Physiology Study Guide Final.docx

Physiology Study Guide Final Hemocrit- % of total blood volume that is occupied by packed red blood cells. It is determined by drawing blood sample into a narrow capillary tube and spinning it in a centrifuge so that the heavier red blood cells go to the bottom and the thin lighter wbcs and platelets in the middle and plasma on top. Normal Hemocrit range is 40-54% FOR A MAN AND 37-47% for a woman The hemoglobin value reflects the oxygen-carrying capacity of red blood cells. In a red cell count, a machine counts erythrocytes as they stream through a beam of light. Total white cell count includes all types of leukocytes but does not distinguish between them. The differential white cell count presents estimates of the relative proportions of the five types of leukocytes in a thin blood smear stained with biological dyes. Platelet count is a suggestive of the bloods ability to clot. Thrombopoietin Regulates Platelet Production Thrombopoietin (TPO) is a glycoprotein that regulates the growth and maturation of megakaryocytes, the parent cells of platelets. Its produced primarily in the liver but also in the kidney. Erythropoitein Regulates RBC Production Red blood cell production= Erythropoiesis It is controlled by the glycoprotein erythropoietin (EPO), assisted by several cytokines Its made primarily in the kidneys of adults. The stimulus for EPO synthesis and release is hypoxia, low oxygen levels in the tissues. Hypoxia stimulates production of a transcription factor called hypoxia-inducible factor 1 or H1F-1. This turns on the EPO gene to increase EPO synthesis. This pathway helps the body maintain homeostasis. By stimulating the synthesis of red blood cells, EPO puts more hemoglobin into the circulation to carry oxygen Red Blood Cells Erythrocytes are the most abundant cell type in the blood. Primary function of rbc?s is to facilitate oxygen transport from the lungs to cells, and carbon dioxide transport from cells to lungs. Mature RBCs Lack a Nucleus In bone marrow, committed progenitor cells differentiate through several stages into large, nucleated erythroblasts. As erythroblasts mature, nucleus condences and cell shrinks in diameter from 20 um to about 7 um. In the last stage before maturation, the nucleusis pinched off and phagocytosed by bone marrow macrophages. At the same time other membranous organelles. At the same time, other membranous organelles break down and disappear. Reticulocyte ? Final immature cell form Functions of Kidneys 5 areas of kidney function Regulation of extracellular fluid volume and blood pressure ECF volume decreases, so does blood pressure. Kidneys work with CVS system to ensure blood pressure and tissue perfusion remain within an acceptable range. Regulation of osmolarity Body integrates kidney function with behavioral drives, such as thirst, to maintain blood osmolarity at a value close to 290mOsM Maintenance of ion balance The kidneys keep concentrations of key ions within a normal range by balancing dietary intake with urinary loss. Sodium (Na+) is the major ion involved with regulation of extracellular fluid volume and osmolarity. Potasium (K+) and calcium (Ca2+) are also closely regulated Homeostatic regulation of pH If ECF fluid becomes too acidic, the kidneys remove H+ and conserve bicarbonate ions, which act as a buffer. When ECF becomes too alkaline, the kidneys remove HCO3- and conserve H+ Excretion of wastes Kidneys remove metabolic waste products and foreign substances, such as drugs and environmental toxins A metabolite of hemoglobin called urobilinogen gives urine its characteristic yellow color. Kidneys remove hormones from blood. Kidneys also actively remove the artificial sweetener saccharin and the anion benzoate, part of the preservative potassium benzoate Production of hormones Kidney cells synthesize erthropoitin, the cytokine/hormone that regulates red blood cell synthesis. They also release rennin, an enzyme that regulates the production of hormones involved in sodium balance and blood pressure homeostasis. Kidneys have a tremendous reserve capacity Anatomy of the Urinary System The urinary system is composed of the kidneys and accessory structures. The study of kidney function is called renal physiology Nephorons- Microscopic hollow tubules that make up the bulk of the paired kidneys. These tubules modify the composition of the fluid as it passes through. The modified fluid leaves the kidney and passes into a hollow tube called a ureter. The nephron is the functional unit of the kidney(which is the smallest structure that can perform all the functions of an organ). The nephron begins with a hollow, ball-like structure called Bowmans capsule that surrounds the glomerulus. 3 basica processes take place in the nephron: filtration, reabsorption, and secretions. There are 2 ureters. One leading from each kidney to the urinary bladder. The bladder expands and fills with urine until, by reflex action, it contracts and expels urine through a single tube, the urethra. Urethra- in males it exits the body through the shaft of the penis. In females the urethral opening is found anterior to the openings of the vagina and anus. Micturition, or urination is the proves by which urine is excreted. Kidneys are site of urine formation. They lie on their side of the spine at the level of the 11th and 12 ribs, just above waist. They are below diaphragm and outside abdominal cavity, sandwiched between the membranous peritoneum, which lines the abdomen, and the bones and muscles of the back. Kidneys are arranged in two layers: an outer cortex and inner medulla. They are formed and arranged by Nephrons 90% of the nephrons in a kidney are almost completely contained within the cortex, but the other 20% called juxtamedullary nephrons dip down into medulla. Renal arteries- branch off the abdominal aorta. They supply blood to the kidneys. Renal veins carry blood from the kidneys to the inferior vena cava Bowmans capsule. The endothelium of the glomerulus is fused to the epithelium of Bowmans capsule so that fluid filtering out of the capillaries passes directly into the lumen of the tubule. The combination of glomerulus and Bowmans capsule is called the renal corpuscle. From Bowmans capsule, filtered fluid flows into proximal tubule, then into the loop of Henle, a hairpin-shaped segment that dips down toward the medulla and then back up. The loop of Henle is divided into two limbs, a thin descending limb and an ascending limb with thin and thick segments. The fluid then passes into the distal tubule. The distal tubules of up to eight nephrons drain into a single larger tube called the collecting duct. The distal tubule and its collecting duct together form the distal nephron. Collecting ducts pass from the cortex through the medulla and drain into the renal pelvis. From the renal pelvis, the filtered and modified fluid, now called urine flows into the ureter on its way to excretion. Juxtaglomerular apparatus- The region where the nephron twists and folds back on itself so that the final part of the ascending limb of the loop of Henle passes between the afferent and efferent arterioles. It consists of macula densa and granular cells. Filtration in the nephron. Is the movement of fluid from blood into the lumen of the nephron. Takes place only in the renal corpuscle, where the walls of glomerular capillaries and Bowmans capsule are modified to allow bulk flow of fluid. Glomerular filtration rate (GFR)- The volume of fluid that filters into Bowmans capsule peer unit time. Autoregulation of glomerular filtration rate is a local control process in which the kidney maintains a relatively constant GFR in the face of normal fluctuations in blood pressure. One important function of GFR autoregulation is to protect the filtration barriers from high blood pressures that might damage them. The myogenic response is the intrinsic ability of vascular smooth muscle to respond to pressure changes. Tubuloglomerular feedback is a paracrine signaling mechanism through which changes in fluid flow through the loop of Henle influence GFR. The myogenic response of afferent arterioles is similar to autoregulation in other systemic arterioles. When smooth muscle in the arteriole wall stretches because of increased blood pressure, stretch-sensitive ion channels open, and the muscle cells depolarize. Depolarization opens voltage-gated Ca2+ channels and the vascular smooth muscle contracts. Vasoconstriction incrases resistance to flow and so blood flow through the arteriole diminishes. The decrease in blood flow decreases filtration pressure in the glomerulus. If blood pressure decreases, the tonic level of arteriolar contraction disappears, and the arteriole becomes maximally dilated. However, vasodilation is not as effective at maintaining GFR as vasoconstriction because normally the afferent arteriole is failry relaxed. When blood pressure drops below 80 mm Hg, GFR decreases ? this decrease is adaptive in the sense that if less plasma is filtered, the potential for fluid loss in the urine is decrased. So a decrease in GFR helps the body conserve blood volume Tubuloglomerular Feedback. It is a local control pathway in which fluid flow through the tubule influences GFR. The twisted configuration of the nephron causes the final portion of the ascending limb of the loop of Henle to pass between the afferent and efferent arterioles. The tubule and arteriolar walls are modified in the regions where they contact each other and together form the juxtaglomerular apparatus. The modified portion of the tubule epithelium is a plaque of cells called the macula densa. The adjacent wall of the afferent arteriole has specialized smooth muscle cells called granular cells. The granular cells secrete rennin, an enzyme involved in salt and water balance. When NaCl delivery past the macula densa increases as a result of increased GFR, the macula densa cells send a paracrine message to the neighboring afferent arteriole. The afferent arteriole constricts, increasing resistance and decreasing GFR. Tubuloglomerular feedback helps GFR autoregulation GFR increases Flow through tubule increases Flow past macula densa increases Paracrine from macula densa to afferent arteriole Afferent arteriole constricts Resistance in afferent arteriole increases Hydrostatic pressure in glomerulus decreases GFR decreases Hormones and Autonomic Neurons also influence GFR The importance of the kidneys in systemic blood pressure homeostasis means that integrating centers outside the kidney can override local controls. Hormones and autonomic nervous system alter glomerular filtration rate in 2 ways: 1. By changing resistance in the arterioles and 2. By altering the filtration coefficient. Neural control of GFR is mediated by sympathetic neurons that innervate both the afferent and efferent arterioles. Sympathetic innervations of a-receptors on vascular smooth muscle causes vasoconstriction. If sympathetic activity is moderate, there is little effect on GFR. If systematic blood pressure drops sharply, however, as occurs