Lecture 20 ? Renal Function Role Of Kidneys (Slide 1) 1. In regulation of systemic arterial blood pressure 2. In influencing salt and water balance 3. In producing dilute and concentrated urine Maintenance Of Arterial Blood Pressure (Slide 2) 1. Arterial blood pressure is usually quite constant over 8-10 cardiac cycles. 2. It will change for two reasons: if emotional distress occurs instantly or with respiration (alters blood pressure on a respiratory cycle to cycle basis). 3. However, we are talking about blood pressure over a lifetime. Mechanisms, Short- And Long-Term, Involved In Regulating Systemic Arterial Blood Pressure (Slide 3) 1. The kidneys are involved with long-term arterial blood pressure regulation. 2. There are mechanisms which respond within seconds to changes in blood pressure, such as carotid sinus or aortic arch baroreceptors. There are also high-pressure renal receptors. 3. There are responses that are initiated within minutes to hours. 4. Finally, there is a curve called renal blood-volume pressure control. It responds within several hours after change in blood pressures. It peaks very high and can respond infinitely long. 5. There is another system called the renal angiotensin system that responds over long term as well. The Renal Juxtaglomerular Apparatus (JGA) And Tubuloglomerular Feedback (Slide 4) 1. There are a few essential structural components of this system. 2. There is a set of glomerular capillaries with the afferent arteriole coming in and the efferent arteriole draining the glomerular bed. 3. There is a transfer section of the distal tubule where it meets with the end of the Loop of Henle. Most of the cells are cuboidal epithelial cells. However, there are some that are in immediate juxtaposition to the arterioles that are longer. They are called the macula densa, large epithelial cells densely packed with low permeability. 4. In the renal arteriole, the cells that are in close proximity to the macula densa are cells called granular cells or juxtaglomerular cells. They are modified renal arteriolar vascular smooth muscle cells. They have a high concentration of granules, or vesicles, that increase in concentration and migrate to the apical border of the cell when the pressure changes. 5. The physiology of blood pressure regulation by the kidney is controlled by the Renin Angiotensin Aldosterone AVP System (RAAA). AVP has the same function as ADH. Renal Tumors, Constriction Of Renal Blood Flow, And Hypertension (Slide 5) 1. If there was a tumor on the blood vessel, it could increase pressure and reduce blood flow. That will also reduce blood pressure downstream from the point of constriction. 2. The two graphs are of systemic arterial pressure/renal arterial pressure and an index of the rate of renin secretion. Something caused a reduction in renal arterial pressure. Thus, there is an increase in the secretory behavior of the granular cells. They secrete an enzyme called renin. As its concentration increases in the systemic plasma, systemic arterial blood pressure increases as well. 3. If the tumor is removed, everything returns to normal. Experimental And Clinical Interventions (Disease States) That Can Activate Renin Release (Slide 6) 1. As renal arterial blood pressure is decreased, granular cells empty their cytoplasmic granules, or vesicles, containing renin into the general systemic circulation. In circulation, renin comes in contact with renin substrate, a macromolecule, called angiotensinogen. It is a macromolecule produced by the liver and is always in circulation. Renin acts on angiotensinogen, cleaves off a decapeptide (10 amino acid chain), called angiotensin I, or A-I. A-I, as it passes through the microcirculation in the lungs pulmonary capillaries, meets another enzyme called angiotensin converting enzyme (ACEase). This enzyme removes two more amino acids from A1, creating an octapeptide called angiotensin II, A-II. A- II has a variety of physiologic properties: it is a potent vasoconstrictor, it acts directly and indirectly on the kidney?s ability to retain salt and water by stimulating the release of aldosterone from the adrenal gland, and there are some others that are not as important. Vasoconstriction coupled with retention of salt and water causes increased arterial pressure. There is negative feedback that shuts down the system once arterial pressure has returned to physiologic levels. 2. The initiating event is hypotension (low systemic arterial pressure). The granular cells are baroreceptors that detect a change in pressure and release renin. So the mechanism of a change in perfusion pressure is detected by baroreceptors at the JGA. If the person is hypotensive, the carotid sinus baroreceptors are also activated. The sympathetic output from those cardioreceptors goes directly to the kidneys, which also augments renin release. By themselves, the granular cells can stimulate the release of renin. This system is a second mechanism that helps recover from low blood pressure. 3. Tubular Glomerular Feedback: The macula densa cells at the JGA have the ability to sense NaCl concentration at the macula densa. When the concentration is decreased, the macula densa can send a signal over to the granular cells and stimulate renin release. This release along with the affect of increased pressure will increase GFR. The increase in filter load will be detected by the macula densa which can then stop renin release. 