proteins, have to be transported across endothelial cells via endocytosis/exocytosis. Venous Blood Flow Slow velocity Venous valves prevent backflow of venous blood Assistance from respiration and skeletal muscle contraction MAINTAINING BLOOD PRESSURE - Mean arterial blood pressure (MAP) has to be maintained in a normal range to secure blood supply to the two most important (central) organs, brain and heart. - If MAP drops, the heart increases cardiac output by enhancing contractility and heart rate while arteries in peripheral organs constrict to elevate blood pressure by increasing peripheral resistance. The body will save brain and heart by sacrificing other relatively less vital organs. - As long as MAP is maintained normal, blood supply to each individual organ is regulated according to its demand, i.e., metabolic activity. Vasoconstriction: reduction of blood vessel diameter Vasodilatation: increase in blood vessel diameter Target cells under neural, hormonal, and auto regulation: The heart Smooth muscles in the wall of arteries and arterioles Precapillary sphincters Neural Control Sympathetic nervous system Innervate arteries and arterioles in almost all organs Release norepinephrine (NE) as neurotransmitter Cause contraction of smooth muscles in the walls of arteries and arterioles in most organs except heart and brain Parasympathetic nervous system Innervate some arteries and arterioles Release acetylcholine (Ach) as neurotransmitter Cause dilation of smooth muscles in the walls of arteries and arterioles Baroreceptor-Initiated Reflexes The reflexes sense variation of MAP, and try to bring MAP back to normal immediately Sensors: Baroreceptors are located in the wall of carotid sinus, aortic arch, and other large elastic arteries Sensitive to stretch send off inhibitory impulses to cardiovascular center Afferent nerves: autonomic nerves Neural Center Cardiovascular center located in the medulla Inhibited by impulses from baroreceptors Send inhibitory commands to effectors Efferent nerves: autonomic nerves Effectors Cardiac cells Smooth muscle cells in the wall of arteries and arterioles When MAP is high, Stretch of baroreceptors to a greater extend Decrease in heart rate and cardiac contractility, and peripheral vasodilatation Drop of MAP When MAP drops, Stretch of baroreceptors to a lesser extend Increase in heart rate and cardiac contractility, and peripheral vasoconstriction Elevation of MAP Chemoreceptor-Initiated Reflexes The reflexes sense variation of oxygen and carbon dioxide content and pH of the blood, and try to bring them back to normal immediately. The reflexes serve the primary purpose of regulating respiration, with side effects on blood vessels. Sensors: Chemoreceptors are found in carotid and aortic bodies close by baroreceptors in the carotid sinus and aortic arch Sensitive to oxygen and carbon dioxide content, and pH of the blood O2(, CO2(, and pH( ( reflexes ( vasoconstriction O2(, CO2(, and pH( ( reflexes ( vasodilatation Hormonal Control of Blood Vessels Epinephrine and Norepinephrine Secreted from adrenal gland cause peripheral vasoconstriction (Note: epinephrine can cause vasodilation in a few organs at low dose) Angiotensin II Converted from blood borne angiotensinogen under the regulation of renin which is produced in kidney Cause peripheral vasoconstriction Vasopressin = antidiuretic hormone (ADH) released from posterior pituitary cause vasoconstriction Atrial Natriuretic peptide Released from atria Cause vasodilation Local Control of Blood Flow Autoregulation -Autoregulation is the automatic adjustment of blood flow to each tissue in proportion to its requirements at any point in time. -Changes in blood flow through individual organs is controlled intrinsically by modifying the diameter of local arterioles feeding the capillaries. METABOLIC (chemical) CONTROLS Declining levels of oxygen, accumulation of metabolic waste products (CO2), low pH, and inflammatory chemicals cause increased blood flow by a. vasodilation of arterioles b. relaxation of precapillary sphincters - MYOGENIC (physical) CONTROLS smooth muscles in the walls of arterioles respond to STRETCH due to changes in blood pressure and blood low to prevent large fluctuations in local blood flow. a. increased stretch from increased pressure causes vasoconstriction b. decreased stretch from decreased pressure causes vasodilation c. overall result is constant perfusion SPECIAL CIRCULATION CEREBARAL CIRCULATION - Two sources of arterial blood flow to the brain Internal carotid arteries Vertebral arteries - Vein: Jugular vein - Receive the highest priority for blood supply (750 ml/min) - Susceptibility to ischemia A few seconds loss of consciousness A few minutes irreversible injury - Regulation of cerebral blood flow - Constant when mean arterial pressure varies between 60 and 160 mmHg - primary regulation by local factors proportional to local neuronal activities Role of CO2, pH, adenosine, and K+ - Less regulation by sympathetic nerve activity or vasoactive agents PULMONARY CIRCULATION Two vascular beds Pulmonary vasculature and bronchial vasculature Pulmonary vasculature Include pulmonary arteries, capillaries, and pulmonary veins Function: gas exchange Low resistance and low pressure system (10-25 mmHg) Larger total surface: 50-70 m2 (500-700 sf) Affected by gravity Bronchial vasculature The bronchial arteries are branches of the thoracic aorta. Function: provide nutrients to tracheo-bronchial tree down to the terminal bronchioles. Regulation of Pulmonary Vasculature Regulated by the autonomic nervous system Hypoxia has the most important influence on pulmonary vasomotor tone. - Hypoxia vasoconstriction (opposite to its effect on systemic circulation) - Help maintain an optimal ventilation-perfusion ratio CUTANEOUS CIRCULATION Cutaneous vasculature is rich in arteriovenous anatonoses. Properties of cutaneous arteriovenous anastomoses Found in the finger tips, palms of the hands, toes, soles of the feet, ears, nose, and lips Principally controlled by sympathetic system Respond to temperature changes Skin vessels under emotional control Head, neck, shoulders, and upper chest Blush with embarrass or anger Blanch with fear or anxiety SKELETAL MUSCLE CIRCULATION Low flow at rest due to asynchronous contraction of precapillary sphinctors Regulation by sympathetic nervous system and local factors Local factors dominate during exercise Local factors include: hypoxia, adenosine, lactic acid, H+, CO2 , and K+. Blood flow can increase more than 20-fold during exercise. EXERCISE The central command (anticipation of exercise) originates in the motor cortex or from reflexes initiated in muscle proprioceptors when exercise is anticipated. initiates the following changes: sympathetic outflow to the heart and blood vessels is increased. As a result, heart rate and contractility (stroke volume) are increased, and unstressed volume (venous blood) is decreased. Cardiac output is increased, primarily as a result of the increased heart rate and, to a lesser extent, the increased stroke volume. Venous return is increased as a result of muscular activity. Increased venous return provides more blood for each stroke volume. Arteriolar resistance in the skin, splanchnic, regions, kidneys, and inactive muscles is increased. Accordingly, blood flow to these organs is decreased. Control by local metabolites Vasodilator metabolites (lactate, K+, and adenosine) accumulate. These metabolites cause arteriolar dilation in the active skeletal muscle (active hyperemia) The number of perfused capillaries is increased. This vasodilation accounts for the overall decrease in total peripheral resistance that occurs with exercise. LYMPHATIC SYSTEM The lymphatic system consists of lymphatic vessels, several lymphoid tissues and lymphoid organs. They are involved in host defense and reabsorption of large molecules in interstitium. LYMPHATIC VESSELS The lymphatic system is not a circuit but rather a system of vessels with unidirectional flow that carries lymph fluid to the heart. Travel along with blood vessels. There is no pump. Lymph is moved primarily by rhythmic contractions of the lymphatic vessels themselves, but is also aided by skeletal and respiratory pumps. Valves are present in the larger vessels to prevent backflow. A. Lymph capillaries - 1.overlap with blood capillaries - blind ended vessels - extremely permeable due to a. loose fitting, overlapping endothelial cells b. fine filament anchors 2.main function is to collect excess tissue fluid 3. Once tissue fluid has entered lymphatic vessels, it is called lymph. It is usually clear, colorless and identical to tissue (interstitial) fluid. It is similar to blood plasma but without some of the formed elements and larger proteins. 4.LYMPHEDEMA - swelling in tissues due to blockage of lymph drainage (tumor pressure or surgery) 5.Elephantiasis - edema due to blockage of lymph drainage by parasitic worms B. Lacteals 1.special lymph capillaries located in the intestinal villi 2.collect digested fats( in chylomicrons) from the small intestine C. Larger lymph vessels 1.in increasing size - -lymphatic collecting vessels -lymphatic trunks -ducts - empty lymph into venous circulation(at junction of internal jugular and subclavian veins) a.Right Lymphatic Duct - drains lymph from the right upper arm and the right side of the head and thorax b.Thoracic Duct - drains lymph from the rest of the body 2.walls have three layers- similar to veins but thinner 3.vasa vasorum in outer tunica adventitia -lymphangitis - inflammation of lymph vessels; visible as red lines under skin due to congestion of blood in vasa vasorum 4.valves are present D. Role of Lymph Vessels in Metastasis LYMPHOID TISSUE loose reticular connective tissue; houses MACROPHAGES and LYMPHOCYTES diffuse -- located throughout body in all organs follicles (nodules) - more discrete shape, spherical; contain germinal centers with dense population of B lymphocytes LYMPHOID ORGANS(fig. 21.4, page 698) Lymph Nodes lie along lymph vessels Phagocytic macrophages remove microorganisms and debris as lymph flows through. activate immune system - lymphocytes mount attack against antigens lymph nodes become swollen when B cells in germinal centers are rapidly dividing to produce plasma cells that make antibodies Spleen located underneath diaphragm in the upper left abdominal cavity site for lymphocyte proliferation and immune surveillance and response extracts aged and defective blood cells and platelets from the blood removes debris, foreign matter, toxins, bacteria, viruses from blood flowing through its sinuses stores and releases breakdown products of red blood cells e.g. iron erythrocyte production in the fetus stores blood platelets readily subject to rupture from mechanical trauma, therefore, often removed Thymus a bilobed organ located in the superior mediastinum houses T lymphocytes ONLY, i.e. no B cells, therefore no antibody producing cells size varies with age - peaks in childhood, atrophies from adolescence to old age site of maturation of T lymphocytes (T stands for thymus) thymocytes secrete thymosins (hormones) that stimulate lymphocytes to become immunologically competent Tonsils ring entrance to the pharynx have CRYPTS that trap bacteria which can then be destroyed The Respiratory System STRUCTURE OF THE RESPIRATORY SYSTEMPRIVATE  consists of nose, pharynx, larynx, trachea, and bronchi and the lungs. The respiratory tract serves for airflow, no gas exchange includes nose, pharynx, larynx, trachea, and bronchi and bronchial tree in the lungs the upper respiratory tract -- from the nose through the pharynx the lower respiratory tract -- from the larynx through the lungs Gas exchange occurs in alveoli in the lungs THE RESPIRATORY TRACT Nose warms, cleanses, and humidifies inhaled air detects odors serves as a resonating chamber to modify the voice Pharynx Larynx epiglottis a flap of tissue at the superior opening of the larynx during swallowing, the extrinsic muscles of the larynx pull it upward toward the glottis, and the epiglottis directs food and drink into the esophagus. vocal cords folds on the interior wall of the larynx The superior pair is the vestibular folds, or false vocal cords. The inferior pair is the true vocal cords. The intrinsic muscles control the vocal cords As air passes through the cords, high-pitched sound occurs when the cords are pulled taut, and lower-pitched sounds occur when the cords are more relaxed. Loudness is determined by the force of air through the cords. Trachea a rigid tube, 12 cm in length, with C-shaped cartilage rings to keep it from collapsing during inhalation. The larynx and trachea are lined with pseudostratified epithelium, which provides a mucociliary escalator for removal of debris trapped in the mucus. THE LUNGS consists of the left and the right lungs The left lung is divided into two lobes; the right into three. Each lung is a conical organ, with its broad, concave base resting on the diaphragm receives the bronchus, blood and lymphatic vessels, and nerves through its hilum. The bronchi extend into alveoli The Bronchial Tree a system of highly branched air tubes primary bronchi enter each lung from the trachea. divides into secondary bronchi secondary (lobar) bronchi enter each lobe of the lung divides into tertiary bronchi tertiary bronchi supply a bronchopulmonary segment divides into bronchioles bronchioles the first air tubes to lack cartilage but with smooth muscle in their walls. The portion ventilated by each bronchiole is a primary lobule. divides into 50-80 terminal bronchioles. Each terminal bronchiole gives off smaller respiratory bronchioles that divide into alveolar ducts ending in alveolar sacs. Alveoli bud off respiratory bronchioles, and alveolar ducts and sacs. Alveoli 1 an immense surface area (70 square meters) for gas exchange. 