with hemorrhage or severe dehydration, sympathetically induced vasoconstriction of the arterioles decreases GFR and renal blood flow. Whatever the fuck that means. This is an adaptive response that helps conserve fluid volume Angiotensin II, a potent vasoconstrictor, and prostaglandins, which act as vasodilators both influence arteriolar resistance. They may affect the filtration coefficient by acting on podocytes or mesangial cells. Podocytes change the size of the glomerular filtration slits. If slit widens more surface area is available for filtration, and GFR increases. Contraction of mesanglial cells apparently changes the glomerular capillary surface area available for filtration. Principles governming the tubular reabsorption of solutes and water. Na+ is reabsorbed by active transport Electrochemical gradient drives anion reabsorbtion Water moves by osmosis, following solute reabsorption Concentrations of other solutes increase as fluid volume in lumen decreases. Permeable solutes are reabsorbed by diffusion Reabsorption- the process of moving substances in the filtrate from the lumen of the tubule back into the blood flowing through peritubular capillaries. Occurs when proximal tubule cells transport solutes out of the lumen and water follows by osmosis. Reabsorption of water and solutes from the tubule lumen to the extracellular fluid depends on active transport. The filtrate flowing out of Bowmans capsule into the proximal tubule has the same solute concentrations as extracellular fluid. To move solute out of the lumen, the tubule cells must therefore use active transport to create concentration or electrochemical gradients. Water osmotically follows solutes as they are reabsorbed. Active transport of Na+ from the tubule lumen to the extracellular fluid creates a transepithelial electrical gradient in which the lumen is more negative than the ECF. Anions then follow thte positively charged Na+ out of the lumen. The net movement of Na+ and anions from lumen to ECF dilutes the luminal fluid and increases the concentration of the ECF, so water leaves the tubule by osmosis. The loss of volume from the lumen increase the concentration of solutes left behind in the filtrate: an unchanged amount of solute in a smaller volume increases concentration. Once luminal solute concentrations are higher than solute concentrations in the extracellular fluid, the solutes diffuse out of the lumen if the epithelium of the tubule is permeable to them. Reabsorption involves both epithelial transport, in which substances cross both the apical and basolateral membranes of the tubule epithelial cell, and the paracellular pathway, in which substances pass through the junction between two adjacent cells. Which route a solute takes depends on the permeability of the epithelial junctions and on the electrochemical gradient for the solute. For solutes that move through the epithelial cells, their concentration or electrochemical gradients determine their transport mechanisms. Solutes moving down their gradient use open leak channels or facilitated diffusion carriers to cross the cell membrane. Molecules that need to be pushed against their gradienct are moved by either primary or secondary active transport. Sodium is directly or indeirectly involved in many instances of both passive and active transport. Secretion- Secretion is the transfer of molecules from extracellular fluid into the lumen of the nephron. Secretion, like reabsorption, depends mostly on membrane transport systems. The secretion of potassium and hydrogen by the nephron is important in the homeostatic regulation of those ions. Secretion enables the nephron to enhance excretion of a substance. If a substance is filtered and not reabsorbed it is excreted very efficiently. If the substance is filtered into the tubule, not reabsorbed, and then more of it is secreted into the tubule from the peritubular capillaries, excretion is even more efficient. Secretion is an active process because it requires moving substrates against their concentration gradients. Most organic compounds are transported across the tubule epithelium into the lumen by secondary active transport. It removes selected molecules from the blood and adds them to the filtrate in the tubule lumen. Although secretion and glomerular filtration both move substances from blood into the tubule, secretion is a more selective process that usually uses membrane proteins to move molecules across the tubule epithelium. Excretion- tells us what the body is eliminating, excretion by itself cannot tell us the details of renal function. Looking at the excretion rate of a substance tells us nothing about hwo the kidney handled the substance. The excretion rate of a substance depends on 1. Its filtration rate and 2. Whether th substance is reabsorbed, secreted, or both as it passes through the tubule. Clearance- the rate at which that solute disappears from the body by excretion or by metabolism 180 liters of fluid filters into Bowmans capsule each day. As filtrate flows through the proximal tubule, about 70% of its volume is reabsorbed, leaving 54 liters in the lumen. Filtrate leaving the proximal tubule has the same osmolarity as filtrate that entered. So we say that the primary function of the proximal tubule is the bulk reabsorption of isosmotic fluid. After leaving the proximal tubule, filtrate passes into the loop of Henle, the primary site for creating dilute urine. As the filtrate passes through the loop, proportionately more solute is reabsorbed than water, and the filtrate becomes hyposmotic relative to the plasma. When filatrate flows out of the loop it averages 100mOsM, and its volume has fallen from 54 to 18 L/day. Now 90% of volume originally filtered into bowmans capsule has been reabsorbed into the capillaries. From the loop of Henle, filtrate passes into the distal tubule and the collecting duct. In these 2 segments, the fine regulation of salt and water balance takes place under the control of several hormones. Reabsorption and secretion determine the final composition of the filtrate. By the end of the collecting duct, the filtrate has a volume of 1.5 L/day and an osmolarity that can range from 50 mOsM to 1200. The final volume and osmolarity of urine depend on the bodys need to conserve or excrete water and solute. Amount excreted= amount filtered- amount reabsorbed + amount secreted Renal Corpuscle- consists of the glomerular capillaries surrounded by Bowmans capsule. Filtration pressure in the renal corpuscle depends on hydrostatic pressure and is opposed by colloid osmotic pressure and capsule fluid pressure Filtration. First step in urine formation. Process which creates a filtrate whos composition is like that of plasma ? most of the plasma proteins. Blood cells remain in the capillary, so that the filtrate is composed only of water and dissolved solutes. Only 1/5 of the plasma that flows through the kidneys filters into the nephrons. The remaining 4/5 of the plasma, along with most plasma proteins and blood cells, flows into the peritublar capillaries. Filtration takes place in the renal corpuscle. Substances leaving the plasma must pass through three filtration barriers before entering the tubule lumen: the glomerular capillary endothelium, a basal lamina, and the epithelium of Bowmans capsule. Filtration fraction: The % of total plasma volume that filters into the tubule. Only 20% of the plasma that passes through the glomerulus is filtered. Less than 1% of filtered fluid is eventually excreted. 1st barrier= Capillary endothelium. Glomerular capillaries are fenestrated capillaries with large pores that allow most components of the plasma to filter through the endothelium. The pores are small enough, however, to prevent blood cells from leaving the capillary. The negatively charged proteins on the pore surfaces also repel negatively charged plasma proteins. Glomerular mesangial cells lie between and around the glomerular capillaries. Mesangial cells have cytoplasmic bundles of actin-like filaments that enable them to contract and alter blood flow through the capillaries. Mesangial cells secrete cytokines associated with immune and inflammatory processes. Disruptions of mesangial cell function have been linked to several disease processes in the kidney. 2nd filtration barrier= basal lamina. An acellular layer of extracellular matrix that separates the capillary endothelium from the epithelial lining of Bowmans capsule. The basal lamina consists of negatively charged glycoproteins, collagen, and other proteins. The lamina acts like a coarse sieve, excluding most plasma proteins from the fluid that filters through it. 3rd filtration barrier= the epithelium of Bowman?s capsule. The portion of the capsule epithelium that surrounds each glomerular capillary consists of specialized cells called podocytes. Podocytes have long cytoplasmic extensions called foot processes that extend from the main cell body. These processes wrap around the glomerular capillaries and interlace with one another, leaving narrow filtration slits closed by a semiporous membrane. The filtration slit membrane contains several unique proteins, including nephrin and podocin. These proteins were discovered by investigators looking for the gene mutations responsible for two congenital kidney diseases. In these diseases where nephrin or podocin are absent or abnormal, proteins leak across the glomerular filtration barrier into the urine. Capillary Pressure Causes Filtration The driving filtration across the walls of the glomerular capillaries. The process is similar in many ways to filtration of fluid out of systemic capillaries and is influence by three pressures The hydrostatic pressure of blood flowing through the glomerular capillaries forces fluid through the leaky endothelium. Capillary blood pressure averages 55 mm Hg and favors filtration into Bowmans capsule. Pressure declines along the length of the capillaries but it remains higher than opposing pressures. Consequently, filtration takes place along nearly the entire length of the glomerular capillaries. The colloid osmotic pressure inside glomerular capillaries is higher than that of the fluid in Bowmans capsule. This pressure gradient is due to the presence of proteins in the plasma. The osmotic pressure gradient averages 30 mm Hg and favors fluid movement back into the capillaries. Bowmans capsule is an enclosed space and so the presence of fluid in the capsule creates a hydrostatic fluid pressure that opposes fluid movement into the capsule. Fluid filtering out of the capillaries must displace the fluid already in the capsule lumen. Hydrostatic fluid pressure in the capsule averages 15 mm Hg, opposing filtration. The 3 pressures- capillary blood pressure, capillary colloid osmotic pressure, and capsule fluid pressure. The net driving force is 10 mm Hg in the direction favoring filtration. Although this pressure may not seem high, when combined with the very leaky nature of the fenestrated capillaries, it results in rapid fluid filtration into the tubules. The volume