4. If you have a hemorrhage, blood pressure drops significantly. If you block the renin-angiotensin system pharmacologically, the feedback regulation is inhibited; pressure only increased slightly. When the renin-angiotensin system was allowed to operate, the blood pressure recovery was much more significant. The Renin-Angiotensin-Aldosterone-AVP System (Slide 7) 1. Extracellular volume is intravascular and interstitial volumes combined together. Effective circulating volume does not represent a discrete anatomic space; it cannot be measured. Physiologically, it is an index of the adequacy of tissue perfusion, such as blood pressure, blood flow, vascular resistance. How well are organs and tissues able to be perfused? So if an animal is hemorrhaged, that affects extracellular volume, which will in turn affect intracellular volume and ultimately, effective circulating volume. 2. So the initiating event is a decrease in effective circulating volume. This system involves many different organs: the liver, hypothalamus, lungs, adrenal gland. This system first acts on baroreceptors. This causes renin to be released, which comes in contact with angiotensinogen that is released by the liver. It gets converted to A-I and then A-II. A-II has vasoconstrictor properties as well as acts directly on the adrenal cortex to stimulate the release of aldosterone and other mineralocorticoids, hormones that regulate salt in the body. It also has a hypothalamic effect that stimulates the release of argenine vasopressin, ADH, and also augments the thirst drive. 3. This results is the retention of water and sodium, which increases extracellular volume. This restores effective circulating volume to normal levels. Summary And Conclusions (Slide 8) 1. Kidneys involved in short- and long-term regulation of blood pressure. 2. Renin-angiotensin-aldosterone-avp (ADH) system (intermediate relative to neural reflexes) 3. Role of ACE inhibitors (antihypertensive pharmaceuticals, NJ) 4. All of these reactions would be reversed if there was a decrease in pressure. Comparison Of Systems Controlling Extracellular Fluid Volume And Osmolarity (Slide 9) 1. Extracellular fluid volume is affected by osmolarity. The most important aspect is the content of sodium in determining osmolarity. 2. There are a few sensors that help regulate extracellular fluid volume: carotid sinus baroreceptors, renal afferent arteriolar baroreceptors, low-pressure baroreceptors in the atria. There are also neurons in the hypothalamus that also detect changes. The atria produce ANP. 3. The table shows how extracellular fluid volume and osmolarity are related. Regulation of ECFV Regulation of Osmolarity What is sensed? Effective circulating volume Plasma osmolarity Sensors Carotid sinus, aortic arch, renal afferent arteriole, atria Hypothalamic osmoreceptors Efferent Pathways Renin, angiotensin, aldosterone, AVP axis, sympathetic nervous system, ANP, ADH AVP (ADH), thirst Effector Short term: heart, blood volume Long term: kidney Kidney, brain (drinking behavior) What is Affected? Short term: blood pressure Long term: sodium excretion Water excretion vs. intake Sodium Balance: Long-Term Regulation (Slide 10) 1. If Na+ intake is seriously increased, the Na+ level is changed immediately. For a few days, the body is in a positive salt balance state; excretion of sodium lags behind the intake. The body has accumulated Na+. At the same time, body weight increases slightly as well, and is maintained at that higher level as long as salt intake is maintained. This weight gain is due to water retention. 2. If the excess salt intake is abruptly stopped, for the next few days, there is negative sodium balance. The excretion rate is higher than the intake rate. It takes several days for this negative salt balance to come back to normal. 3. The more salt you take in during a day, the longer you are in a positive salt intake state, the greater your extracellular volume will increase. Salt Intake, ECFV, And Systemic Arterial Pressure (Slide 11) 1. If salt intake is increased, extracellular fluid volume (ECFV) increases and so does arterial pressure. 2. If renin release is blocked, then arterial pressure remains at that level. 3. However, if the renin-angiotensin system is active, there is a decrease in the release of renin, which will decrease the production of angiotensinogen as well as the release of aldosterone. It will decreases water and salt retention, which will result in a return of extracellular fluid volume and arterial pressure to near normal. PET (Slide 12) 1. This is a saggital section through a human brain. 2. If you make a person thirsty by infusing them with salt, you notice that the dark area, which represents cerebral ventricles, have yellow and red noise in what are called circumventricular organs. Those are osmoreceptors being activated. 3. If you then allow the person to drink water until they are satiated, you notice that in the same region, the singulet gyrus, none of the red and yellow noise appears. This means that the osmoreceptors are deactivated because their thirst drive was satiated. Saggital Section Of The Rat Brain (Slide 13) 1. There are specific regions noted in the figure. These are all the regions where sensory afferent signals from baroreceptors and osmoreceptors end in the rat. 2. In the lower portion of the figure, called the AV3V (anteroventril region of the 3rd ventricle), is the most important region of the mammalian brain for detecting changes in the osmolarity of extracellular fluid. It helps regulate the homeostasis of everything related to it. If you destroy the AV3V, that causes many changes in the rat that affect its functioning. Schematic Of Neural And Hormonal Inputs To The Brain That Help Determine Thirst and Consumption Of H2O (Slide 14) 1. All you need to note are the curves: a change in osmolarity will either facilitate or inhibit the AV3V region of the brain. 2. There are visceral osmoreceptors in the gut wall and abdominal organs that also detect changes in volume, pressure or osmolarity and can either facilitate or inhibit thirst drives and regulation. 