2 onsists mostly of squamous (type I) alveolar cells that are thin to allow for rapid gas diffusion through them. Around 5% are great (type II) alveolar cells that secrete pulmonary surfactant. 3 lso present within the lumens of the alveoli are alveolar macrophages (dust cells) that are the last line of defense against inhaled matter. 4 Each alveolus is surrounded with a basket of capillaries. 5 respiratory membrane is made up of: the wall of the alveolus the endothelial wall of the capillary their fused basement membranes 6 contain elastic fibers which helps expiration Pulmonary circulation has a very low blood pressure to prevent the alveoli from filling with fluid. The osmotic uptake of water overrides filtration and keeps alveoli dry. Air-blood gas exchange occurs in alveoli. MECHANICS OF VENTILATION Terms: inspiration or inhalation: breathing in expiration or exhalation: breathing out Driving Force for Air Flow Airflow in and out of the lungs is driven by the pressure difference between atmosphere (barometric pressure) and inside the lungs (intrapulmonary pressure). Boyles law: Volume x Pressure = Constant; (Volume ( (Pressure; or (Volume ((Pressure Air moves into the lungs because the volume of the lungs is increased, thus dropping intrapulmonary pressure. During exhalation, the volume of the lungs decreases, resulting in a lower intrapulmonary pressure than the atmospheric pressure. So, air leaves the lungs. The Lungs can NOT expand by themselves. Instead, the lungs move passively along the thoracic cage as the results of respiratory muscle contraction and relaxation. Respiratory Muscles The Diaphragm the principal muscle of inspiration A thin dome-shaped sheet of muscle that is inserted into the lower ribs Contraction increases the vertical, anteroposterior, and lateral dimensions of the thoracic cage. External Intercostal Muscles Inspiration muscles Extend downward and forward from the lower surface of the rib above to the upper surface of the rib below. Contraction raises the ribs and increases the anteroposterior and transverse dimensions of the chest. The Abdominal Muscles Expiration muscles Contraction pushes diaphragm up, reducing the vertical dimension of the thoracic cage. Coupling Between Lungs and Thoracic Cage The lungs and thoracic cage are coupled by the pleurae and a negative pressure inside pleural cavity visceral pleura covers the surface of each lung; parietal pleura lines the chest cavity. Between the two is the closed potential space of the pleural cavity containing pleural fluid. The pleural fluid serves to reduce friction during chest expansion Inspiration The diaphragm and the external intercostal muscles contract, causing expansion of the chest cavity. The lungs are carried along due to intrapleural pressure, and expand. Intrapulmonary pressure decreases because volume increases; air flows in. Expiration Resting expiration is a passive process, due to relaxation of the diaphragm and external intercostal muscles. The elastic fibers in the lungs cause the shrinkage of the longs to their original size. Forced expiration requires contraction of abdominal muscles and other accessory respiratory muscles Intrapulmonary pressure increases because volume of the lungs is smaller; air flows out. Resistance to Airflow Alveolar Surface Tension tends to cause a collapse of the alveoli generated by a thin film over the surface of alveolar epithelium reduced by surfactant, which is secreted by type II alveolar epithelial cells Premature infants often have a deficiency of pulmonary surfactant and experience great difficulty breathing. Elastic Resistance Met during inspiration due to elastic fibers in the lungs and chest wall resist Airway Resistance Due to friction, affected by airway caliber, seen in asthma (spasm of smooth muscles in the wall of bronchioles) Compliance Reciprocal of resistance An indicator of ease with which the lungs expand Alveolar Ventilation 1. Not all the air that enters the lungs reaches the alveoli to be available for gas exchange. Dead air is air in the lungs that cannot exchange gases with blood, and in the conducting respiratory tract (from nose to bronchiole) is called anatomic dead space. Physiologic (total) dead space is the sum of anatomic dead space and any pathological dead space that may exist. In healthy people, the anatomic and physiologic dead spaces are identical. Alveolar ventilation rate gives the most directly relevant measure of the body's ability to get oxygen to the tissues. Measurements of Ventilation 1. A spirometer is used to measure expired breath. Four spirometric measures are called respiratory volumes: tidal volume: volume of air in each resting inhalation or exhalation inspiratory reserve volume: the extra volume of air beyond tidal volume inhaled in each maximum inhalation expiratory reserve volume: the extra volume of air beyond tidal volume exhaled in each maximum exhalation residual volume: The amount of air trapped in the lungs even after maximum exhalation. Others, called respiratory capacities, are calculated by adding two or more of the respiratory volumes. Vital Capacity = tidal volume + inspiratory reserve volume+ expiratory reserve volume 3. Restrictive disorders, such as pulmonary fibrosis, reduce compliance and vital capacity. Obstructive disorders do not reduce respiratory volumes but reduce the speed of airflow. NEURAL CONTROL OF VENTILATION A. Control Centers in the Medulla Oblongata 1. Breathing relies on repetitive stimulation from the brain. 2. The medulla oblongata contains inspiratory (I) neurons, which fire during inhalation, and expiratory (E) neurons, which fire during forced expiration. 3. The medulla has two respiratory nuclei. a. The inspiratory center (dorsal respiratory group, or DRG) is composed of I neurons that stimulate the muscles of inspiration. The other medullary nucleus is called the expiratory center, or ventral respiratory group (VRG). Its I neurons inhibit the inspiratory center when deeper expiration is needed. B. Control Centers in the Pons 1. The pons regulates ventilation by means of a pneumotaxic center in the upper pons and an apneustic center in the lower pons. a. The pneumotaxic center sends a continual stream of impulses to the inspiratory center of the medulla. When impulse frequency increases, breathing becomes shallower and faster. Conversely, if frequency declines, breathing is slower and deeper. b. The role of the apneustic center is still hypothetical. C. Afferent Connections to the Brainstem Nuclei 1. The brainstem respiratory centers receive input from the limbic system, hypothalamus, Chemoreceptors, and the lungs themselves. 2. Emotional state, especially anxiety, alters respiratory rate and depth. 3. Chemoreception of oxygen, carbon dioxide, and pH levels result in adjustments to pulmonary ventilation. 4. The vagus nerves transmit sensory input about irritants in the airways, and the medulla returns signals that initiate bronchoconstriction or coughing. Excessive inflation triggers the inflation (Hering-Breuer) reflex that stops inspiration. Regulation via Chemoreceptor-initiated Reflexes The purpose of respiration is to maintain pH, oxygen, and carbon dioxide levels in the blood within homeostatic limits. Thus, the brainstem respiratory centers monitor these conditions in the blood by various means. 1. Peripheral chemoreceptors are the aortic and carotid bodies located in the aortic arch and in the carotid arteries. a. The aortic bodies send signals to the medulla by way of the vagus nerves. b. The carotid bodies send signals to the medulla by way of the glossopharyngeal nerves. The central chemoreceptors are close to the surface of the medulla oblongata, and primarily monitor the pH of the cerebrospinal fluid (CSF). (O2, (CO2, or (pH ( stimulate chemoreceptors ( reflex ( ( frequency and depth of respiration E. Voluntary Control 1. Voluntary control over pulmonary ventilation originates in the motor cortex of the frontal lobe of the cerebrum, which sends impulses down the corticospinal tracts to the respiratory neurons in the spinal cord, bypassing the brainstem respiratory centers. There are limits to voluntary control. Even when a person has held their breath until they pass out, a breaking point is finally reached where autonomic controls override volition, forcing breathing to resume. GAS EXCHANGE in the LUNGS Driving force for gas exchange Gas flows is directed by pressure gradient Air is a mixture of gases, each of which contributes a share of the total atmospheric pressure called its partial pressure. (p. 814, Table 22.3) The partial pressure of a gas determines the rate of its diffusion, and therefore strongly affects the rate of gas exchange between the blood and alveolar air. Oxygen partial pressure in alveolar air is higher than that in the blood; carbon dioxide partial pressure in the blood is higher than that in alveolar air. Penetration through Respiratory Membrane The respiratory membrane is made up of: the wall of the alveolus, the endothelial wall of the capillary, and their fused basement membranes. Very permeable to oxygen and carbon dioxide The Air-Water Interface Gases cross the interface along the partial pressure gradients The blood unloads carbon dioxide and load oxygen. Factors That Affect the Efficiency of Alveolar Gas Exchange concentration gradients of the gases: effect high altitude and hyperbaric oxygen chamber. solubility of the gases: CO2 has a higher solubility than O2. membrane thickness: effect of pneumonia and emphysema membrane area: effect of pneumonia and emphysema ventilation-perfusion coupling - Average ventilation-perfusion ratio = 0.8 - Autoregulation of Ventilation-perfusion Coupling An increase in PCO2 causes: 1)Vasoconstriction of pulmonary arterioles 2) 2)Dilation of brochioles GAS TRANSPORT Oxygen O2 from alveolar air gets dissolved in the blood, then binds to hemoglobin. 98.5% of total O2 in the blood are carried by hemoglobin. The rest is physically dissolved in plasma. One hemoglobin molecule can carry up to four O2. Association of O2 to hemoglobin is affected by partial pressures of O2 and CO2, pH, and metabolic intermediates such as DPG (2,3-diphosphoglycerate) High O2, low CO2 ( lung ) ( increased association ( loading O2 High CO2, low O2( tissue ), low pH, DPG ( decreased association ( unloading O2 The poisonous effect of carbon monoxide stems from its competition for the same binding site as oxygen. Carbon Dioxide Carbon dioxide is transported in three forms: carbonic acid in the plasma carbaminohemoglobin dissolved in the blood as a gas GAS EXCHANGE in the TISSUES 1. Carbon Dioxide Loading a. As a result of metabolic activity, the partial pressure of carbon dioxide is relatively high in the tissues. Thus, carbon dioxide diffuses into the blood and is carried in the three forms noted. In an exchange called the chloride shift, most of the bicarbonate diffuses out of the RBCs in exchange for chloride ions diffusing in. Most of the hydrogen ions bind to hemoglobin or oxyhemoglobin, which thus buffers the intracellular pH. 2. Oxygen Unloading a. When oxyhemoglobin unloads its oxygen, it is called deoxyhemoglobin. When oxyhemoglobin in the blood reaches an area in the tissues with a much lower partial pressure of oxygen (in metabolically active tissues), the oxyhemoglobin unloads its oxygen, which then diffuses into the tissues. Blood Oxygen Content -average 20 ml/dL -determined by: 1)saturation of hemoglobin - Hypoventilation - CO poisoning 2) content of hemoglobin - Anemia Utilization Coefficient -The amount of oxygen uptake by tissue versus the arterial blood oxygen content Hypoxemia A state of low blood PO2 Common causes of Hypoxemia include: 1) Hypoventilation caused by respiratory diseases 2) an insufficient number of normal red blood cells or hemoglobin content Oxygen Toxicity - developed when pure O2 is inhaled at >2.5 atm - Excessive oxygen generates hydrogen peroxide and free radicals, which destroy enzymes and damage nervous tissue. - Oxidative toxicity is one of the factors for aging. Hypercapnia - A state of high blood PCO2 ( > 43 mmHg ) - caused by hypoventilation (respiratory diseases) Hypocapnia - A state of low blood PCO2 ( < 37 mmHg ) - caused by hyperventilation The Urinary System PRIVATE  GENERAL CONCEPTS Composition of the urinary System The urinary system consists of two kidneys, two ureters, the urinary bladder, and the urethra. Functions of the Urinary System homeostatic regulation of the volume and composition of the body fluids. All of the following processes contribute to this basic purpose. filter blood plasma, separate wastes, return useful materials to the blood, and eliminate the wastes. regulate blood volume and osmolarity. produce hormones 1. Renin, a hormone that activates mechanisms that control blood pressure and electrolyte balance. 