of fluid that filters into the Bowmans capsule per unit time is the glomerular filtration rate (GFR). Average GFR is 125 mL/min, or 180 L/day, an incredible rate considering that total plasma volume is only about 3 liters. This rate means that kidneys filter the entire plasma volume 60 times a day, or 2.5 times every hour. If most of the filtrate were not reabsorbed during its passage through the nephron, we would run out of plasma in only 24min of filtration GFR is influenced by two factors: the net filtration pressure just described and the filtration coefficient. Filtration pressure is determined primarily by renal blood flow and blood pressure. The filtration coefficient has two components: the surface area of the glomerular capillaries available for filtration and the permeability of interface between the capillary and Bowmans exchange at the alveoli, where the rate of gas exchange depends on partial pressure differences, the surface area of the alveoli, and the permeability of the alveolar membrane. GFR is Relatively Constant Blood pressure provides the hydrostatic pressure that drives glomerular filtration. Therefore, it might seem reasonable to assume that if blood pressure increased, GFR would increase, and if blood pressure fell, GFR would decrease. That is usually the case but instead GFR is relatively constant over a wide range of blood pressures. As long as mean arterial blood pressure remains between 80 mm Hg and 180 mm Hg, GFR averages 180 L/day. GFR is controlled primarily by regulation of blood flow through the renal arterioles. If the overall resistance of the renal arterioles increases, renal blood flow decreases, and blood is diverted to other organs. The effect of increased resistance on GFR, however, depends on where the resistance change takes place. If resistance increases in the afferent arteriole, hydrostatic pressure decreases on the glomerular side of the constriction. This translates into a decrease in GFR. If resistance increases in the efferent arteriole, blood dams up in front of the constriction and hydrostatic pressure in the glomerular capillaries increases. Increased glomerualar pressure increases GFR. The opposite changes occur with decreased resistance in the afferent or efferent arterioles. Most regulation occurs at the afferent arteriole. Aldosterone Controls Sodium Balance The regulation of blood Na+ levels takes place through one of the most complicated endocrine pathways of the body. The reabsorption of sodium in the distal tubules and collecting ducts of the kidney is regulated by the steroid hormone aldosterone: the more aldosterone the more sodium reabsorption. Because one target of aldosterone is increased activity of sodium ? potassium ? ATPase, aldosterone also causes potassium secretion. Aldosterone is a steroid hormone synthesized in the adrenal cortex, the outer portion of the adrenal gland that sits atop each kidney. Like other steroid hormones, aldosterone is secreted into the blood and transported on a protein carrier to its target. The primary site of aldosterone action is the last 1/3 of the distal tubule and the portion of the collecting duct that runs through the kidney cortex. The primary target of aldosterone is principal cells, or P cells. Principal cells are arranged much like other polarized transporting epithelial cells, with Na+ - K+ - ATPase pumps on the basolateral membrane, and various channels and transporters on the apical membrane. In principal cells, the apical membrane contain leak channels for Na+ and for K+. Aldosterone enters P cells by simple diffusion. Once inside it combines with cytoplasmic receptor. In the early response phase, apical Na+ and K+ channels increase their open time under the influence of an as-yet- unidentified signal molecule. As intracellular Na+ levels rise, the Na+ - K+ - ATPase speeds up, transporting cytoplasmic Na+ into the ECF and bringing K+ from the ECF into the Pcell. The net result is a rapid increase in Na+ reabsorption and K+ secretion that does not require the synthesis of new channel or ATPase proteins. In the slower phase of aldosterone action, newly synthesized channels and pumps are inserted into epithelial cell membranes. Note: Na+ and water reabsorption are separately regulated in the distal nephron. Water doesnot automatically follow Na+ reabsorption: vasopressin must be present to make the distal- nephron epithelium permeable to water. In contrast, Na+ reabsorption in te proximal tubule is automatically followed by water reabsorption because the proximal tubule epithelium is always freely permable to water/ Aldosterone acts on principle cells. Process Aldosterone combines with a cytoplasmic receptor Hormone-receptor complex initiates transcription in the nucleus New protein channels and pumps are made Aldosterone-induced proteins modify existing proteins Result is increased Na+ reabsorption and K+ secretion Low Blood Pressure Stimulates Aldosterone Secretion There are two primary stimuli that controls physiological aldosterone secretion form the adrenal cortex. 1. Increased extracellular K+ concentration and 2. Decreased blood pressure. Elevated K+ concentrations act directly on the adrenal cortex in a reflex that protects the body from hyperkalemia. Decreased blood pressure initiates a complex pathway that results in release of hormone, angiotensin II, that stimulates aldosterone secretion in most situations. Two additional factors modulate aldosterone release in pathological states: an increase in ECF osmolarity acts directly on adrenal corted cells to inhibit aldosterone secretion during dehydration and abnormally large decrease in plasma Na+ can directly stimulate aldosterone secretion. The Renin-Angiotensin-Aldosterone Pathway Angiotensin II (ANG II) is the usual signal controlling aldosterone release from the adrenal cortex. ANG II is one component of the rennin-angiotensin-aldosterone system (RAAS), a complex, multistep pathway for maintainging blood pressure. The RAAS pathway begins when juxtaglomerular granular cells in the afferent arterioles of a nephron secrete an enzyme called rennin. Renin converts an inactive plasma protein, angiotensinogen, into angiotensin I (ANG I). When ANG I in the blood encounters an enzyme called angiotensin- converting enzyme (ACE), ANG I is converted into ANG II. This conversion was originally thought to take place only in the lungs, but ACE is now known to occur on the endothelium of blood vessels throughout the body. When ANG II in the blood reaches the adrenal gland, it causes synthesis and release of aldosterone, Finally, at the distal nephron, aldosterone initiates a series of intracellular reactions that cause the tubule to reabsorb sodium Na+ The rennin-angiotensin-aldosterone system (RAAS). The stimuli that begin the RAAS pathway are all related either directly or indirectly to low blood pressure. The granular cells are directly sensitive to blood pressure. They respond to low blood pressure in renal arterioles by secreting rennin Sympathetic neurons, activated by the cardiovascular control center when blood pressure decreases, terminate on the granular cells and stimulate rennin secretion Paracrine feedback-from the macula densa in the distal tubule to the granular cells-stimulates rennin release. When fluid flow thorugh the distal tubule is relatively high, the macula densa cells release paracrines, which inhibit rennin release. When fluid flow in the distal tubule decreases, macula densa cells signal the granular cells to secrete rennin. Sodium reabsorption does not directly raise low blood pressure, but retention of Na+ increase osmolarity, which stimulates thirst. Fluid intake when the person drinks more water increases ECF volume. When blood volume increase, blood pressure also increases. The effects of RAAS pathway are not limited to aldosterone release, however, Angiotensin II is a remarkable hormone with additional effects directed at raising blood pressure. These actions make ANG II an important hormone in its own right, not merely an intermediate step in the aldosterone control pathway. ANG II ANG II has major effects on fluid balance and blood pressure beyond stimulating aldosterone secretion, underscoring the integrated functions of the renal and cardiovascular systems. ANG II increases blood pressure both directly and indirectly through four additional pathways. ANG II increases vasopressin secretion. ANG II receptors in the hypothalamus initiate this reflex. Fluid retention in the kidney under the influence of vasopressin helps conserve blood volume, thereby maintaining blood pressure. ANG II stimulates thirst. Fluid ingestion is a behavioral response that expands blood volume and raises blood pressure ANG II is one of the most potent vasoconstrictors known in humans. Vasoconstriction causes blood pressure to increase without a change in blood volume Activation of ANG II receptors in the cardiovascular control center increases sympathetic output to the heart and blood vessels. Sympathetic stimulation increase cardiac output and vasoconstriction, both of which increase blood pressure. ACE inhibitors- drugs that block the ACE-mediated conversion of ANG I to ANG II< thereby helping to relax blood vessels and lower blood pressure. Less ANG II also means less aldosterone release, a decrease in Na+ reabsorption and, untimely a decrease in ECF volume. All these responses contribute to lowering blood pressure. ACE inhibitors have side effects. ACE inactives a cytokine called bradykinin. When ACE is inhibited by drugs, bradykinin levels increase, and in some patients this creates a dry, hacking cough. One solution was the development of drugs called angiotensin receptor blockers that block the blood pressure raising effects of ANG II at target cells by binding to AT 1 receptors. Direct rennin inhibitors. New drug. They decrease the plasma activity of rennin, which in turn blocks production of ANG I and inhibits the entire RAAS pathway ANP Promotes Sodium and Water Excretion Natriuresis- sodium loss caused by hormones. Diuresis-water loss. If these two are found they are used to clinically lower blood volume and blood pressure in patients with essential hypertension. Natriuretic peptide (NP)- one member of a family of hormones? that appear to be endogenous RAAS antagonists. Atrial Natriuretic peptide (ANP)- a peptide hormone produced in specialized myocardial cells in the atria of the heart. It is synthesized as part of a large prohormone that is cleaved into several active hormone fragments. Brain natriuretic peptide (BNP)- related hormone to atrial natriuretic peptide. It is synthesized by ventricular myocardial cells and certain brain neurons. Both natriuretic peptides are released by the heart when myocardial cells stretch more than normal, as would occur with increased blood volume. The peptides bind to membrane receptors that work though a cGMP second message system. At the systematic level, natriuretic peptides enhance Na+ and water excretion, but the exact mechanisms by which they do so are not clear. NPs increase GFR and directly