3. There are cardiopulmonary receptors. 4. There are arterial baroreceptors. 5. These drive thirst and help regulate osmolarity as well as ECFV. Summary And Conclusions (Slide 15) 1. Kidneys regulate ECFV, ECV, osmolarity 2. Sensors in vessels, atria, tubules, CNS 3. Decreased renal perfusion pressure increases release of renin, activates RAAA system. Increased renal perfusion pressure decreases release of renin, inactivates RAAA system. 4. Thirst drive helps regulate blood pressure, ECFV, ECV, and ECF osmolarity. Urine Concentration And Dilution In States Of Dehydration/Excess Hydration (Slide 16) 1. Medullary interstitial osmolarity 2. Single effect 3. Role of the vasa recta 4. Concentration (diluting) urine 5. Obligatory loss of water Osmotic Gradient In Renal Medullary Interstitial Fluid (Slide 17) 1. If you were to sample the osmolarity of interstitial fluid in the cortex, outer medulla and inner medulla, you would find different osmolarities. 2. On average, the osmolarity of the plasma in arterial blood is about 280-300 milliosmoles/liter, the same as the cortex of the kidney. Theory Behind Counter-Current Multiplication (Slide 18) 1. Osmotic gradient established by counter-current multiplier 2. Dependent on loop of Henle 3. The descending limb is highly permeable to water, but there are no transporters for Na+, Cl- or K+ 4. The ascending limb is not permeable to water but does have active transport for Na+, Cl- and K+. Proposed Mechanism Of Counter-Current Multiplication (Slide 19) 1. Peritubular means the same as interstitial. 2. Right now, your kidneys are producing an ultrafiltrate that has an osmolarity of about 300 milliosmoles in Bowman?s space. Perhaps the osmolarity leaving the loop of Henle is also about 300. They are all in equilibrium (proximal tubule, distal tububle and interstitial fluid in the cortex). 3. In the first figure, we see that the descending loop is permeable to water but no anions. The opposite is true of the ascending loop. All the numbers are 300, so nothing happens. 4. In the third figure, you have 300 at the cortex but 400 at the papilla. If you compare any level of the ascending vs. descending limbs, there is a lateral gradient of about 200. It is caused by water being lost from the tubular fluid, thus concentrating the fluid in the descending limb. By the time the fluid reaches the tip of the papilla, it is no longer isotonic. As the next amount of ultrafiltrate is produced, the same volume of fluid is released on the other side. The concentrated urine is moved further up the ascending loop. 5. The main point (panel 1 ( panel 3 ( panel 6): Not only is there a lateral gradient of about 200 milliosmoles. There is also a vertical gradient of about 1100 milliosmoles between the proximal tubule and the tip of the papilla. Since the ascending loop is impermeable to water, ions are pumped out into the interstitial fluid. 6. Counter-current means that the ascending loop runs up while the descending loop runs down. Experimental Evidence Supporting Countercurrent Multiplication (Slide 20) 1. Thawing of frozen kidney slices of thirsting rats a. You would find that the slices of the cortex thaw at the same rate that the afferent arteriolar or renal plasma thaw (room temperature). b. If you look at the slices of the outer medulla, inner medulla and papilla, they thaw at progressively lower temperatures. This is because the osmolarity concentration is higher in the papilla, so that causes the freezing point depression to drop. 2. Swelling and weight gain in kidney slices of thirsting dogs a. If you take a kidney slice from the cortex and put it in a beaker of isotonic saline, that kidney slice will not swell or retain water, so no weight gain occurs. b. If you take the same slice from the outer medulla, inner medulla or papilla and put it in the same beaker, all three of those will gain weight and accumulate water. The greater the osmolarity of the slice, the more the water/weight gain. 3. Osmolarity of fluid entering/exiting Loops of Henle (entering isotonic/exiting hypotonic re. to proximal tubule/arterial plasma) a. You can sample the fluid directly and measure osmolarities. If you are very close to the cortex, the osmolarity is very similar to plasma osmolarity. Osmolality In Restricted And Excess States Of Body H2O (Slide 21) 1. If tubular fluid is isotonic with plasma, the TF/P ratio is 1 (proximal tubule). 2. The loop of Henle has a gradient, and the ratio changes. It depends on the state of hydration or dehydration. If dehydrated, the fluid has a greater osmolarity than plasma, and the ratio goes up. If you are hyperhydrated, there is only a small peak due to a small gradient. 3. If you follow the dehydrated line, the osmolarity is high in the collecting tubule and duct. This is accounted for by the release of ADH as part of the renin-angiotensin system. Water is reabsorbed, and the osmolar concentration of urine increases as water is taken out. 4. If the person is severely dehydrated, the urine has very little water: obligatory water loss. It is a small amount of water required to dissolve the constituents of the urine that cannot flow on their own (a few tenths of a milliliter per minute). * The RAAA system and thirst system can fail when you get older, and you could be dangerously dehydrated without knowing it. * It is possible to die from excess water consumption. There are psychological diseases that cause a person to drink much more water than they need, which can dilute potassium, sodium and other ions and cause life-threatening rhythms in the heart.
Want to see the other 5 page(s) in Systems Lecture 20 - Renal Function.doc?JOIN TODAY FOR FREE!