2. Erythropoietin, which controls RBC production. 3. Calcitrol, which controls calcium homeostasis regulate acid-base balance of the body fluids. detoxify superoxides, free radicals, and drugs. deaminate amino acids in times of starvation for use in energy (gluconeogenesis) pathways. Nitrogenous Wastes 1. A metabolic waste is a waste produced by metabolic reactions within cells. Two of the most toxic metabolic wastes are carbon dioxide and nitrogenous wastes including urea, uric acid, and creatinine. The accumulation of toxic nitrogenous wastes in the blood, as a consequence of renal failure, can cause diarrhea, vomiting, and cardiac arrhythmia. These symptoms are followed, within a few days, by convulsions, coma, and death. Treatments include hemodialysis or kidney transplant. Excretion Excretion is the process of separating wastes from the body fluids and eliminating them. Osmolarity 1. Since much of renal physiology depends on the process of osmosis, it is important to understand the concept of osmotic concentration. Osmotic concentration (osmolarity) is determined by the number of dissolved solute particles. Normal osmotic concentration of body fluid is 280-300 mOsm/L. A solution of 280-300 mOsm/L is isotonic. A solution of >300 mOsm/L is hypertonic. A solution < 280 mOsm/L is hypotonic. When separated by a semi-permeable membrane, water moves from low osmotic concentration to high osmotic concentration. Depending on blood volume and osmolarity, the kidneys can produce isotonic, hypertonic, or hypotonic urine. Hypertonic urine is produced to eliminate wastes without undue water loss. ANATOMY OF THE KIDNEY A. Gross Anatomy The kidneys lie along the posterior abdominal wall, the right kidney lying slightly lower than the left. The lateral surface of the kidney is convex, while the medial surface is concave with a hilum carrying renal nerves and blood vessels. The kidney is protected by three layers of connective tissue. The outer renal fascia binds the kidney to the abdominal wall. The adipose capsule, a layer of fat that cushions the kidney, lies beneath the renal fascia. The innermost layer, the renal capsule, is a fibrous sac that is anchored at the hilum and encloses the rest of the kidney, protecting from trauma and infection. 3. The renal parenchyma is divided into an outer cortex and inner medulla. The renal tissue is a C-shaped unit, opening into a renal sinus that holds blood and lymphatic vessels along with nerves and urine-collecting vessels. a. Extensions of the cortex (renal columns) project toward the sinus, dividing the medulla into 6-10 renal pyramids. Each pyramid is conical with a blunt point called the papilla facing the sinus. The papilla is nestled into a cup called a minor calyx, which collects its urine. Two or three minor calyces merge to form a major calyx. The major calyces merge to form the renal pelvis. B. The Nephron The kidney contains 1.2 million nephrons, the functional units of the kidney. A nephron consists of : i. blood vessels including afferent arteriole, glomerulus, efferent arteriole, peritubular capillary ii. renal tubules including proximal convoluted tubule, loop of Henle, distal convoluted tubule. Most components of the nephron are within the cortex. Nephrons closer to the medulla, called juxtamedullary nephrons, differ slightly in structure and function than cortical nephrons, located closer to the surface. 2. Renal Circulation The renal fraction of the cardiac output is 21%. Each kidney is supplied by a renal artery that give rise to a vascular tree composed of interlobar arteries, arcuate arteries, interlobular arteries, and afferent arterioles. Each afferent arteriole supplies blood to a single nephron. It ends in a rounded cluster of capillaries, called a glomerulus, where urine production begins. The glomerulus is drained by an efferent arteriole that leads to the peritubular capillaries surrounding the renal tubule. Blood flows from the peritubular capillaries into the interlobular veins, arcuate veins, interlobar veins, and the renal veins, which drain blood from the kidney and return it to the vena cava. The renal medulla is supplied by the vasa recta - long straight vessels that arise from the efferent arterioles of the juxtamedullary nephrons. 3. The Renal Corpuscle The renal corpuscle consists of a glomerulus enclosed in a two-layered glomerular (Bowman's) capsule. The visceral layer of the glomerular capsule has special cells, called podocytes, wrapped around the capillaries. 4. The Renal Tubule a. The renal tubule is a duct that leads away from the glomerular capsule and ends at the tip of a medullary pyramid. It consists of the proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting duct. b. The proximal convoluted tubule (PCT) is the longest and most coiled region of the renal tubule, and arises from the glomerular capsule. It has prominent microvilli that aid the absorption occurring here. c. The nephron loop (loop of Henle) is a U-shaped portion of the renal tubule. The descending limb passes into the medulla and forms an ascending limb that returns to the cortex. Juxtamedullary nephrons have long loops; cortical nephrons have shorter loops. d. The distal convoluted tubule (DCT) is shorter and less convoluted than the PCT and marks the end of the nephron. The DCTs of several nephrons merge to form a collecting duct that passes down into the medulla. Urine in the collecting duct will be passed to a papillary duct, then to a minor and major calyx, to the renal pelvis, and out the ureter. 5. The Juxtaglomerular Apparatus The juxtaglomerular apparatus is a structure located where the afferent and efferent arterioles meet, and enables autoregulation of blood filtration. URINE FORMATION The kidney produces urine by four processes: glomerular filtration, tubular reabsorption, tubular secretion, and concentration by collecting duct. Glomerular Filtration The Filtration Membrane 1. To get from the bloodstream to the capsular space, fluid passes through three barriers that make up the filtration membrane. a. The fenestrated epithelium of the capillary allows these cells to be more permeable than endothelial cells elsewhere. b. The basement membrane is a proteoglycan gel that excludes molecules larger than 8 nm. Some smaller molecules are also prevented from passing by a negative electrical charge on the proteoglycans. c. The arm-like podocytes of the glomerular capsule have little extensions called foot processes (pedicels) that, in turn, have negatively charged filtration slits, which are an additional obstacle to large anions. 2. Almost any molecule smaller than 3 nm can pass freely through the filtration membrane into the capsular space. This includes water, electrolytes, glucose, amino acids, nitrogenous wastes, and vitamins. 3. Kidney infections and trauma commonly damage the filtration membrane and allow albumin or blood cells to pass through. Filtration Pressure 1. Glomerular filtration follows the same principles that govern filtration in other capillaries, but there are significant differences in the magnitude of the forces involved. a. The blood pressure (BP) is higher here than elsewhere. This results from the fact that the afferent arteriole is substantially larger than the efferent arteriole. b. The hydrostatic pressure in the capsular space results from the high rate of filtration occurring here and the continual accumulation of fluid in the capsule. c. The colloid osmotic pressure (COP) of the blood is the same here as elsewhere. d. The glomerular filtrate is almost protein-free and has no significant COP. Glomerular Filtration Rate 1. Glomerular filtration rate (GFR) is the amount of filtrate formed per minute by the two kidneys combined. For the average adult male, GFR is about 125 mL of filtrate per minute. This amounts to a rate of 180 L/day. An average of 99% of the filtrate is reabsorbed, so that only 1-2 L of filtrate per day is excreted as urine. Regulation of Glomerular Filtration 1. GFR must be precisely controlled. a. If GFR is too high, urine output rises and creates a threat of dehydration and electrolyte depletion. b. If GFR is too low, fluid flows sluggishly through the tubules, and they reabsorb wastes that should be eliminated in the urine. c. The only way to adjust GFR from moment to moment is to change glomerular blood pressure. 2. Renal Autoregulation a. Renal autoregulation is the ability of the kidneys to maintain a relatively stable GFR in spite of changes in arterial blood pressure. b. The nephron has two ways to prevent drastic changes in GFR when blood pressure rises: it can constrict the afferent arteriole and reduce blood flow into the glomerulus, or it can dilate the efferent arteriole and allow the blood to flow out more easily. Conversely if blood pressure falls, the nephron can compensate by either dilating the afferent arteriole or constricting the efferent arteriole. c. The juxtaglomerular apparatus (JGA) that allows the nephron to compensate for pressure differences is made up of these cells: (1) juxtaglomerular (JG) cells that are enlarged smooth muscle cells of the afferent arteriole that can dilate or constrict and secrete renin in response to a drop in BP; (2) the macula densa, a patch of slender epithelial cells of the distal tubule that apparently monitor the salinity of the tubular fluid in the DCT; and (3) mesangial cells between the afferent and efferent arterioles, whose role is not yet understood. d. It must be noted that renal autoregulation does not completely prevent changes in glomerular blood pressure and the GFR during extreme blood pressure variations. In strenuous exercise or acute conditions (circulatory shock), the sympathetic nervous system and adrenal epinephrine stimulate the afferent arterioles to constrict. This reduces GFR and urine production, while it redirects blood from the kidneys to the heart, brain, or skeletal muscles. Tubular Reabsorption and Secretion About 99% of Water and other useful small molecules in the filtrate are normally reabsorbed back into plasma by renal tubules. A. The Proximal Convoluted Tubule The proximal convoluted tubule (PCT) is formed by one layer of epithelial cells which reabsorb about 65% of the glomerular filtrate and return it to the blood. To maximize reabsorption capacity, PCT cells have dense and long apical microvilli. 1. Routes of Proximal Tubular Reabsorption transcellular route and paracellular route 2. Mechanisms of Proximal Tubular Reabsorption Solvent drag by high colloid osmotic pressure (COP) in the peritubular capillaries Water is reabsorbed by osmosis and carries all other solutes along. Both routes are involved. For transcellular route, channels and transporters (carriers) in the plasma membranes help hydrophilic solutes cross the plasma membranes. Active transport of sodium. Sodium pumps (Na-K ATPase) in basolateral membranes transport sodium out of the cells against its concentration gradient using the energy of ATP. As the result, intracellular Na+ is lower than extracellular Na+ concentration. This Na+ transmembrane concentration gradient drives the reabsorption of not only sodium but also many other solutes including glucose, amino acids, and other nutrients. There are also pumps for ions other than Na+. Secondary active transport of glucose, amino acids, and other nutrients. There are various cotransporters (in the apical plasma membrane) that can carry both Na+ and other solutes. For example, the sodium-dependent glucose transporter (SDGT) can carry both Na+ and glucose. Transport of solutes via this mechanism is driven by the Na+ transmembrane concentration gradient which is established by Na+-K+-ATPase. Amino acids and many other nutrients are reabsorbed by their specific cotransporters with sodium. Secondary water reabsorption via osmosis Sodium reabsorption makes both intracellular and extracellular fluid hypertonic to the tubular fluid. Water follows sodium into the peritubular capillaries. Secondary ion reabsorption via electrostatic attraction Negative ions tend to follow the positive sodium ions by electrostatic attraction. Endocytosis of large solutes The glomerulus filters a small amount of protein from the blood. The PCT reclaims it by endocytosis, hydrolzes it to amino acids, and releases these to the ECF by facilitated diffusion. 