decrease NaCL and water reabsorption in the collecting duct. The cellular mechanism by which NPs affect tubular reabsorption is not clear. Natriurectic peptides also act indirectly to increase Na+ and water excretion by inhibiting the release of rennin, aldosterone, and vasopressin, actions that reinforce the natriuretic- diuretic effect. In addition, natriurectic peptides act directly on the cardiovascular control center of the medulla to lower blood pressure. Brain natriurectic peptide (BNP) is now recognized as an important biological marker for heart failure because production of this substance increases with ventricular dilation and increased ventricular pressure. Chemically gated channels- the gating is controlled by intracellular messenger molecules or extracellular ligands that bind to the channel protein. Mecanically gated channels respond to physical forces such as increased in temp or pressure that puts tension on the membrane and pops the channel open. Carrier Proteins Change Conformation to Move Molecules 2nd type of transport protein is carrier protein. Carrier proteins bind with specific substrates and carry them across the membrane by changing conformation. Small organic molecules that are too large to pass through channels cross membranes using carriers. Some carrier proteins move only one kind of molecule and are known as uniport carriers. A carrier that moves more than one kind of molecule at one time is called a cotransporter. If molecules being transported are moving in the same direction, whther into or out of the cell, the carrier proteins are symport carriers. If molecules are being carried in opposite directions, the carrier proteins are antiport carriers. Carriers are large, complex proteins with multiple sub-units. The conformation change required of a carrier protein makes this mode of transmembrane transport much slower than movement through channel proteins. A carrier protein can only move 1000 to 1000000 molecules per second in contrast to tens of millions of ions per second that move through a channel protein. Carriers never create a continous passge between the inside and outside of the cell unlike channel proteins. One side of the carrier protein always creates a barrier that prevents free exchange across the membrane. Movement across the membrane through a carrier prtein is similar. The molecule to be transported binds to the carrier on one side of the membrane. This binding changes the conformation of the carrier so that the opening closes. After a briedf transition in which both sides are closed, the opposite side of the carrier opens to the other side of the membrane. The carrier then releases the molecule being transported into the opposite compartment, having brought it through the membrane without creating a continuous connection between the extracellular and intracellular compartments. Saturation- The rate of substrate transport depends on both the substrate concentration and the number of carrier molecules, a property that is shared by enzymes. For a fixed number of carriers, however, as substrate concentration increases, the transport rate increases up to a maximum, the point at which all carrier binding sites are filled with substrate. This is the point where carriers are said to have reached saturation. At saturation the carriers are working at their maximum rate, and a further increase in substrate concentrations has no effect. Transport maximum- maximum transport rate. Increase the number of carriers can increase a cells transport capacity and avoid saturation. The transport rate at saturation. Reabsorption Active Transport of Sodium The active transport of sodium is the primary driving force for most renal reabsorption. Filtrate entering the proximal tubule is similar in ion composition to plasma, with a higher Na+ concentration than is found in cells, so Na+ in filtrate can enter tubule cells passively by moving down its electrochemical gradient. Apical movement of Na+ uses a variety of symport and antiport transport proteins, or open leak channels. Secondary Active Transport: Symport with Sodium Sodium linked secondary active transport in the nephron is responsible for the reabsorption of many substances, including glucose, amino acids, ions , and various organic metabolites. The apical membrane contains the Na+ - glucose transporter (SGLT) that brings glucose into the cytoplasm against its concentration gradient by harnessing the energy of Na+ moving down its electrochemical gradient. On the basolateral side of the cell, Na+ is pumped out by the Na+ - K+ - ATPase while glucose diffuses out with the aid of a facilitated diffusion GLUT transporter. The same basica pattern holds for many other molecules absorbed by Na+ - dependent transport: an apical symport protein and a basolateral facilitated diffusion carrier. Passive Reabsorption: Urea The nitrogenous waste product urea has no active transporters in the proximal tubule but can move across the epithelium by diffusion if there is a urea concentration gradient. Initially, urea concentrations in the filtrate and extracellular fluid are equal. However, the active transport of Na+ and other solutes in the proximal tubule creates a urea concentration gradient by the following process: When sodium and other solutes are reabsorbed form the proximal tubule, the transfer of osmotically active particles makes the extracellular fluid more concentrated than the filtrate remaining in the lumen. In response to osmotic gradient, water moves by osmosis across the epithelium. Up to this point, no urea molecules have moved out of the lumen because there has been no urea concentration gradient. Now, however, when water leaves the lumen, the filtrate concentrations of urea increases because the same amount of urea is contained in a smaller volume. Once a concentration gradient for urea exists, urea uses facilitated diffusion transporters to move out of the lumen into the extracellular fluid. Transcytosis: Plasma Proteins Filtration of plasma at the glomerulus normally leaves most plasma proteins in the blood, but some smaller protein hormones and enzymes can pass through the filtration barrier. Most filtered proteins are reabsorbed in the proximal tubule, with the result that normally only trace amounts of protein appear in urine. Filtered proteins are too larege to be reabsorbed by carriers or through channels. Instead they enter proximal tubule cells by receptor mediated endocytosis at the apical membrane. Once in the cells, the proteins may be digested and released as amino acids or delivered intact to the extracellular fluid via transcytosis Megalin. Responsible for filtered protein reabsorption and may also play a role in cellular uptake of carrier bound steroid hormeones and lipid soluble vitamins. The protein is a member of the LDL receptoer family. Renal Transport can Reach Saturation Most transport in the nephron uses membrane proteins and exhibits the three characteristics of mediated transport: saturation, specificity, and competition. Saturation refers to the maximum rate of transport that occurs when all vailable carriers are occupied by substrate. At substrate concentrations below the saturation point, transport rate is directly related to substrate concentration. At substrate concentrations equal to or above the saturation point, transport occurs at a maximum rate aka transport maximum. Glucose reabsorption in the nephron is an excellent example of the consequences of saturation. At normal plasma glucose concentrations, all glucose that enters the nephron is reabsorbed before it reaches the end of the proximal tubule. The tubule epithelium is well supplied with carriers to capture glucose as the filtrate flows past. Glucose molecules entering Bowmans capsule in the filtrate are like passengers stepping onto the moving sidewalk. To be reabsorbed, each glucose molecule must bind to a transporter as the filtrate flows through the proximal tubule. If only a few glucose molecules enter the tubule at a time, each one can find a free transporter and be reabsorbed, just as a small number of people moving on the sidewalk all find seats on the train. However if glucose molecules filter into the tubule faster than the glucose carriers can transport them, some glucose remains in the lumen and is excreted in the urine. The plasma concentration at which glucose first appears in the urine is called the renal threshold for glucose. Amount excreted= amount filtered ? amount reabsorbed + amount secreted Glucose excreted= glucose filtered ? glucose reabsorbed Excretion = filtration ? reabsorption Excretion of glucose in the urine is called glucosuria or glycosuria and usually indicates an elevated blood glucose concentration. Raretly, glucose appears in the urine even though the blood glucose concentrations rae normal. Peritubular Capillary Pressures Favor Reabsorption Low pressure favors reabsorption The peritubular capillaries have an average hydrostatic pressure of 10mm Hg where hydrostatic pressure averages 55 mm Hg. Colloid osmotic pressure, which favors movement of fluid into the capillaries, is 30mm Hg. The pressure gradient in peritubular capillaries is 20 mm Hg, favoring the absorption of fluid into the capillaries. Fluid that is reabsorbed passes from the capillaries to the venous circulation and returns to the heart. The Vasa Recta Removes Water. Water or solutes that leave the tubule move into the vasa recta if an osmotic or concentration gradient exists between the medullary interstitium and the blood in the vasa recta. As blood flows deeper into the medulla , it loses water and picks up solutes transported out of the ascending limb of the loop of Henle, carrying these solutes farther into the medulla. By the time blood reaches the bottom of the vasa recta loop, it has a high osmolarity , similar to that of the surrounding interstitial fluid. As blood in the vasa recta flows back toward the cortex, the high plasma osmolarity attracts the water that is being lost from the descending limb. The movement of this water into the vasa recta decereases the osmolarity of the blood whilte simulataneously preventing the water from diluting the concentrated medullary interstitial fluid. The end result of this is that blood flowing through the vasarecta removes the water reabsorbed from the loop of Henle. Without the vasa recta, water moving out of the descending limb of the loop of Henle would eventually dilute the medulalary interstitium. Urea increases the osmolarity of the medullary interstitium The high solute concentration in the medullary interstitium is only partly due to NaCL. Nearly half the solute in this compartment is urea. Membrane transporters for urea are present in the collecting duct and loops of Henle. One family of transporters consists of facilitated diffusion carriers, and the other family has Na+ - dependent secondary active transporters. These urea transporters help concentrate urea in the medullary interstitium, where it contributes to the high interesitial osmolarity Sodium balance and ECF Volume The