3. The Transport Maximum There is a limit to the amount of solute that the renal tubule can reabsorb because there are limited numbers of transport proteins in the plasma membranes. If all the transporters are occupied as solute molecules pass through, some solute will remain in the tubular fluid and appear in the urine. 4. Tubular Secretion Tubular secretion is a process in which the renal tubule extracts chemicals from the capillary blood and secretes them into the tubular fluid. Tubular secretion serves the purposes of waste removal and acid-base balance. The secretion of hydrogen and bicarbonate ions serves to regulate pH. B. The Nephron Loop The primary purpose of the nephron loop is to establish a high extracellular osmotic concentration. The thick segment (ascending limb) of the loop reabsorbs solutes but is impermeable to water. Thus, the tubular fluid becomes very diluted while extracellular fluid becomes very concentrated with solutes. The high osmolarity enables the collecting duct to concentrate the urine later. C. The Distal Convoluted Tubule 1. Fluid arriving in the DCT still contains about 20% of the water and 10% of the salts of the glomerular filtrate. A distinguishing feature of these parts of the renal tubule is that they are subject to hormonal control. 2. Aldosterone a. Aldosterone secretion from adrenal gland is stimulated by a drop in blood sodium or rise in potassium concentration. b. The general effect of aldosterone is to cause the DCT and cortical portion of the collecting duct to reabsorb more sodium and to secrete more potassium. Thus the urine volume is reduced. Salt and water reabsorption helps to maintain blood volume and pressure. 3. Atrial Natriuretic Factor Atrial natriuretic factor (ANF) is secreted by the atrial myocardium of the heart in response to high blood pressure. It inhibits sodium and water reabsorption, increasing the output of both in the urine, and thus reducing blood volume and pressure. Concentrating the Urine by Collecting Duct A. The Collecting Duct 1. The collecting duct (CD) begins in the cortex, where it receives tubular fluid from numerous nephrons. CD primarily functions to reabsorb water and concentrate urine. 2. Two facts enable the collecting duct to concentrate urine. a. The osmolarity of extracellular fluid increases from 300 mOsm/L at inner cortex to 1,200 mOsm/L at inner medulla. The major solutes in medullary extracellular fluid are NaCl and urea. The high extracellular osmolarity is the driving force for water reabsorption by collecting duct. b. The medullary portion of the CD is permeable to water but not to NaCl. Therefore, as urine passes down the CD through the increasingly salty medulla, water leaves the tubule by osmosis. B. Control of Concentration 1. The degree of concentrating urine depends on the body's state of hydration. a. In a state of full hydration, antidiuretic hormone (ADH) is not secreted and the CD permeability to water is low, leaving the water to be excreted. b. In a state of dehydration, ADH is secreted; the CD permeability to water increases. With the increased reabsorption of water by osmosis, the urine becomes more concentrated. Urine and Renal Function Tests A. Composition and Properties of Urine 1. Fresh urine is clear, containing no blood cells and little proteins. If cloudy, it could indicate the presence of bacteria, semen, blood, or menstrual fluid. Normal chemical composition of urine is compared to that of blood plasma in the following table. SubstanceBlood Plasma (total amount)Urine (amount per day)Urea4.8 g25 gUric acid0.15 g0.8 gCreatinine0.03 g1.6 gPotassium0.5 g2.0 gChloride10.7 g6.3 gSodium9.7 g4.6 gProtein200 g0.1 gBicarbonate4.6 g0 gGlucose3 g0 g B. Urine Volume 1. An average adult produces 1-2 L of urine per day. a. Excessive urine output is called polyuria. b. Scanty urine output is oliguria. An output of less than 400 mL/day is insufficient and can lead to azotemia. 2. Diabetes a. Diabetes is chronic polyuria resulting from various metabolic disorders. In most cases, the polyuria results from a high concentration of glucose in the renal tubule. Diabetes mellitus can be caused by either deficiency of insulin (Type I) or insulin receptors (Type II). Diabetes mellitus features high glucose in the blood (hyperglycemia), leaving too much glucose in glomerular filtrates. When glucose in tubular fluid exceeds the transport maximum (180 mg/100 ml), it appears in urine (glycosuria). Glucose in tubular fluid hinders water reabsorption by osmosis, causing polyuria. Diabetes insipidus is caused by inadequeate ADH secretion. Due to the shortage of ADH, water reabsorption in CD is compromised, leading to polyuria. 3. Diuresis, Natriuresis, and Diuretics a. Diuresis refers to excretion of large amount of urine. b. Natriuresis refers to enhanced urinary excretion of sodium c. Diuretics are chemicals that increase urine volume. They are used for treating hypertension and congestive heart failure because they reduce overall fluid volume. d. Diuretics work by either increasing glomerular filtration or reducing tubular reabsorption. Caffeine falls into the former category; alcohol into the latter (alcohol suppresses the release of ADH). e. Many diuretic drugs produce osmotic diuresis by inhibiting sodium reabsorption. Renal Function Tests 1. Renal Clearance a. Renal clearance is the volume of blood plasma from which a particular waste is removed in 1 minute. b. Renal clearance can be measured indirectly by collecting samples of blood and urine, measuring the waste concentration in each, and measuring the urine output. 2. Glomerular Filtration Rate a. Measuring GFR requires a substance that is not secreted or reabsorbed at all. Garlic and artichoke produce inulin, a polymer of glucose that is suitable. b. All inulin filtered by the glomerulus remains in the renal tubule and appears in the urine; none is reabsorbed, and the tubule does not secrete it. For this solute, GFR is equal to the renal clearance. Hemodialysis 1) dialysis machine 2) continuous ambulatory peritoneal dialysis Urine Storage and Elimination A. The Ureters 1. The ureters are muscular tubes leading from the renal pelvis to the lower bladder. B. The Urinary Bladder 1. The urinary bladder is a muscular sac on the floor of the pelvic cavity. The bladder is highly distensible and expands superiorly. The openings of the two ureters and the urethra mark a triangular area called the trigone on the bladder floor. C. The Urethra The urethra conveys urine from the urinary bladder to the outside of the body. In females, it is 3-4 cm long and its opening, the external urethral orifice, lies between the vaginal orifice and clitoris. The male urethra is 18 cm long and has three regions: prostatic urethra, membranous urethra, and penile urethra. In both sexes, the detrusor muscle is thickened near the urethra to form an internal urethral sphincter. It is under involuntary control. Where the urethra passes through the pelvic floor, it is encircled by an external urethral sphincter of skeletal muscle that provides voluntary control over the voiding of urine. D. Voiding Urine 1. When the bladder contains about 200 mL of urine, stretch receptors in the wall send impulses to the spinal cord. Parasympathetic signals return to stimulate contraction of the bladder and relaxation of the internal urinary sphincter. This is the micturation reflex that voids the bladder in infants. 2. Once voluntary control has developed, emptying of the bladder is controlled predominantly by a micturition center in the pons. This center receives signals from stretch receptors and integrates this information with cortical input concerning the appropriateness of urinating at the moment. It sends back impulses to stimulate relaxation of the external sphincter. Water, Electrolyte, and Acid-Base BalancePRIVATE  Water Balance Function of Water: Most of cellular activities are performed in water solutions. Fluid Compartments Water makes up 60% of total body weight, and is distributed among fluid compartments. Intracellular fluid (ICF) = 40% of total body weight. tissue fluid = 16% of total body weight. blood plasma = 4% of total body weight. Fluid Exchanged Between Compartments Fluid is continually exchanged between compartments. Exchange between Blood & Tissue Fluid - Determined by four factors: capillary blood pressure forcing water to move from blood ( tissue fluid 2) plasma colloid osmotic pressure mainly determined by plasma proteins content forcing water to move from tissue fluid ( blood interstitium Hydrostatic Pressure forcing water to move from tissue fluid ( blood interstitium colloid osmotic pressure forcing water to move from blood ( tissue fluid - not affected by electrolyte concentrations because capillaries are permeable to electrolytes - Edema = water accumulation in tissue fluid Exchange between Tissue Fluid & Intracellular Fluid mainly determined by two factors: intracellular osmotic pressure mainly determined by intracellular electrolyte content forcing water to move from tissue fluid ( intracellular fluid interstitial osmotic pressure mainly determined by interstitium electrolyte content - forcing water to move from intracellular fluid ( tissue fluid Osmotic pressures are under physiological regulation Normal osmotic pressure in all the three compartment = 280-300 mOsm Hypotonic = lower than normal osmotic pressure Hypertonic = higher than normal osmotic pressure Osmotic gradient drives water movement and is eliminated after water movement (transient). Water Gain and Loss Water is gained from three sources. food (~700 ml/day) drink voluntarily controlled metabolic water (200 ml/day) --- produced as a byproduct of aerobic respiration Routes of water loss include: Urine obligatory (unavoidable) and physiologically regulated, minimum 400 ml/day Feces -- obligatory water loss, ~200 ml/day Breath obligatory water loss, ~300 ml/day Cutaneous evaporation -- obligatory water loss, ~400 ml/day Sweat for releasing heat, varies significantly Regulation of Intake Fluid intake is governed mainly by thirst. a. Dehydration reduces blood volume and pressure and raises its osmolarity. Peripheral volume sensors and central osmoreceptors send signal to hypothalamus. Thirst is felt. Regulation of Output 1. The only way to control water output significantly is through variations in urine volume. a. The kidneys cannot restore fluid volume or osmolarity, but in dehydration they can support existing fluid levels and slow down the rate of loss until water and electrolytes are ingested. 2. Antidiuretic hormone (ADH) provides a means of controlling water output independently of sodium. a. In true dehydration, blood volume declines and sodium concentration rises. The increased osmolarity and the decreased volume of the blood stimulate the hypothalamic receptors and peripheral volume sensors respectively, which stimulate the posterior pituitary to release ADH. b. ADH targets the collecting duct of the nephrons, and the kidneys reabsorb more water and produce less urine. c. Sodium continues to be excreted, so the ratio of sodium to water in the urine increases. 3. If blood volume and pressure are too high or blood osmolarity too low, ADH release is inhibited. The renal tubules absorb less water, urine output increases, and total body water declines. Dehydration Caused by: 1) the lack of drinking water 2) excessive loss of body fluid due to overheat, diabetes, overuse of diuretics, and diarrhea Edema the accumulation of fluid in the interstitial spaces marked by swelling of the face, fingers, abdomen, or ankles caused by: increased capillary filtration, or reduced capillary reabsorption, or obstructed lymphatic drainage ELECTROLYTE BALANCE Terms Electrolytes = small ions which carry charges Electrolytes includes cations (positive charge) and anions (negative charge) Major cations of the body are sodium, potassium, calcium, and hydrogen. Major anions of the body are chloride, bicarbonate, and phosphate. Function of Electrolytes: chemically and electrically reactive and participate in all metabolism affect the osmolarity of the body fluids and the body's water content and distribution. Sodium Functions: one of the principal ions responsible for the action membrane potential of cells the principal cation of the extracellular fluid, and is therefore the most significant solute in determining total body water and its concentration among fluid compartments. Regulation: 1) Aldosterone The primary regulator of sodium excretion Act on renal distal tubule, causing retention of Na+ and excretion of K+ secreted from adrenal gland Renin-angiotensin-aldosterone mechanism: ( blood Na ( ( renin ( conversion of angiotensinogen to angiotensin-I and to angiotensin-II ( ( aldosterone ( ( renal Na+ excretion ( ( blood Na. Antidiuretic hormone (ADH or vasopressin) released from posterior pituitary increases water reabsorption in renal collecting ducts ( water retention response to an increase in Na and the decrease in blood volume 3) Atrial natriuretic factor (ANF) secreted by the atrial myocardium in response to hypertension inhibits sodium and water reabsorption and the excretion of renin and ADH. The kidneys thus eliminate more sodium and water and lower blood pressure. 4) Several other hormones affect sodium homeostasis. These include estrogen, progesterone, and glucocorticoids. Sodium imbalance hypernatremia, characterized by a plasma sodium concentration in excess of 145 mEq/L, hyponatremia (less than 130 mEq/L). Potassium Functions: the most abundant cation in the intracellular fluid the greatest contributor to intracellular osmosis and cell volume determine the resting membrane potentials also an essential cofactor for protein synthesis and some other metabolic processes. Regulation Potassium homeostasis is closely linked to that of sodium, and regulated by aldosterone and the kidneys. a. The DCT and cortical portion of the CD control potassium excretion by changing the amount of potassium secreted into the tubular fluid. b. Aldosterone stimulates potassium secretion by the DCT. Potassium Imbalance hyperkalemia (> 5.5 mEq/L) hypokalemia (< 3.5 mEq/L). Chloride Functions: the most abundant anions of the extracellular fluid make a major contribution to extracellular osmolarity required for the formation of stomach acid (HCl) Regulation Cl is strongly attracted to Na+, K+, and Ca2+, so Cl homeostasis is achieved primarily as an effect of Na+ homeostasis. As sodium is retained or excreted, Cl passively follows. Chloride Imbalance hyperchloremia (> 105 mEq/L) hypochloremia (< 95 mEq/L). Calcium Distribution: Extracellular Ca++ concentration is much higher than the intracellular concentration. Functions: lends strength to the skeleton activates the sliding filament mechanism of muscle contraction serves as a second messenger for some hormones and neurotransmitters activates exocytosis of neurotransmitters and other cellular secretions essential factor in blood clotting. activates many cellular enzymes Regulation Homeostasis of calcium is regulated chiefly by: parathyroid hormone (PTH): increases blood calcium by desolving calcium in the skeleton and reducing renal excretion of calcium calcitonin (secreted by C cells in thyroid gland): decreases blood calcium by depositing calcium in the skeleton calcitrol (derivative of vitamin D): increase blood calcium increases blood calcium by enhancing intestinal absorption of calcium from food Sources of Plasma Calcium: food and bone Excretion of Calcium: kidney Calcium imbalances hypocalcemia (< 4.5 mEq/L) hypercalcemia (> 5.8 mEq/L). Phosphates Functions: relatively concentrated in the intracellular fluid needed for the synthesis of ATP, other nucleotide phosphates, nucleic acids, and phospholipids Regulation Parathyroid hormone increases the excretion of phosphate as part of the mechanism for increasing the concentration of free calcium ions in the ECF. There are no real imbalances with respect to phosphates because phosphate homeostasis is not as critical as that of other electrolytes. ACID-BASE BALANCE Terminology Acid An acid is any chemical that releases H+ in solution; a strong acid ionizes freely. A weak acid ionizes only slightly. Base A base is any chemical that accepts H+. A strong base has a strong tendency to bind H+ and raise the pH, whereas a weak base binds only a small portion of the available H+ and has less effect on pH. pH: pH is the negative logarithm of H+ concentration, and an indicator of acidity. Physiological pH range: 7.35-7.45. Buffer A buffer is any mechanism that resists changes in pH by converting a strong acid or base to a weak one. The body has both physiological and chemical buffers. Function of Normal pH Variation of pH has to be strictly kept within 7.35-7.45 to maintain normal cell functions. Regulation Chemical Buffers respond to pH changes within a fraction of a second. Bind to H( but can not remove H( out of the body Limited ability to correct pH changes Three major buffer systems 1) The Bicarbonate (HCO3-) Buffer System H( + HCO3- ( H2CO3 ( H2O + CO2 a. The bicarbonate buffer system is a solution of carbonic acid and bicarbonate ions. Carbonic acid (H2CO3) forms by the hydration of carbon dioxide and then dissociates into bicarbonate (HCO3) and H+. This is a reversible reaction. The bicarbonate system work well because the lungs constantly remove CO2 and prevent an equilibrium from being reached. 2) The Phosphate Buffer System H( + HPO42 ( H2PO4 3) The Protein Buffer System (p. 876) a. Proteins are more concentrated than either bicarbonate or phosphate buffers, especially in the ICF and blood plasma. b. The protein buffer system accounts for about three-quarters of all chemical buffering ability of the body fluids. c. The buffering capacity of proteins is due to the carboxyl groups that release H+ when pH begins to rise and thus lower pH, or to amino side groups, which bind H+ when pH falls too low, thus raising pH toward normal. Respiratory Control of pH 1. Addition of carbon dioxide to body fluids raises H+ and lowers pH, while removal of CO2 has the opposite effects. This is the basis for the strong buffering capacity of the respiratory system. a. Rising CO2 concentration and falling pH stimulate peripheral and central chemoreceptors, which stimulate an increase in pulmonary ventilation. This expels excess CO2 and thus reduces H+ concentration. b. Conversely, a drop in H+ concentration raises pH and reduces pulmonary ventilation. c. limited capacity because this mechanism cannot remove H+ out of the body. Renal Control of pH 1. The kidneys can neutralize more acid or base than either the respiratory system or chemical buffers. a. Renal tubules secrete hydrogen ions into the tubular fluid, where most of it combines with bicarbonate, ammonia, and phosphate buffers. b. Bound and free H+ are then excreted in urine. 2. The kidneys are the only organs that actually expel H+ from the body. Other buffering systems only reduce its concentration by binding it to another chemical. 3. Tubular secretion of H+ continues only as long as there is a sufficient concentration gradient between a high H+ concentration in the tubule cells and a lower H+ concentration in the tubular fluid. Disorders of Acid-Base Balance Acidosis: < pH 7.35 , Alkalosis: > pH 7.45 a. Mild acidosis depresses the central nervous system and causes such symptoms as confusion, disorientation, and coma. Mild alkalosis makes the nervous system hyperexcitable. Nerves fire spontaneously and overstimulate skeletal muscles. Severe acidosis or alkalosis is lethal. 2. Acid-base imbalances are classified as respiratory or metabolic. a. Respiratory acidosis or respiratory alkalosis is caused by hypoventilation or hyperventilation, respectively. d. Metabolic acidosis or alkalosis can result from any causes but respiratory problems. An elevated production of organic acids such as in diabetes can cause metabolic acidosis while the loss of stomach acid in chronic vomiting can cause metabolic alkalosis. The Digestive SystemPRIVATE  General Concepts Composition The digestive system has two anatomical subdivisions: the accessory organs and the digestive tract. a. The accessory organs are the teeth, tongue, salivary glands, liver, gallbladder, and pancreas. The digestive tract is a tube extending from mouth to anus. It includes the oral cavity, pharynx, esophagus, stomach, small intestine, and large intestine. Functions Digestion the process to break ingested food into usable forms that can be absorbed into the blood. There are two stages of digestion: mechanical and chemical. Mechanical digestion is achieved by the cutting and grinding action of the teeth and the churning contractions of the stomach and small intestine. Chemical digestion consists solely of hydrolysis reactions that break the dietary macromolecules into their monomers. It is carried out by digestive enzymes produced by the salivary glands, stomach, pancreas, and small intestine. Absorption the process to take usable forms of nutrients from digestive tract into the blood The Mouth The mouth, or oral or buccal cavity, functions in the following: breaking food into pieces small enough to be swallowed (mastication) Sense of taste swallowing speech Saliva and the Salivary Glands 1. Saliva moistens the mouth, digests a small amount of starch and fat, cleanses the teeth, inhibits bacterial growth, dissolves molecules so they can stimulate taste buds, and moistens food and binds particles together to aid in swallowing. It is secreted by the salivary glands. The Stomach serves as a food storage organ. When empty, it has a volume of 50 mL. When very full, it may hold up to 4L. breaks up food particles, liquefies the food, and begins the chemical digestion of proteins and a small amount of fat, producing a mixture of semidigested food called chyme. The Stomach Wall a. The gastric mucosa is pocked with depressions called gastric pits. At the bottom of the pits lie glands. The gastric glands have a greater variety of cell types and secretions: mucous neck cells: produce mucus chief cells: produce pepsinogen parietal cells: produce HCl and intrinsic factor endocrine (G) cells: produce hormones that regulate digestion Gastric Secretion The gastric glands produce 2-3 L of gastric juice daily, composed mainly of water, HCl, and pepsinogen. 1) Hydrochloric Acid a. Gastric juice has a high concentration of HCl and a pH as low as 0.8. b. Stomach acid has several functions: (1) It activates pepsinogen into the active enzyme pepsin. (2) It breaks up connective tissues and plant cell walls. (3) It converts ferric ions to ferrous ions. (4) It destroys ingested bacteria and other pathogens. 2) Intrinsic Factor a. a glycoprotein that is essential to the absorption of vitamin B12 b. The secretion of intrinsic factor is the only indispensable function of the stomach. 3) Pepsinogen a. Pepsinogen is the inactive precursor of the active enzyme pepsin. Inactive precursors of enzymes are called zymogens. b. Pepsinogen is activated by HCl or pepsin. 4) Gastrin a. a hormone that stimulates the secretion of HCl and pepsinogen, and stimulates motility of the large intestine. is secreted in the bloodstream or diffuses to nearby parietal and chief cells. Gastric Motility 1. During swallowing, signals from the swallowing center of the medulla oblongata stimulate the stomach to relax in preparation of the arrival of food. When food enters the stomach, it is stimulated to stretch further, a phenomenon known as the stress-relaxation response. 2. Next, the stomach shows a rhythm of peristaltic contractions, initiated by pacemaker cells in the greater curvature. 3. The antrum of the stomach holds about 30 mL of chyme. As a peristaltic wave passes down the antrum, it squirts about 3 mL of chyme into the duodenum. Digestion and Absorption in Stomach minor role in digestion or absorption of nutrients But, the stomach does absorb aspirin and some lipid-soluble drugs. Protection of the Stomach 1. The living stomach is protected in three ways from the harsh chemical of its interior. a. It has a highly alkaline mucous coat. b. Epithelial cells are replaced every 3-6 days. c. Tight junctions between epithelial cells prevent gastric juice from seeping between cells. Regulation of Gastric Function Gastric activity is divided into three stages called the cephalic, gastric, and intestinal phases. 1) The Cephalic Phase a. The cephalic phase is stimulated by the sight, smell, taste, or mere thought of food. 2) The Gastric Phase a. The gastric phase is stimulated by food in the stomach and accounts for two-thirds of gastric secretion. 