addition of NaCL to the body raises osmolarity. This stimulus triggers two responses: Vasopressin secretion and thirst. Vasopressin release causes the kidneys to conserve water and concentrate the urine. Thirst promts us to drink water or other fluids. The increased fluid intake decreases osmolarity, but the combination of salt and water intake increases both ECF volume and blood pressure. These increases then trigger another series of control pathways which bring ECF volume, blood pressure, and total body osmolarity back into the normal range by excreting extra salt and water. Only renal sodium absorption is regulated. Daily Water Intake and Excretion are balanced Fluid can be added directly to the plasma by means of intravenous (IV) injection, a medical procedure. Water leaves the body through insensible water loss. This water loss, called insensible because we are not normally aware of it, occurs across the skin surface and during the exhalation of humidified air. Although urine is normally the major route of water loss, in certain situations other routes of water loss can become significant. Excessive sweating is one example. Pathological water loss disrupts homeostasis in two ways. Volume depletion of the extracellular compartment decreases blood pressure. If blood pressure cant be maintained through homeostatic compensations, the tissues do not get adequate oxygen. If the fluid los is hyposmotic to the body, the solutes left behind in the body raise osmolarity, potentially disrupting cell function. Kidneys conserve volume not replace it. The Renal Medulla Creates Concentrated Urine The concentration or osmolarity of the urine is a measure of how much water is excreted by the kidneys.; Removal of excess water in urine is known as dieresis. When the kidneys are conserving water, the urine becomes quite concentrated, up to 4x as concentrated as the blood. The kidneys control urine concentration by varying the amounts of water and sodium reabsorbed in the distal nephrone. To produce dilute urine the kidney must reabsorb solute without allowing wawter to follow by osmosis. This means that the apical tubule cell membranes must not be permeable to water. On the other hand, if urine is to become concentrated, the nephron must be able to reabsorb water but leave solute in the tubule lumen. Fluid leaving the loop of Henle, however, is hyposmotic, with an osmolarity of around 100 mOsM. This hyposmotic fluid is created when cells in the thick portion of ascending limb of the loop transport sodium, potassium, and CL- out of the tubule lumen. These cells are unusual because their apicial surface is impermeable to water. When tehse cells transport solute out of the lumen, water cannot follow, decreasing the concentration of the tubule fluid. The loop of Henle is the primary site where the kidney creates hyposmotic fluid. Once the hyposmotic fluid leaves the loop of Henle, it passes into the distal nephron. Here the water permeability of the tubule cells is variable and under hormonal control. When the apical membrane of distal nephron cells isn?t permeable to water, water cannot leave the tubule, and the filtrate remains dilute. A small amount of additional solute can be reabsorbed as fluid passes along the collecting duct, making the filtrate even more dilute. When this happens, the concentration of urine can be as low as 50 mOsM. When body needs to conserve water by reabsorbing it, the tubule epithelium in the distal nephron must become permeable to water. The cells accomplish this by inserting water pores into their apical membranes. Once water enters the cell osmosis draws water out of the less-concentrated lumen and into the more concentrated interstitial fluid. Water reabsorption in the kidneys conserves water and can decrese body osmolarity to some degree when coupled with excretion of solute in the urine. Only ingestion or infusion of water can replace water that has been lost Vasopressin Controls Water Reabsorption Vasopressin- causes the body to retain water, it is also known as antidiuretic hormone (ADH). When it acts on target cells, water pores are inserted into the apical membrane, allowing water to move out of the lumen by osmosis. The water moves by osmosis because solute concentration in the cells and interstitial fluid of the renal medulla is higher than that of fluid in the tubule. If vasopressin is absent, the collecting duct is impermeable to water. Although a concentration gradient is present across the epithelium, water remains in the tubule, producing dilute urine. The graded effect of vasopressin allows the body to match urine concentration closely to the bodys needs. Vasopressin and Aquaporins Aquaporins- water pores, a family of membrane channels with at least 10 different isoforms that occur in mammalian tissues. The kidney has multiple isoforms of aquaporins, like aquaporin-2 (AQP2), the water channel regulated by vasopressin. AQP2 in a collecting duct cell may be found in 2 locations: on the apical membrane facing the tubule lumen and in the membrane of cytoplasmic storage vesicles. When vasopressin levels are low, the collecting duct cell has few water pores in its apical membrane and stores its AQP2 water pores in cytoplasmic storage vesicles. When vasopressin from the posterior pituitary arrives at its target, it binds to tis V2 receptor on the basolateral side of the cell. Binding activates a G-protein/cAMP second messenger system. Subsequent phosphorylation of intracellular proteins causes the AQP2 vesicles to move to the apical membrane and fuse with it. Exocytosis inserts the AQP2 water pores into the apical membrane. Now the cell is permeable to water. This process which parts of the cell membrane are alternately added by exocytosis and withdrawn by endocytosis is known as membrane recycling. The Loop of Henle is a Countercurrent Multiplier Vasopressin is the signal for water reabsorption out of the nephron tubule, but the key to the kidneys ability to produce concentrated urine is the high osmolarity of the medullar interstitium. Countercurrent Exchange Systems Countercurrent exchange systems require arterial and venous blood vessels that pass very close to each other, with their fluid flow moving in opposite directions. This allows the passive transfer of heat or molecules from one vessel to the other. b/c the countercurrent heat exchanger is easier to understand, we first examine how it works and then apply the same principle to the kidney. With cc heat exchanger, warm arterial blood entering the limb transfers its heat to cooler venous blood flowing from the tip of the limb back into the body. This reduces the amount of heat lost to the external environment. The countercurrent exchange system of the kidney- the lop of Henle- works on the same principle, except that it transfers water and solutes instead of heat. However, because the kidney forms a closed system, the solutes are not lost to the environment. Instead, the solutes concentrate in the interstitium. This process is aided by active transport of solutes out of the ascending limb, which makes the ECF osmolarity even greater. A countercurrent exchange system in which exchange is enhanced by active transport of solutes is called a countercurrent multiplier. The Renal Countercurrent Multiplier The countercurrent multiplier system in the renal medulla. The system has 2 components. 1. Loops of Henle that leave the cortex, dip down into the more concentrated environment of the medulla, then ascend into the cortex again, and the peritubular capillaries known as vasa recta. These capillaries, like the loop of Henle, dip down into the medulla and then go back up to the cortex, also forming hairpin loops. Countercurrent exchange in the medulla of the kidney. The tick ascending limb of the loop of Henle transports salt to create dilute urine. Isosmotic filtrate from the proximal tubule first flows into the descending limb of the loop of Henle. The descending limb is permeable to water but does not transport ions. As the loop dips into the medulla, water moves by osmosis from the descending limb into the progressively more concentrated interstitial fluid, leaving solutes behind in the tubule lumen. The filtrate becomes more concentrated as it moves deeper into the medulla. At the tips of the longest loops of Henle, the filtrate reaches a concentration of 1200 mOsM. Filtrate in shorter loops does not reach such a high concentration. When the fluid flow reverses direction and enters the ascending limb of the loop, the properties of the tubule epithelium change. The tubule epithelium in this segment of the nephron is impermeable to water while actively transporting sodium, potassium, and CL- out of the tubule into the ISFL. The net result of the countercurrent multiplier in the kidney is to produce hyperosmotic ISFL in the medulla and hyposmotic filtrate leaving the loop of Henle. 25% of all sodium and potassium reabsorption takes place in the ascending limb of the loop. Some transporters responsible for active ion reabsorption in the thick portion of the ascending limb. The NKCC symporter uses energy stored in the sodium concentration gradient to transport sodium, potassium, and 2 CL- leave the cells together on a co-trasnport protein or through open channels. NKCC-mediated transport can be inhibited by drugs known as ?loop diuretics,? such as furosemide. DIGESTION The gastrointestinal tract or GI tract, is a long tube passing through the body. The tube has muscular walls lined with epithelium and is closed off by a skeletal ?muscle sphincter at each end. B/c the GI tract opens to the outside world, the lumen and its contents are actually part of the external environment. The primary function of the GI tract is to move nutrients, water, and electrolytes from the external environment into the bodys internal environment. The three enzymes must not digest the cells of the GI tract itself(autodigestion). If protective mechanisms against autodigestion fail, we may develop raw patches known as peptic ulcers on the walls of the GI tract. A challenge the digestive system faces daily is mass balance: matching fluid input with output. People ingest 2 liters of fluid a day. Exocrine glands and cells secrete 7 lieters or so of enzymes, mucus, electrolytes, and water into the lumen of the GI tract. That volume secreted fluid is the equivalent of one sixth of the bodys total body water or more than twice the plasma volume of 3 liters, and it must be reabsorbed or the body would rapidly dehydrate. To maintain homeostasis, the volume of fluid entering the GI tract lumen by intake or secretion must equal the volume leaving the lumen. Another challenge the digestive system faces is repelling foreign invaders. It is counterintuitive, but the largest area of contact between the internal environment and the outside world is in the lumen of the digestive system. As a result, the GI tract, with a total surface area about the size of a tennis court, faces daily conflict between the need to absorb water and nutrients, and the need to keep bacteria, viruses and other pathogens from entering the body. The transporting epithelium of the GI tract is assisted by an array of physiological defense mechanisms, including mucus, digestive enzymes, acid, and the largest collection of lymphoid tissue in the body, the gut-associate lymphoid tissue (GALT). 