3) The Intestinal Phase The intestinal phase is stimulated by chyme entering the duodenum. Chyme initially stimulates the secretion of intestinal gastrin which stimulates gastric secretion and mobility. c. Gastric secretion and mobility are then quickly inhibited via the enterogastric reflex which is initiated by HCl, fats, and peptides. d. Chyme in the duodenum also stimulates its enteroendocrine cells to release secretin, cholecystokinin, and gastric inhibitory peptide. All the three hormones suppress gastric motility. c. Inhibition of gastric secretion and motility and contraction of the pyloric sphincter limit the addition of more chyme into the duodenum, giving the duodenum more time to work on the chyme. The Liver, Gallbladder, and Pancreas The small intestine receives not only chyme from the stomach but also secretions from the liver and pancreas. The Liver 1. The liver is the body's largest gland and performs a tremendous variety of functions, including the secretion of bile for digestive purposes. 2. Microscopic Anatomy (p. 907, Figs. 25.18, 25.19) a. The liver parenchyma consists mostly of hepatocytes arranged in cylinders called hepatic lobules. Each lobule has a central vein passing through its core. b. The liver secretes bile into narrow channels, the bile canaliculi, between sheets of hepatocytes. Bile passes from there into the small bile ductules and then into the right and left hepatic ducts. These two ducts converge to form the common hepatic duct, which then joins the cystic duct coming from the gallbladder. The common bile duct descends through the lesser omentum and joins the duct of the pancreas, forming the hepatopancreatic ampulla. This ampulla contains the hepatopancreatic sphincter, which regulates the passage of bile and pancreatic secretion into the duodenum. The Gallbladder and Bile a. When no chyme is in the small intestine, the hepatopancreatic sphincter is closed. Bile then fills up the common bile duct and spills over into the gallbladder, which absorbs water and stores the bile for later use. The liver produces 500-1,000 mL of bile per day. It is a yellow-green fluid containing minerals, bile pigments, bile salts, cholesterol, neutral fats, and phospholipids. Bile salts and phospholipids emulsifies fat globule into emulsification droplets which can be digested more easily by lipase. Bile salts also coat digested lipids and form micelles, facilitating in fat absorption. Bile salts and phospholipids are not excreted in the feces but are reabsorbed in the ileum and returned to the liver via enterohepatic circulation. The Pancreas The pancreas has both endocrine and exocrine functions. Exocrine means secretion into the lumen of a duct; endocrine means secretion into the blood. Exocrine 1) Most of the pancreas is exocrine tissue, which secretes 1,200-1,500 mL of pancreatic juice per day into the main pancreatic duct. It empties into the small intestine through the hepatopancreatic ampulla or by way of a smaller accessory pancreatic duct in some people. 2) Pancreatic juice is an alkaline mixture of: water sodium bicarbonate: buffers the hydrochloric acid from the stomach. enzymes: pancreatic amylase (digesting starch), pancreatic lipase (digesting fat), ribonuclease (digesting RNA), and deoxyribonuclease (digesting DNA). They are activated upon exposure to bile acid and ions in the intestinal lumen. zymogens: trypsinogen, chymotrypsinogen, and procarboxypeptidase (digesting proteins and peptides). They are activated by enterokinase located on the surface of intestine. Regulation of Bile and Pancreatic Secretion Bile and pancreatic juice are secreted in response to similar stimuli. During the cephalic and gastric phases of gastric secretion, the vagus nerves also stimulate pancreatic secretion. a. As chyme enters the duodenum laden with acid and fat, it stimulates the duodenal mucosa to secrete cholecystokinin (CCK). b. CCK stimulates relaxation of the hepatopancreatic sphincter, the contraction of the gallbladder, releasing more bile into the duodenum common bile duct, and secretion of pancreatic enzymes. Acidic chyme also stimulates the duodenum to release secretin, which stimulates the production of bicarbonate ions by both the hepatic and pancreatic ducts to neutralize stomach acid in the duodenum. The Small Intestine Nearly all chemical digestion and nutrient absorption occur in the small intestine. The term "small" applies to its diameter, not its length. Circular folds, villi, and microvilli all serve to increase the surface area inside the small intestine. Gross Anatomy 1. The small intestine is divided into three regions. a. The duodenum constitutes the first 25 cm. It receives the stomach contents, pancreatic juice, and bile. Stomach acid is neutralized here, pepsin is inactivated by the elevated pH, and pancreatic enzymes take over the job of chemical digestion. b. The jejunum comprises the next 2.5 m. The ileum forms the last 3.6 m and ends at the ileocecal junction. Intestinal Secretion 1. The intestinal crypts secrete 1-2 L of intestinal juice per day, especially in response to acid, hypertonic chyme, and intestinal distension. 2. The duodenum endocrine cells secret cholecystokinin (CCK) and secretin. Intestinal Motility Contractions of the small intestine serve three functions: 1) to mix chyme with intestinal juice, bile, and pancreatic juice; 2) to churn chyme and bring it in contact with the brush border for digestion and absorption; 3) to move residue toward the large intestine. 2. Segmentation is the most common type of movement of the small intestine. Ring-like constrictions appear at several places along the intestine and then relax while constrictions occur elsewhere. The effect is to churn the contents of the intestine. a. The intensity (but not frequency) of the contractions is modified by nervous and hormonal influences. 3. When most nutrients have been absorbed and little remains but residue, segmentation slows and peristalsis (synchronized contraction) begins. 4. At the ileocecal junction, the muscularis of the ileum is thickened to form a sphincter, the ileocecal valve. The valve is usually closed. a. Food in the stomach triggers the release of gastrin as well as the gastroileal reflex, both of which enhance segmentation in the ileum and relax the valve. As the cecum fills with residue, the pressure pinches the valve shut, preventing the reflux of cecal contents into the ileum. The Large Intestine Absorption and Motility 1. Each day, about 500 mL of food residue enters the large intestine. It undergoes no further chemical digestion, but its volume is reduced as it passes through the large intestine. The average adult voids about 150 mL of feces per day, consisting of 75% water and 25% solid matter, of which 30% is bacteria, and 30% undigested fiber. Strong contractions called mass movements occur one to three times a day, last about 15 minutes each, and occur especially an hour after breakfast. Bacterial Flora and Intestinal Gas 1. The large intestine is densely populated with several species of useful bacteria referred to collectively as the bacterial flora. They ferment cellulose and other undigested carbohydrates and synthesize B vitamins and vitamin K, which are absorbed by the colon. The average person expels about 500 mL of flatus per day. It is composed of nitrogen, carbon dioxide, hydrogen, methane, hydrogen sulfide, and indole and skatole. Defecation 1. In the intrinsic defecation reflex, stretch signals travel by the mesenteric nerve plexus to the muscularis of the descending and sigmoid colons and the rectum. This triggers a peristaltic wave that drives the feces downward, and it relaxes the internal anal sphincter. Defecation occurs only if the external anal sphincter is voluntarily relaxed at the same time. Chemical Digestion and Absorption Carbohydrates 1. Most digestible dietary carbohydrate is starch. 2. Carbohydrate Digestion a. Starch is digested first to oligosaccharides three to eight glucose residues long, then into the disaccharide maltose, and finally to glucose, which is absorbed by the small intestine. b. The process of starch digestion begins in the mouth. Salivary amylase hydrolyzes starch into oligosaccharides, and functions best at the pH of the mouth cavity. It is denatured quickly upon contact with stomach acid. c. Starch digestion resumes in the small intestine when the chyme mixes with pancreatic amylase that entirely converts it to oligosaccharides and maltose within 10 minutes. Its digestion is completed by brush border enzymes. 3. Carbohydrate Absorption a. In the plasma membrane adjacent to the brush border enzymes, there are transport proteins that absorb monosaccharides as soon as they are produced. Most of the absorbed sugar is glucose, which is taken up by a sodium-dependent glucose transporter (SGLT). After a high-carbohydrate meal, two to three times as much glucose is absorbed by solvent drag as by SGLT. Proteins 1. Enzymes that digest proteins are called proteases or peptidases. They are absent from the saliva but begin their job in the stomach. a. In the stomach, pepsin hydrolyzes any peptide bond between tyrosine and phenylalanine, thus digesting 10-15% of the dietary protein into shorter polypeptides. b. In the small intestine, the pancreatic enzymes trypsin and chymotrypsin take over protein digestion by hydrolyzing polypeptides into even shorter oligopeptides. Finally these are taken apart one amino acid at a time by carboxypeptidase, aminopeptidase, and dipeptidase. All three of these enzymes are found on the brush border. Amino acid absorption is similar to that of monosaccharides. There are several sodium-dependent amino acid cotransporters for different classes of amino acids. Lipids 1. Fats are digested by enzymes called lipases. a. Lingual lipase from the intrinsic salivary glands is activated by stomach acid, where it digests as much as 10% of the ingested fat. b. Most fat digestion occurs in the small intestine through the action of pancreatic lipase. c. In the small intestine, fats are first broken up into smaller emulsification droplets by lecithin and bile salts in the bile. When lipase digests fats, the products are two fatty acids (FFAs) and a monoglyceride. Bile salts coat these and other lipids and form droplets called micelles. 2. Micelles pass between the microvilli of the brush border, and upon reaching the surface of the epithelial cell, they release their lipids. The lipids diffuse freely across the phospholipid plasma membrane. 3. Within the cell, the FFAs and monoglycerides are resynthesized into triglycerides. They are coated with a thin film of protein, forming droplets called chylomicrons. 4. Although some free fatty acids enter the blood capillaries, chylomicrons are too large to do so and must be first transported in the lymphatic lacteal. Nucleic Acids Nucleic acids are generally present in small quantities compared to the other polymers. The nucleases of pancreatic juice hydrolyze these to their component nucleotides. Nucleosidases and phosphatases of the brush border further break them down, and the products are transported across the intestinal epithelium by membrane carriers. Vitamins 1. Vitamins are absorbed unchanged. a. The fat-soluble vitamins are absorbed with other lipids. Water soluble vitamins are absorbed by simple diffusion, with the exception of vitamin B12. This is an unusually large molecule that can only be absorbed if it binds to intrinsic factor from the stomach. Minerals 1. Minerals (electrolytes) are absorbed along the entire length of small intestine. Iron and calcium are unusual in that they are absorbed in proportion to the body's need, whereas other minerals are absorbed at fairly constant rates regardless of need. Water 1. The digestive system is one of several systems involved in water balance. 2. The digestive tract receives about 9 L of water per day - 0.7 L in food, 1.6 L in drink, 6.7 L in gastrointestinal secretions. About 8 L of this is absorbed by the small intestine and 0.8 L by the large intestine. Water is absorbed by osmosis. a. Diarrhea occurs when the large intestine absorbs too little water from the feces. b. Constipation occurs when fecal movement is slow, too much water is reabsorbed, and the feces become hardened. Metabolism Appetite Hunger and satiety are regulated by a complex interaction of multiple brain centers, hormones, and sensory and motor pathways. 1. Feeding center and satiety center Feeding center: a region in the lateral hypothalamus that triggers the desire for food Satiety center: a region in the ventromedial hypothalamus that suppresses the desire for food The satiety center has neurons called glucostats that rapidly absorb blood glucose after a meal. One hypothesis on hunger is that glucose uptake causes the satiety center to send inhibitory signals to the hunger center and thus suppresses the appetite. 2. Gastric peristalsis stimulates hunger. Mild hunger contractions begin soon after the stomach is emptied and increase in intensity over a period of hours. 3. Hormones also play a role in appetite regulation. Cholecystokinin, secreted by the duodenum in response to amino acids and fatty acids in the chyme, is a well-known appetite suppressant. Also, evidence suggests that adipocytes secrete appetite-stimulating hormones when their lipid stores decline. Nutrients Nutrients fall into six major classes: carbohydrates, lipids, proteins, minerals, vitamins, and water. Nutrients are used for: providing energy growth, repair, or maintenance of body cells Metabolic rate The amount of energy released in the body per unit of time, expressed as kcal/hr or kcal/day A kilocalorie (kcal) is the amount of heat that will raise the temperature of 1 kg of water by 1oC. An average adult needs 2,000-5,000 kcal/day, depending on physical activity, mental state, and other factors such as room temperature. Importance of blood glucose in providing energy ATP is the universal cellular energy, and can be produced from glucose, fat, and proteins. Blood glucose is more important than fat and proteins since glucose can be used by all tissue cells while neurons in the brain and some other cells such as erythrocytes normally obtain energy only from glucose. Thus blood glucose levels are carefully maintained by insulin and glucagon. A total of 38 ATP or 2 ATP is generated per molecule of glucose in the presence or absence of oxygen. Maintenance of blood glucose Absorptive State 1. Absorptive state lasts about 4 hours after a meal. During this time, blood glucose is readily available for ATP synthesis. It serves as a primary fuel and spares the body from having to draw on stored fuels. a. Absorbed sugars are transported by the hepatic portal system to the liver. Most glucose passes through the liver and is available to body cells. Excessive glucose is stored as glycogen or body fat. b. Fats enter lymph as chylomicrons and initially bypass the liver. Lipoprotein lipase removes fats from the chylomicrons for uptake by the tissues, especially adipose and muscular tissue. c. Amino acids, like sugars, circulate first to the liver. Most pass through and become available for protein synthesis. Some are removed by the liver for protein synthesis and fatty acid synthesis after deamination. 2. Regulation of the Absorptive State a. The absorptive state is regulated largely by insulin, which stimulates nearly all cells to absorb glucose. Neurons are an exception and absorb glucose at their own independent rate. Postabsorptive State 1. Postabsorptive state (fasting) prevails hours after meals and overnight. The essence of this state is to regulate blood glucose levels, which is especially critical to the brain. Glucose is drawn from the body's glycogen reserves in liver and muscles, or synthesized from fats (gluconeogenesis). b. Adipocytes and hepatocytes hydrolyze fats and convert the glycerol to glucose. After 4 to 5 days of fasting, the brain begins to use ketone bodies as supplemental fuel. c. If glycogen and fat reserves are depleted, the body begins to use proteins as fuel. The first to go are skeletal muscle proteins, and starvation results in wasting away of muscle mass. 2. Regulation of the Postabsorptive State a. Postabsorptive metabolism is regulated mainly by the sympathetic nervous system and several hormones. b. As blood glucose drops, the pancreas releases glucagon that promotes glycogenolysis and gluconeogenesis, raising blood glucose level. It also promotes lipolysis and a rise in FFA levels, thus making both glucose and lipids available for fuel. c. The sympathoadrenal system richly innervates adipose tissue and can mobilize stored energy reserves as needed. d. Growth hormone has the opposite effects of insulin and raises blood glucose concentrations. V. Body Heat and Thermoregulation A. Body Temperature 1. Body temperature fluctuates about 1oC in a 24-hour cycle. 2. The most important body temperature is the core temperature - that of the cranial, thoracic, and abdominal cavities. 3. Shell temperature is closer to the surface, especially skin and oral temperature. Adult oral temperature is normally 36.6oC to 37oC (97.9o - 98.6oF) but may be higher during strenuous exercise. B. Heat Production and Loss 1. Most body heat comes from nutrient oxidation and ATP use. At rest, skeletal muscles contribute 20-30% of the total resting heat. Increased muscle tone or exercise greatly increases heat generation in the muscles. During vigorous exercise, they produce 30-40 times as much heat as the rest of the body. 2. The body loses heat through radiation, conduction, and evaporation. C. Thermoregulation 1. Thermoregulation is achieved through several negative feedback loops. Within the hypothalamus lies a hypothalamic thermostat that monitors the blood temperature and receives signals from peripheral thermoreceptors in the skin. When necessary, it sends impulses to either a heat-losing center or a heat-promoting center, both located separately within the hypothalamus. a. When blood temperature is too high, the heat-losing center signals the dilation of dermal arterioles, conducting more heat to the body surface. If this fails, sweating is triggered. b. When blood temperature drops too low, the heat-promoting center causes dermal vasoconstriction and the body may resort to shivering thermogenesis. c. During colder seasons, the body raises its metabolic rate by 20-30% through nonshivering thermogenesis. D. Disturbances of Thermoregulation 1. Exposure to excessive heat causes heat cramps, heat exhaustion, and heat stroke. a. Heat cramps are painful muscle cramps that result from excessive electrolyte loss in the sweat. b. Heat exhaustion results from more severe electrolyte loss, and is characterized by hypotension, dizziness, vomiting, and sometimes fainting. c. During heat stroke, the body temperature can rise to as high as 43oC (110oF). Brain cells malfunction, hypothalamic mechanisms break down, and convulsions, coma, and death may suddenly occur. 2. Hypothermia can result from exposure to cold weather or immersion in icy water. a. If the core temperature falls below 33oC (91oF), the metabolic rate drops so low that heat production cannot keep pace with heat loss, and the temperature falls further. b. A body temperature below 24oC (75oF) is usually fatal. Reproductive System Overview of the Reproductive System The reproductive system consists of primary and secondary sex organs. The primary sex organs (gonads) are those that produce gametes (sperms and eggs) Male: testes Female: ovaries The secondary sex organs are those that are essential to reproduction, Male: ducts, glands, and a penis Female: uterine tubes, uterus, vagina Secondary sex characteristics are features that are not essential for reproduction but that attract the sexes to each other. The sex of an individual is determined by 2 sex chromosomes: Male: XY; Female: XX Male Reproductive System Testes produce sperm cells which are developed from germ cells in seminiferous tubule secret testosterone by interstitial (Leydig) cells Scrotum protect testes and maintain the temperature of the testes 2 degrees lower than body temperature. Epididymus is the storage site of sperm cells. It reabsorbs about 90% of the fluid secreted by the testis. Sperm remain stored here for 40-60 days and become reabsorbed if not ejaculated prior to that time. The Spermatozoan The spermatozoan, or sperm cells, has a pear-shaped head and a long tail. a. The head contains the haploid nucleus, an acrosome bearing enzymes used to dissolve a path to penetrate the egg, and a flagellar basal body. The tail contains large mitochondria that produce ATP for sperm motility. Semen The fluid expelled during orgasm is called semen or seminal fluid. Its major constituents are as follows. a. Sperm cells from epididymus are present at a count of 50-120 million sperm/mL. b. Fructose, produced by the seminal vesicles, provides a source of energy for the sperm. c. Clotting and anticoagulant factors are produced by seminal vesicles and prostate. After ejaculation, semen clots like blood, causing it to stick inside the female vagina. About 15-30 minutes later, fibrolysin in the prostatic fluid dissolves the clot and sperm can begin their migration up the reproductive tract of the female. d. Prostaglandins, produced by the prostate and seminal vesicles, stimulate peristaltic contractions of the female reproductive tract that may help draw semen into the uterus. Spermine is a base that reduces acidity of the female vagina, increasing the survival rate of sperm. Sexual Intercourse The male sexual response include two phases: 1) erection of the penis, allowing it to penetrate the female vagina, and 2) ejaculation, expelling semen into the vagina. Ejaculation Ejaculation is the propulsion of semen from the male duct system. Initiated by massive discharge of sympathetic nerve impulses The ducts and accessory glands contract, emptying their contents into the urethra The bladder sphincter constricts, preventing shunt of semen into the bladder. The bulbospongiosus muscles of the penis contract rapidly and rhythmically, propelling semen from the urethra. Refractory Period A period following ejaculation and lasting anywhere from 10 minutes to a few hours impossible to attain another erection and orgasm The Female Reproductive SystemPRIVATE  The Ovaries produce oocytes produce sex hormones The ovarian follicles secrete estrogens, progesterone, inhibin, and a small amount of androgen. The Uterine Tubes a. The uterine tube (oviduct or fallopian tube) is a canal 10 cm long leading from the ovary to the uterus. It has a trumpet-shaped infundibulum with projections called fimbriae. b. The wall of the uterine tube is well endowed with smooth muscle, and its mucosa has ciliated cells. c. The cilia beat toward the uterus and, with the help of muscular contractions of the tube, convey the egg in that direction. It takes about 3 days for an egg to travel the length of the uterine tube, but an unfertilized egg lives only 24 hours. The Uterus is a thick, muscular chamber that functions to: harbor the embryo provide a source of nutrition expel the fetus at the end of its development Vagina a. a tube 8-10 cm long that allows for the discharge of menstrual fluid, receipt of the penis and semen, and birth of a baby. The vaginal wall is thin but very distensible. Adult vaginal epithelium is a stratified squamous epithelium. The epithelial cells are rich in glycogen. Bacteria ferment this to lactic acid, resulting in a low vaginal pH. Accessory Glands and Erectile Tissues On each side of the vagina is a pea-sized greater vestibular (Bartholin) gland with a short duct opening into the vestibule or lower vagina. These glands are homologous to the bulbourethral glands of the male. They keep the vagina moist and provide most of the lubrication for intercourse. Climacteric and Menopause 1. Women, like men, go through a midlife change in hormone secretion called the climacteric. In women, it is accompanied by menopause, the cessation of menstruation. 2. With age, the ovaries have fewer remaining follicles and those that remain are less responsive to gonadotropins. Consequently, they secrete less estrogen and progesterone. Without these steroids, the uterus, vagina, and breasts atrophy. Menopause is the cessation of menstrual cycles, usually occurring between the ages of 45 and 55. The average age has increased steadily in the last century and is now about 52. III. Oogenesis and the Sexual Cycle A. Oogenesis 1. Egg production is called oogenesis, which is a distinctly cyclic event. 2. Most primary oocytes undergo a process of degeneration called atresia. Only 2 million remain at the time of birth, and by puberty, only 400,000 remain. 3. Beginning in adolescence, FSH stimulates the primary oocytes to complete meiosis I, which yields two haploid daughter cells of unequal size. One will become the egg with large amounts of cytoplasm. The other, a polar body, will serve only as a dumping ground for the extra set of chromosomes. The secondary oocyte proceeds as far as metaphase II and then arrests until ovulation. If it is fertilized, it completes meiosis II and produces a second polar body. The large remaining egg unites its chromosomes with those of the sperm and produces a zygote. B. The Sexual Cycle a 28-day cycle of sequential changes caused by shifting patterns of hormone secretion. starts at the first day of menstruation. Changes in the ovaries constitute the ovarian cycle which is subdivided into 3 phases: the follicular phase, ovulation, and luteal phase. The parallel changes in the uterus are called the menstrual or unterine cycle, which is subdivided into 3 phases: menstruation, proliferative phase, and secretory phase. Ovarian Cycle 1) The Follicular Phase (Day 1-14) The follicular phase extends from the beginning of menstruation until ovulation. It averages 14 days, but is also the most variable portion of the cycle. FSH causes follicular cells around the oocyte to develop into granulosa cells, and the follicle is now a primary follicle. Granulosa cells secrete an estrogen-rich follicular fluid, which pools to form the antrum. The follicle is now called the secondary follicle. One follicle rapidly outpaces the others and becomes the dominant follicle. 