80% of all lymphocytes in the body are found in the small intestine. The human body meets these sometimes conflicting physiological challenges by coordinating the four basic processes of the digestive system Digestion- the chemical and mechanical breakdown of foods into smaller units that can be taken across the intestinal epithelium into the body Absorption- the active or passive transfer of substances from the lumen of the GI tract to the extracellular fluid Motility- is movement of material in the GI tract as a result of muscle contraction Secretion- refers to both the transepithelial transfer of water and ions from the ECF to the digestive tract lumen and the release of substances synthesized by GI epithelial cells. Motility and secretion are continuous ly regulated to maximize the availability of absorbable material. Motility is regulated because if food moves through the system too rapidly , there is not enough time for everything in the lumen to be digested and absorbed. Secretion is regulated because if digestive enzymes are not secreted in adequate amounts, food in the GI tract cannot be broken down into absorbable form. When digested nutrients have been absorbed and have reached the body?s cells, cellular metabolism directs their use or storage. Some of the same chemical signal molecules that alter digestive motility and secretion also participate in the control of metabolism, providing an integrating link between the two steps. ANATOMY OF THE DIGESTIVE SYSTEM Digestive system- begins with the oral cavity, which serves as a receptacle for food. In the oral vacity the first stages of digestion begin with chewing and the secretion of aliva by three pairs of salivary glands: sublingual glads under the tongue, submandibular glads under the mandible (jawbone), and parotid glands( lying near the hinge of the jaw. Once swallowed, food moves into the GI tract. At intervals along the tract, rings of smooth muscle function as sphincters to separate the tube into segments with distinct functions. Food moves through the tract propelled by waves of muscle contraction. Along the way, secretions are added to the food by secretory epithelium, the liver, and the pancreas, creating a soupy mixture known as chyme. Digestion takes place primarily in the lumen of the tube. The products of digestion are absorbed across the epithelium and pass into the extracellular compartment. From there, they move into the blood or lymph for distribution throughout the body. Any waste remaining in the lumen at the end of the GI tract leaves the body through the opening of the anus. THE DIGESTIVE SYSTEM IS A TUBE When you swallow a piece of food, it passes into the esophagus, a narrow tube that travels through the thorax to the abdomen. The esophageal walls are skeletal muscle initially but transition to smooth muscle about 2/3 of the way down the length. Just below the diaphragm, the esophagus ends at the stomach, a baglike organ that can hold as much as 2 liters of food and fluid when fully expanded. The Stomach is divided into three sections: the upper fundus, the central body, and the lower antrum. The stomach continues digestion that began in the mouth by mixing food with acid and enzymes to create chyme. The pylorus or opening between the stomach and the small intestine is guarded by the pyloric valve- thickened band of smooth muscle relaxes to allow only small amounts of chyme into the small intestine at any one time. The stomach acts as intermediary between the behavioral act of eating and the physiological events of digestion and absorption in the intestine. Integrated signals and feedback loops between the intestine and stomach regulate the rate at which chyme enters the duodenum, ensuring that the intestine is not overwhelmed with more than it can digest and absorb. Most digestion takes place in the small intestine, which is also divided into 3 sections: the duodenum, jejunum, and ileum. Digestion is carried out by intestinal enzymes, aided by exocrine secretions from two accessory glandular organs: the pancreas and the liver. Secretions from these two organs enter the initial section of the duodenum through ducts. A tonically contracted sphincter keeps pancreatic fluid and bile from entering the small intestine except during a meal. Digestion is essentially completed in the small intestine, and nearly all digested nutrients and secreted fluids are absorbed there, leaving about 1.5 liters of chyme per day to pass into the large intestine. In the colon- the proximal section of the large intestine- watery chyme is converted into semisolid feces as water and electrolytes are absorbed out of the chyme and into the ECF. When feces are propelled into the terminal section of the large intestine, known as the rectum, distension of the rectal wall triggers a defacation reflex. Feces leave the GI tract through the anus, with its external anal sphincter of skeletal muscle, which is under voluntary control. The portion of the GI tract running from the stomach to the anus is collectively called the gut. THE GI TRACT WALL HAS 4 LAYERS The basic structure of the GI wall is similar in the stomach and instestines. The 4 layers of the wall are- An inner mucosa facing the lumen A layer known as the submucosa Layers of smooth muscle known collectively as the muscularis externa A covering of connective tissue called the serosa. MUCOSA The mucosa, the inner lining of the GI tract, is created form A single layer of epithelial cells The lamina propria, subepithelial connective tissue that holds the epithelium in place The muscularis mucosae, a thin layer of smooth muscle. Several structural modifications increase the amount of mucosal surface area to enhance absorption First the entire wall is crumped into folds: rugae in the stomach, and plicae in the small intestine. The intestinal mucosa also projects into the lumen in small fingerlike extensions known as villi. Additional surface area is added by tubular invaginations of the surface that extend down into the tubular invaginations of the surface that extend down into the supporting connective tissue. These invaginations are called gastric glands in the stomach and crypts in the intestine. Some of the deepest invaginations from secretory submucosal glands that open into the lumen through ducts. Epithelial cells are the most variable feature of the GI tract, changing from section to section. The cells include transporting epithelial cells, endocrine and exocrine secretory cells, and stem cells. Transporting epithelial cells move ions and water into the lumen, and absorb ions, water, and nutrients into the ECF. At the mucosal, secretory cells release enzymes, mucus, and paracrine molecules into the lumen. At the serosal surface, secretory cells secrete hormones into the blood or paracrine messengers into the ISF, where they act on neighboring cells. The cell to cell junctions that tie GI epithelial cells together very. In the stomach and colon, the junctions form a tight barrier so that little can pass between the cells. In the small intestine, junctions are not as tight. This intestinal epithelium is considered ?leaky? b/c some water and solutes can be absorbed between the cells instead of through them. GI stem cells are rapidly dividing, undifferentiated cells that continuously produce new epithelium in the crypts and gastric glands. As stem cells divide, the newly formed cells are pushed toward the luminal surface of the epithelium. The average life span of a GI epithelial cell is only a few days, a good indicator of the rough life such cells lead. As with other types of epithelium, the rapid turnover and cell division rate in the GI tract makes these organs susceptible to developing cancers. The lamina propria is subepithelial connective tissue that contains nerve fibers and small blood and lymph vessels into which absorbed nutrients pass. This layer also contains wandering immune cells, such as macrophages and lymphocytes, patrolling for invaders that enter through breaks in the epithelium. In the intestine, collections of lymphoid tissue adjoining the epithelium form small nodules and larger Peyer?s patches that create visible bumps in the mucosa. These lymphoid aggregations are a major part of the gut-associated lymphoid tissue (GALT). 3rd region of the mucosa, the muscularis mucosae, separates the mucosa from the submucosa. The muscularis mucosae is a thin layer of smooth muscle, and contraction of this layer alters the effective surface area for absorption by moving the villi back and forth, like waving tentacles of a sea anemone. SUBMUCOSA The layer of the gut wall adjacent to the mucosa, the submucosa, is composed of connective tissue with larger blood and lymph vessels. The submucosa also contains the submucosal plexus, one of the two major nerve networks of the enteric nervous system- helps coordinate digestive function, and the submucosal plexus innervates cells in the epithelial layer as well as smooth muscle of the muscularis mucosae. MUSCULARIS EXTERNA AND SEROSA The outer wall of the GI tract, the muscularis externa, consists primarily of two layers of smooth muscle: an inner circular layer and an outer longitudinal layer. Contraction of the circular layer decreases the diameter of the lumen, and contraction of the longitudinal layer shortens the tube. The stomach has an incomplete third layer of oblique muscle between the circular muscles and submucosa. The 2nd nerve network of the neteric nervous system, the myenteric plexus, lies between the longitudinal and circular muscle layers. The myenteric plexus controls and coordinates the motor activity of the muscularis externa. The outer covering of the entire digestive tract, the serosa, is a connective tissue membrane that is a continuation of the peritoneal membrane lining the abdominal cavity. The peritoneum also forms sheets of mesentery that hold the intestines in place so that they do not become tangled as they move. MOTILITY Serves 2 purposes: 1. Moving food from the mouth to the anus 2. Mechanically mixing food to break it into uniformly small particles. This mixing maximizes exposure of the particles to digestive enzymes by increasing their surface area. Gastrointestinal motility is determined by the properties of the tracts smooth muscle and modified by chemical input from nerves, hormones, and paracrine signals. GI SMOOTH MUSCLE CONTRACTS SPONTANEOUSLY Tonic Contractions that are sustained for minutes or hours occur in some smooth muscle sphincters and in the anterior portion of the stomach. Phasic contractions, with contraction-relaxation cycles lasting only a few seconds, occur in the posterior region of the stomach and in the small intestine. Cycles of smooth muscle contraction and relaxation are associate with spontaneous cycles of