2) Ovulation (Day 14) Ovulation is triggered by a sudden burstlike release of LH (Luteining Hormone) secretion from pituitary when estrogen rises beyond a critical concentration. The LH surge is the consequence of an exceptional positive feedback of estrogen on hypothalamus-pituitary axis. Only the oocyte in the dominant follicle is released in each ovarian cycle. Oocytes in other follicles degenerate. 3) Luteal Phase (Day 15-28) When the follicle expels the oocyte, it collapses and bleeds into the antrum. Under the influence of LH, this structure now develops into a glandular corpus luteum that secretes progesterone and some estrogen. Corpus luteum also secretes inhibin at this point, which suppresses FSH and further ovulations. In the absence of pregnancy the corpus luteum begins to degenerate in about 10 days because rising progesterone output inhibits further release of FSH and LH. Without LH, the corpus luteum begins to shrink. If pregnancy occurs, the corpus luteum continues to secrete progesterone and estrogen for about 3 months under the stimulation of LH-like hormone released by the developing embryo. The secretion by corpus luteum does not stop until the placenta is ready to take over its homone-producing duties. Menstrual (Uterine) Cycle 1) Menstruation (Day 1-5) The superficial layer stratum functionalis of the uterus detaches from the uterine wall, accompanied by bleeding for 3-5 days. Sex hormones are at their lowest normal levels at Day 1 Menstrual fluid contains fibrolysin, therefore it normally does not clot. 2) Proliferative Phase (Day 6-14) Estrogen stimulates mitosis, the prolific growth of blood vessels, and the formation of a new stratum functionalis. Estrogen also stimulates the endometrium to develop progesterone receptors. As ovulation approaches, the uterine tune becomes edematous, its fimbriae develop and caress the ovary, and its cilia create a gentle current in the nearby peritoneal fluid. The ovulated egg is usually caught up in this current and swept into the tube. An oocyte has only 24 hours to be fertilized. The chance of fertilization is enhanced by changes in the cervical mucus at the time of ovulation. It becomes thinner and more stringy. 3) Secretory Phase (Day 15-28) a. In response to rising level of progesterone, the endometrium of the uterus proliferates further in preparation for possible pregnancy. Spiral arteries elaborate and coil more tightly Uterine glands enlarge, coil, and begin secreting nutritients into the uterine cavity to sustain the embryo until implantation. The cervical mucus becomes viscous, forming the cervical plug, which prevents sperm entry. b. If pregnancy does not occur towards the end of the secretory phase, LH level drops due to negative feedback of high level of progesterone. Progesterone level decline following the drop of LH. Without the support of progesterone, the endometrium undergoes degeneration in the following sequence. The spiral arteries close due to continuous and intensive constriction (spasm). The superficial layer stratum functionalis of the uterus is deprived of blood supply. The endometrial cells die of ischemia. The spiral arteries suddenly relax and open wide. Blood gushes into the weakened capillary beds, causing the capillaries to fragment and the stratum functionalis to slough off. c. The menstrual cycle starts over again on this first day of vaginal discharge. The Endocrine System I. An Overview of the Endocrine System A hormone is a chemical messenger secreted by one endocrine gland or cell into the bloodstream and targeted toward cells in another organ. Its another regulatory mechanism in addition to nervous system. A hormone binds to specific receptors on plasma membranes or cytoplasm of its target cells. Only those cells bear the specific receptors are affected. Receptors of some hormones are found only in a limited number of cells while receptors of other could be distributed more extensively. The endocrine system is a collective term for all such hormone-secreting glands as well as the hormone-secreting cells located elsewhere. General Concepts about Hormones and Their Actions Hormones fall into three major chemical classes: steroids, biogenic amines, and peptide hormones. Steroid hormones Include estrogens, progesterone, androgens, glucocorticoids, and aldosterone Derived from cholesterol plasma membrane permeable Receptors located in the nucleus of their target cells Activate DNA transcription Biogenic amines Include epinephrine, norepinephrine, dopamine, serotonin, melatonin, and thyroid hormones Synthesized from amino acids Plasma membrane impermeable (except thyroid hormones) Receptor located in plasma membrane (except thyroid hormones) Effects mediated through second-messenger systems Peptide hormones Include all the hormones that are not listed above. Derived from proteins Plasma membrane impermeable Receptor located in plasma membrane Hormone Receptors Hormones stimulate only those cells that have specific receptors for them. To each of many hormones, there can be several types and subtypes of receptors. Different subtypes of the receptors mediate different effects. The effects of each hormone on individual target cells are determined by the specific subtype of receptors that the cells carry. Hormones bind to their receptors located either in the plasma membrane or in the nucleus, and activate the receptors. The activated receptors then turn on or off certain metabolic pathways. The intermediate processes between receptor activation and the final biological effects of the hormone, are called signal transduction. Up- and Down-Regulation of Receptors Up-regulation: Long-term exposure to low levels of the hormone causes an increase in the number of receptors and sensitivity to the hormone. Down-regulation (desensitization): Long-term exposure to high levels of the hormone causes a decrease in the number of receptors and sensitivity to the hormone. Hormone Deactivation Hormones must be deactivated after carrying out their tasks. The liver performs this function in less than two minutes after they have gone into circulation in the bloodstream. Individual Endocrine Glands The Pituitary Gland Anterior Lobe Hormones The anterior pituitary synthesizes and secretes six hormones. a. Follicle-stimulating hormone (FSH) stimulates follicle and egg development in the ovaries, and sperm production in the testes. b. Luteinizing hormone (LH) stimulates female ovulation and growth of the corpus luteum. In males, LH stimulates the testes to secrete testosterone. c. Thyroid-stimulating hormone (TSH) or thyrotropin stimulates the thyroid to produce and secrete its hormones. d. Adrenocorticotropic hormone (ACTH) stimulates the adrenal cortex to secrete its hormones, as well as fat catabolism in adipose tissue and insulin secretion by the pancreas. e. Prolactin (PRL) acts on the female mammary gland to promote milk synthesis. In males, it indirectly enhances the secretion of testosterone. Growth hormone (GH), or somatotropin, stimulates cellular growth, mitosis, and differentiation, promoting overall tissue and organ growth. FSH, LH, TSH, and ACTH are called tropic hormones because their targets also are endocrine glands. Secretion of the tropic hormones are subject to the feedback control of their target hormones in the blood. Posterior Lobe Hormones The posterior lobe stores and secretes two hormones manufactured in the hypothalamus. Antidiuretic hormone (ADH) or vasopressin Two receptors, V1 and V2, mediates totally different effects. V1 receptors in vascular smooth muscles mediate vasoconstriction while V2 receptors in renal collecting ducts mediate an increase in water reabsorption. Oxytocin (OT) stimulates uterine labor contractions and milk release by mammary glands. Hypothalamus The hypothalamus secretes both releasing hormones and inhibiting hormones to regulate the release of anterior pituitary hormones. They include thyrotropin-releasing hormone (TRH), corticotropin-releasing hormone (CRH), gonadotropin-releasing hormone (GnRH), prolactin-releasing factor (PRF), prolacting-inhibiting factor (PIF), growth hormone-releasing hormone (GHRH), and growth hormone-inhibiting hormone (GHIH). Secretion of hypothalamic hormones is controlled normally via negative feedback inhibition by their target pituitary hormones. The Pineal Gland The pineal gland (epiphysis cerebri) is attached to the roof of the third ventricle. Its size regresses with age. The pineal gland produces serotonin during the day, and melatonin at night. There may be a relationship between pineal gland and sexual maturation, mood, including depression and sleep disorders, and aging. The Thymus The thymus, located in the mediastinum, undergoes involution after puberty. The thymus secretes thymopoietin and thymosins that regulate the development and activation of T-lymphocytes. The Thyroid 1. The thyroid, located below the larynx, is the largest endocrine gland, and receives the highest rate of blood flow per gram of tissue. 2. Thyroid follicular cells secrete thryoxine (T4) and triiodothyronine (T3). Target cells convert T4 to T3. The effects of T3 on target cells increase the oxygen consumption and heat production in the cell, accounting for the calorigenic effect. This effect is stimulated by cold weather and pregnancy. 3. C cells (parafollicular cells) secrete calcitonin, a hormone that lowers blood calcium levels by promoting calcium deposition in bone. The Parathyroids 1. The parathyroids (usually four) are located on the posterior of the thyroid. 2. The parathyroids secrete parathyroid hormone (PTH) in response to hypocalcemia. PTH raises blood levels of calcium by promoting its absorption through the intestines, by inhibiting urinary excretion of calcium, and by increasing osteoclast activity. PTH reduces blood levels of phosphate. The Adrenals The Adrenal Medulla The medulla secretes catecholamines (epinephrine and norepinephrine) in response to sympathetic stimulation. Their effects mimic those of the sympathetic nervous system but last longer because they are secreted into the bloodstream. The Adrenal Cortex a. The adrenal cortex consists of three layers of modified epithelial cells: the outer zona glomerulosa, a middle zona fasciculata, and an inner zona reticularis. b. The cortex secretes more than 25 steroid hormones (corticosteroids) that fall into three categories: sex steroids (androgens, such as DHEA), mineralocorticoids (aldosterone), and glucocorticoids (cortisol). Glucocorticoid secretion, as stimulated by ACTH, stimulates fat and protein catabolism, and increases energy supplies in the bloodstream. These hormones are secreted in response to stress. The Pancreas a. Insulin, from beta cells, is secreted in response to rising blood levels of glucose and other nutrients. Insulin promotes the synthesis of glycogen, fat, and protein, thus lowering blood glucose levels. b. Glucagon, from alpha cells, is secreted in response to low blood levels of glucose. It stimulates fat catabolism, glycogenolysis, and gluconeogenesis. c. Somatostatin (from delta cells) is chemically identical to GHIH, and is secreted by the pancreas as a paracrine secretion. It diffuses to alpha and beta cells and modulates their secretion of glucagon and insulin. The Gonads 1. The gonads are both exocrine and endocrine. 2. Ovarian follicles produce estradiol prior to menstruation, and progesterone afterward. The follicle secretes inhibin to prevent further release of FSH. 3. Interstitial cells between seminiferous tubules secrete testosterone, which stimulates development of the male reproductive system and masculine physique. Sustentacular cells of the testes secrete inhibin, which also slows FSH release. Endocrine Cells in Other Organs 1. The heart secretes atrial natriuretic factor (ANF) when overstretched by high blood pressure. This increases urine output to help lower blood pressure. 2. The kidneys produce calcitrol that affects the handling of calcium by the kidneys, small intestines, and bones, and erythropoietin that stimulates bone marrow to produce more red blood cells. 3. The liver secretes somatomedians, some of the body's erythropoietin, and a prohormone, angiotensinogen. 4. The stomach and small intestine produce enteric hormones that coordinate the activities of the digestive system. 5. 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