depolarization and repolarizatoin known as slow wave potentials. Slow wave potentials differ from myocardial pacemaker potentials in that the former have a much slower rate and do not reach threshold with each cycle. A slow wave that does not reach threshold does not cause a contraction in the muscle fiber. When a slow wave potential does reach threshold, voltage gated Ca2+ channels in the muscle fiber open, Ca2+ enters, and the cell fires one or more action potentials. The depolarization phase of the action potential, like that in myo cardial autorhythnmic cells, is the result of Ca2+ entry into a cell. Contraction of smooth muscle, like that of cardiac muscle, is graded according to the amount of Ca2+ that enters the fiber. The longer the duration of slow wave, the more action potentials fire, and the greater the contraction force in the muscle. Longer the slow wave the longer the contraction. Both amplitude and duration can be modified by neurotransmitters, hormones, or paracrine molecules. Slow wave frequency varies by region of the digestive tract, ranging from 3 waves/min in the stomach to 12 waves/min in the duodenum. Current research indicates that slow waves originate in a network of cells called the interstitial cells of Cajal or ICCs- modified smooth muscle cells lie between smooth muscle layers and the intrinsic nerve plexuses, and they may act as an intermediary between neurons and smooth muscle. Function as the pacemakers for slow wave activity in different regions of the GI tract. Slow waves that begin spontaneously in ICCs spread to adjacent smooth muscle layers through gap junctions. GI SMOOTH MUSCLE EXHIBITS DIFFERENT PATTERNS OF CONTRACTION Muscle contractions in GI tract occur in 3 patterns- Migrating motor complex, Peristalsis and Segmental contractions. Migrating motor complex- a housekeeping function that sweeps food remnants and bacteria out of the upper GI tract and into the large intestine Peristalsis- progressive waves of contraction that move from one section of the GI tract to the next, Circular muscles contract just behind a mass, or bolus, of food. This contraction pushes the bolus forward into a receiving segment, where the circular muscles are relaxed. These contractions push a bolus forward at 2-25 cm/sec. It propels material from pharynx to stomach. Peristalsis contributes to food mixing in the stomach, but in normal digestion intestinal peristaltic waves are limited to short distances. Hormones, paracrine signals, and autonomic nervous system influence peristalsis in all regions of the GI tract. Segmental contractions- short segments of intestine alternately contract and relax. In the contracting segments, circular muscles contract while longitudinal muscles relax. These contractions may occur randomly along the intestine or at regular intervals. Alternating segmental contractions churn the intestinal contents, mixing them, and keeping them in contact with the absorptive epithelium. When segments contract sequentially, in an oral to aboral deirection digesting material is propelled short distances Motility disorders are among the more common gastrointestinal problems. They range from esophageal spasm and delayed gastric emptying to constipation and diarrhea. Irritable bowel syndrome is a chronic functional disorder characterized by altered bowel habits and abdominal pain. SECRETION Cystic fibrosis transmembrane conductance regulator (CFTR chloride channel)- Gated CL- channel. Defects in CFTR channel structure or function lead to the disease cystic fibrosis. ACID SECRETION Parietal cells deep in the gastric glands secrete hydrochloric acid into the lumen of the stomach. Acid secretion in the stomach averages 1 to 3 lieters per day and can create a luminal pH as low as 1. Process begins with H+ from water inside the parietal cell is pumped into the stomach lumen by an H+ - K+ - ATPase in exchange for K+ entering the cell. While acid is being secreted into the lumen, bicarbonate made from CO2 and the OH- from water is absorbed into the blood. The buffering action of HCO3= makes blood leaving the stomach less acidic, creating the ?alkaline tide? that can be measured as a meal is being digested BICARBONATE SECRETION Bicarbonate secretion into the duodenum neutralizes acid entering from the stomach. A small amount of bicarbonate is secreted by duodenal cells, but most comes from the pancrease, which secretes a watery solution of NaHCO3. The exocrine portion of the pancreas consists of lobules called acini that open into ducts whose lumens are part of the bodys external environment. The acinar cells secrete digestive enzymes, and the duct cells secrete the NaHCO3 solution. The pancreas also secretes hormones from islet cells tucked among the acinar cells. Bicarbonate production requires high levels of the enzyme carbonic anhydrase, levels similar to those found in renal tubule cells and red blood cells. Chloride enters the cell on a basolateral NKCCC cotransporter and leaves via an apical CFTR channel. Luminal Cl- then re-enters the cell in exchange for HCO3- entering the lumen. Hydrogen ions produced along with bicarbonate leave the cell on basolateral Na+ - H+ exchangers. The H+ thus reabsorbed into the intestinal circulation helps balance HCO3- put into the blood when parietal cells secrete H+ into the stomach. Electrochecmical and osmotic gradients drive Sodium and water movement. The net movement of negative ions from the ECF to the lumen attracts Na+, which moves down its electrochemical gradient thorugh leaky junctions between the cells. The secretion of Na+ and HCO3- into the lumen creates an osmotic gradient, and water follows by osmosis. Net results= secretion of watery sodium bicarbonate solution In cystic fibrosis, an inherited defect causes the CFTR channel to be defective or absent. As a result, secretion of C?- and fluid ceases, but goblet cells continue to secrete mucus, resulting in thickened mucus. In the digestive system, the thick mucus clogs small pancreatic ducts and prevents digestive enzyme secretion into the intestine. In airways of the respiratory sytem, where the CFTR channel is also found, failure to secrete fluid clogs the mucociliary escalator with thick mucus, leading to recurrent lung infections Bicarbonate secretion in the pancreas and duodenum. Cells that produce bicarbonate have high concentrations of carbonic anhydrase NaCL SECRETION Crypt cells in the small intestine and colon secrete an isotonic NaCl solution that mixes with mucus secreted by goblet cells to help lubricate the contents of the gut. Chloride from the ECF enters cells via NKCC transports, then exits into the lumen via apical CFTR channels. Na+ and water follow along the paracellular pathway, with the end result being secretion of isotonic saline solution DIGESTIVE ENZYMES ARE SECRETED INTO THE LUMEN Digestive enzymes are secreted either by exocrine glands or by epithelial cells in the mucosa of the stomach and small intestine. Enzymes are proteins, which means they are synthesized on the rough endoplasmic reticulum, packaged by the Golgi complex into secretory vesicles, and then stored in the cell until needed. On demand, they are released by exocytosis. Some digestive enzymes are secreted in an inactive proenzyme form known as zymogens. Zymogens must be activated in the Gl lumen before they can carry out digestion. SPECIALIZED CELLS SECRETE MUCUS Mucus is a viscous secretion composed primarily of glycoproteins collectively called mucins. The primary functions of mucus are to form a protective coating over the GI mucosa and to lubricate the contents of the gut. SALIVA IS AN EXOCRINE SECRETION Saliva is a complex hyposmotic fluid secreted by the salivary glands of the oral cavity. Components of saliva= water, ions, mucus, and proteins such as enzymes and immunoglobulins. At resting slow rates, saliva is slightly acidic. The ionic composition of saliva is determind in two epithelial transport steps. The salivary glands are exocrine glands, with a secretory epithelium that opens to the outside environment thoruhg a duct. Fluid secreted by the acinar cells resembles extracellular fluid in its ionic composition. As this fluid passes through the duct on its way to the oral cavity, epithelial cells along the duct reabsorb Na+ and secrete K+ until the ion ratio in the duct fluid is more like that of intracellular fluid. Salivation is controlled by the autonomic nervous system. Parasympathetic innervations is the primary stimulus for secretion of saliva, but there is also some sympathetic innervations to the glands. THE LIVER SECRETES BILE Bile is a nonenzymatic solution secreted from hepatocytes, or liver cells. The key components of bile are Bile salts, which facilitate enzymatic fat digestion. They are made from steroid bile acids combined with amino acids Bile pigments, such as billirubin, which are the waste products of hemoglobin degradation and Cholesterol, which is excreted in the feces. Drugs and other xenobiotics are cleared from the blood by hepatic processing and are also excreted in bile. Bile is secreted into hepatic ducts that lead to the gallbladeder, which stores and concentrates the bile solution. During a meal, contraction of the gallbladder sends bile into the duodenum through the common bile duct, along with a watery solution of bicarbonate and digestive enzymes from the pancreas. DIGESTION AND ABSORPTION The GI system digests macromolecules into absorbale units using a combination of mechanical and enzymatic breakdown. The pH at which different digestive enzymes function best reflects the location where they are most active. Enzymes that act in the stomach work well at acidic pH, and those secreted into the small intestine work best at alkaline pH. Most absorption takes place in the small intestine, with additional absorption of water and ions in the large intestine. The surface area of the intestine is greatly increased by the presence of fingerlike villi and by the brush border on the luminal surface of enterocytes, created from numerous microvilli on each cell. Absorption of nutrients and ions across the GI epithelium, like secretion, uses many of the same transport proteins as the kidney tubule. Once absorbed, most nutrients enter capillaries within the villi. The exception is fats, which mostly enter lymph vessels called lacteals. Digestion and absorption are not directly regulated except in a few instances. Influenced by motility and secretion in the digestive tract, 2 provesses that in turn are regulated by hormones= nervous system, and local control mechanisms CARBOHYDRATES ARE ABSORBED AS MONOSACCHARIDES The enzyme amylase breaks long glucose polymers into smaller glucose chains and into the disaccharide maltose. Maltose and other disaccharides are broken down by intestinal brush-border enzymes known as disaccharidases. The end products of carbohydrate digestion are glucose, galactose, and fructose. The enzymes for protein digestion are classifiend into two broad groups: endopeptidases and exopeptidases. Endopeptidases, or proteases, attack peptide bonds in the interior of the amino acid chain and break a long peptide chain into smaller fragments. Proteases are secreted as inactive proenzymes from epithelial cells in the stomach, intestine, and pancreas and are activated in the GI tract lumen. Ex. Of proteases are pepsin secreted in stomach, and trypsin and chymotrypsin secreted in pancreas. Digests internal peptide bonds Exopeptidases release single amino acids from peptides by chopping them off the ends, one at a time. The most important digestive exopeptdases are two isozymes of carboxypeptidase secreted by the pancrease. Primary products of protein digestion are free amino acids, dipeptides, and tripeptides, all of which can be absorbed. Amino acid structure is so variable that multiple amino acid transport systems are found in the intestine. Dipeptides and tripeptides are carried into the mucosal cell on the oligopeptide transporter. Once inside the epithelial cell, the oligopeptides have 2 possible fates. Most are digested by cytoplasmic peptidases into amino acids, which are then transported across the basolateral membrane and into the circulation. Those oligopeptides that are not digested are dependent exchagneer. The transport system that moves oligopeptides also is responsible for intestinal uptake of certain drugs. Digests terminal peptide bonds to release amino acids SOME LARGER PEPTIDES CAN BE ABSORBED INTACT Some peptides larger than 3 amino acids are absorbed by transcytosis after binding to membrane receptors on the luminal surface of the intestine. Absorbtion may be significant factor in the development of food allergies and food intolerances. In newborns peptide absorption takes place primarily in intestinal crypt cells. As the villi gro and the crypts have less acces to chyme, the high peptide absorption rates present at birth decline. BILE SALTS FACILITATE FAT DIGESTION Enzymatic fat digestion is carried out by lipases, enzymes that remove 2 fatty acids from each trigyceride molecule. The result is 1 monoglycerie and 2 free fatty acids. Most lipids are not water soluble. Bile salts are amphipathic which mean they have both a hydrophobic region and a hydrophilic region. The hydrophobic regions of bile salts associate with the surface of lipid droplets while the polar side chains interact with water, creating a stable emulsion of small, water soluble fat droplets. Bile salt coating of the intestinal emulsion complicates digestions, however, b/c lipase is unable to penetrate the bil satls. For this reason fat digestion also requires colipase, a protein cofactor secreted by the pancrease. Colipase displaces some bile salts, allowing lipase acces to fats inside the bile salt coating. As enzymatic and mechanical digestion proceed, fatty acids, bile salts, monoglycerides, phospholipids, and cholesterol form small disk shaped micelles. Micelles then enter the unstirred aqueous layer close to absorptive cells lining the small intestine lumen. Fats are lipophilic so most absorb thorugh simple diffusion. Chylomicrons- large droplets of proteins. They must be packaged into secretory vesicles and leave the cell by exocytosis. Size prevents them form crossing basement membrane to enter capillaries. NUCLEIC ACIDS ARE DIGESTED INTO BASES AND MONOSACCARIDES The nucleic acid polymers DNA and RNA are only a very small part of most diests. They are digested by pancreatic and intestinal enzymes, The bases are absorbed by active transport, and monosaccharides are absorbed by facilitated diffusion and secondary active trasnnport Bile salts from liver coat fat droplets Pancreatic lipase and collapse break down fats into monoglycerides and fatty acids stored in micelles Monoglycerides and fatty acids move out of micelles and enter cells by diffusion Cholesterol is transported into cells by a membrane transporter Absorbed fats combine with cholesterol and proteins in the intestinal cells to form chylomicrons Chlylomicrons are released into the lympathic system THE INTESTINE ABSORBS VIATMINS AND MINERALS Fat soluble vitamins ( A D E K) are abhosrbed in the small intestine along with fats. The water soluble viatedms (C B) are absorbed by mediated transport. The exeption is vitamin B12, or cobolamin. This vitamin is made by bacteria but we obtain most of our dietary supply from seafood, meat, milk. The intestinal transporter for B12 is found only in the ileum and recognizes B 12 only when the vitamin is complexed with a protein called intrinsic factor, sectered by the stomach. INTESTINE ABSORBS IONS AND WATER Most water absorbtion takes place in the small intestines. Enterocytes in the small intestine and colonocytes, the epithelial cells on the luminal surface of the olon, absorb sodium using 3 membrane proteins: Apical sodium channels a Na+ - Cl- symporter, NHE Na+ - H+ exchanger. THE CEPHALIC PHASE Long reflexes that begin in the brain are known as cephalic phase of digestion. Anticipatory stimuli and the stimulus of food in the oral vacity activates neurons in the medulla oblongata. The medulla in turns sends an efferent signal thorugh autonomic neurons to the salivary glands, and through the vagus nerve to the enteric nervous system. CHEMICAL AND MECHANICAL DIGESTOINS BEGINS IN THE MOUTH Mechanical digestions of food begins in the oral cavity with chewing. The lips, tongue, and teeth all contribute to the mastication of food, creating a softened moistened mass(bolus) that can be easily swallowed REGULATION OF GI FUNCTION Varios control mechanisms control the digestive system. With neural, endocrine, and local components, include the following Long reflexes integrated in the CNS. A classic neural reflex begins with a stimulus transmitted along a sensory neuron to the CNS, where the stimulus is integrated and acted on. In the digestive system some classic reflexes originate with sensory recepotrs in the GI tract, but others originate outside the digestive system. No matter where they origininate, digestive reflexes integrated in the CNS are called long reflexes- long reflexes that originate completely outside the digestive system include feedforward reflexes and emotional reflexes. These reflexes are called cephalic reflexes b/c they originate in the cephalic brain. Short reflexes integrated in the enteric nervous system. Neural control of the GI tract does not rely strictly on the CNS. Instead, the enteric nerve plexus in the gut wall acts as a littler brain, allowing local reflexes to begin, be integrated, and end completely in the GI tract. Reflexes that originate within the enteric nervous system and are integrated there without outside input are called short reflexes. Reflexes involving GI peptides. Peptides secreted by cells of the digestive tract may act as hormones or paracrine signals. Some of the peptide signal molecules in volved in digestive regulation were first identified iin other body segments. GI hormones, like all hormones are secreted into blood. They act on the GI tract, on accessory organs such as the pancreas, and on more distant targets, such as the brain. In the digestive system, GI peptides excite or inhibit motility and secretion. THE ENTERIC NERVOUS SYSTEM CAN ACT INDEPENDENTLY The anemones nervous system consists of a network composed of sensory neurons, interneurons, and efferent neurons that control the muscles and secretory cells of the anemones body. Anatomically and functionally, the ENS shares many features with the CNS. Intrinsic neurons. The intrinsic neurons of the two nerve plexuses of the digestive tract are those neurons that lie completely within the wall of the gut, just as interneurons are completely contained within the CNS. Autonomic neurons that bring signals from the CNS to the digestive system are called extrinsic neurons. Neurotransmitters and neuromodulaters. ENS neurons release more than 30 neurtransmitters and neuromodulators, most of which are identical to molecules found in the brain. Serotonin, vasoactive intestinal peptide, and nitric oxide are the best known neurotransmitters Glial support cells. The glial cells of neurons within the ENS are more similar to astroglia of the brain than to Schwann cells of the peripheral nervous system Diffusion barrier. The capillaries that surround ganglia in the ENS are not very permeable and create a diffusion barrier that is similar to the blood brain barrier of the cerebral blood vessels Integrating center. The neuron network of the ENS is its own integrating center much like brain and spinal cord. GI PEPTIDES INCLUDE HORMONES NEUROPEPTIDES AND CYTOKINES The gastrointestinal hormones are usually divided into 3 families. All the members of a family have similar amino acid sequences, and in some cases there is overlap in their ability to bind to receptors The gastrin family includes the hormones gastrin and cholecystokinin (CCK), plus several variants of each. Their structural similarity means that both gastrin and CCK can bind to and activate the CCKB receptor found on parietal cells The secretin family includes secretin; vasoactive intestinal peptide (VIP), a neurocrine molecule; and GIP, a hormone that inhibites gastric acid secretion. Does not block acid secretion in later studies so new name came about ? glucose-dependent insulinotropic peptide- that more accurately describes the hormones action: it stimulates insulin release in response to glucose in the intestinal lumen. Another membr of the secretin family is the hormone glucagon-like peptide 1, which also plays an important role in glucose homeostatis. The 3rd family of peptides contains those that do not fit into the other 2 families. The primary member of this group is the hormone motilin. THE LARGE INTESTINE CONCENTRATES WASTE Chyme enters the large intestine through the ileocecal valve. This is a tonically contracted region of muscularis that narrows the opening between the ileum and the cecum, the initial section of the large intestine. The ileocecal valve relaxes each time a peristalitic wave reaches it. It also relaxes when food leaves the stomach as part of the gastrioleal reflex. The large intestine has 7 regions. The cecum is a dead end puch with the appendix, a small fingerlike projection, at its ventral end. Material moves from the cecum upward through the ascending colon, horizontally across the body through the transverse colon, then down through the descending colon and sigmoid colon. The rectum is the short terminal section of the large intestine. Wall of the colon differs from that of the small intestine in that the muscularis of the large intestine has an inner circular layer but a longitudinal muscle layer concentrated into three bands called the tenia coli. Contractions of the tenia pull the wall into bulging pockets called haustra. MOTILITY IN THE LARGE INTESTINE Mass movement- unique colonic contraction which impacts foreward movement, Its responsible for the sudden distension of the rectum that triggers defecation. Defecation reflex removes undigested feces from the body. Smooth muscle of the internal anal sphincter relaxes, and peristaltic contractions in the rectum push material toward the anus.