ADH

Regulation of Water Excretion

July 23, 2016 Cardiology, Critical Care, Nephrology, Physiology and Pathophysiology No comments , , , , ,

Water excretion, as with sodium excretion, is regulated in partnership with the CV system. Central goals in regulating both salt and water excretion are to: 1).preserve vascular volume and 2).maintain plasma osmolality at a level that is healthy for tissue cells. The main regulators of water excretion, not surprisingly, relate to osmolality and volume.

Quantitatively, renal water excretion is determined by 2 values: 1).the amount of solute in the urine and 2).the osmolality of the urine.

Screen Shot 2016-07-31 at 2.12.05 PM

Urine water excretion = urine solute excretion/urine osmolality

Excreted solute consists mostly of organic waste and excess electrolytes. In a given metabolic state, the rate of organic waste excretion is more or less constant, and is not altered for purposes of controlling water excretion. Electrolyte excretion is highly regulated, but more to achieve balance of individual substances like sodium and potassium than to control water excretion per se. Given that solute excretion is so variable, the main way the body controls water excretion in normal circumstances is to control urine osmolality. In other words, given a certain amount of solute that is excreted, the body controls the amount of water accompanying it by controlling urine osmolality.

When the body excretes urine that is more dilute than plasma (osmolality below 285 mOsm/kg H2O), the body is excreting "free water" (like adding pure water to otherwise isosmotic urine). Conversely, when the excreted urine is more concentrated than plasma, there is "negative free water" excretion. It is as if the body has reclaimed pure water from otherwise isosmotic urine.

The kidneys first generate hypo-osmotic tubular fluid in the loop of Henle. Then, as the fluid subsequently flows through the collecting duct system, variable amounts of water are reabsorbed by allowing the tubular fluid to equilibrate to varying degrees with the surrounding interstitum. The final urine osmolality, and hence final volume, depends on the peak medullary osmolality and how closely the tubular osmolality approaches that value. We also know that equilibration with the interstitium is a function of water permeability in the collecting ducts under the control of the hormone antidiuretic hormone (ADH). Therefore the regulation of water excretion, that is independent of solute excretion, focuses on control over ADH secretion.


Osmoreceptor Control of ADH Secretion

Plasma osmolality is one of the most tightly regulated variables in the body. Plasma osmolality is set mainly by the ratio of ECF sodium (plus its assocaited anions) to water. Other solutes (e.g., glucose and potassium) make some contribution, but those other solutes are regulated for reasons other than plasma osmolality. Thus, except under unusual circumstances such as severe hyperglycemia, variations in plasma osmolality mostly reflect variations in sodium concentration. If the body keeps the inputs and outputs of sodium and water matched in lock step, osmolality remains constant. But inputs are often not matched. The major effect of gaining or losing water or salt without corresponding changes in the other is a change in the osmolality of the body fluids. When osmolality deviates from normal, strong reflexes come into play to change ADH secretion, and thus change the excretion of water.

Baroreceptor Control of ADH Secretion

There is another major influence on ADH secretion. This originates in systemic baroreceptors. A decreased extracellular volume or major decrease in arterial pressure reflexively activates increased ADH secretion. The response is mediated by neural pathways originating in cardiopulmonary baroreceptors, and if arterial pressure decreases, from arterial baroreceptors.

Decreased CV pressures cause less firing by the baroreceptors, which relieves inhibition of stimulatory pathways and results in more ADH secretion. In effect, the low CV pressures are interpreted as low volume, and the response of increased ADH appropriately serves to minimize loss of water. Conversely, baroreceptors are stimualted by increased CV pressures, interpreted as excess volume, and this causes inhibition of ADH secretion. The decrease in ADH results in decreased reabsorption of water in the collecting ducts, and more excretion. The adaptive value of these baroreceptor reflexes is to help stabilize ECF volume and, hence, blood pressure.

There is a second adaptive value to this reflex: Large decreases in plasma volume, as might occur after a major hemorrhage, elicit such high concentrations of ADH – much higher than those needed to produce maximal antidiuresis – that the hormone is able to exert direct vasoconstrictor effects on arteriolar smooth muscle. The result is increased total peripheral resistance, which helps restore arterial blood pressure independently of the slower restoration of body fluid volumes. Renal arterioles and mesangial cells also participate in this constrictor response, and so a high plasma concentration of ADH, quite apart form its effect on water permeability and sodium reabsorption in the distal nephron, promotes retention of both sodium and water by lowering GFR.

Others

The cells that synthesize ADH in the hypothalamus also receive synaptic input from many other brain areas. Thus, ADH secretion and, hence, urine flow can be altered by pain, fear, and a variety of other factors, including drugs such as alcohol, which inhibits ADH release. However, this complexity should not obscure the generalization that ADH secretion is determined over the long term primarily by the states of body fluid osmolality and plasma volume.


We have described 2 different major afferent pathways controlling the ADH-secreting hypothalamic cells: 1 from baroreceptors and 1 from osmoreceptors. These hypothalamic cells are, therefore, true integrators, whose activity is determined by the total synaptic input to them. Thus, a simultaneous increase in plasma volume and decrease in body fluid osmolality causes strong inhibition of ADH secretion. Conversely, a simultaneous decrease in plasma volume and increase in osmolality produces very marked stimulation of ADH secretion. However, what happens when baroreceptor and osmoreceptor inputs oppose each other? In general, because of the high sensitivity of the osmoreceptors, the osmoreceptor influence predominates over that of the baroreceptors when changes in osmolality and plasma volume are small to moderate. However, a dangerous reduction in plasma volume will take precedence over decreased body fluid osmolality in influencing ADH secretion; under such conditions, water is retained in excess of solute even though the body fluids become hypo-osmotic (for the same reason, plasma sodium concentration decreases). In essence, when blood volume reaches a life-threatening low level, it is more important for the body to preserve vascular volume and thus ensure an adequate cardiac output than it is to preserve normal osmolality.


Thirst and Salt Appetite

Deficits of salt and water cannot be corrected by renal conservation, and ingestion is the ultimate compensatory mechanism. The subjective feeling of thirst, which drives one to obtain and ingest water, is stimulated both by reduced plasma volume and by increased body fluid osmolality. Note that these are precisely the same changes that stimulate ADH production, and the receptors – osmoreceptors and the nerve cells that respond to the CV baroreceptors – that initiate the ADH-controlling reflexes are near those that initiate thirst. The thirst response, however, is significantly less sensitive than the ADH response.

There are also other pathways controlling thirst. For example, dryness of the mouth and throat causes profound thirst, which is relieved by merely moistening them. Also, when animals such as the camel (and humans, to a lesser extent) become markedly dehydrated, they will rapidly drink just enough water to replace their previous losses and then stop. What is amazing is that when the stop, the water has not yet had time to be absorbed from the gastrointestinal tract into the blood.

Regulation of Sodium Excretion

June 25, 2016 Cardiology, Critical Care, Nephrology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , , , , , , , , , ,

Percentage of Sodium Reabsorbed

Screen Shot 2016-07-31 at 2.12.05 PM

The Goals of Regulation

The overriding goals of regulating sodium and water excretion are to support the requirements of the cardiovascular system. This is manifested in 3 ways: 1.the kidneys maintain a sufficient ECF volume to fill the vascular space (mean circulatory filling pressure); 2.keep the osmolality of the ECF at a level consistent with cellular health; and 3.limit the changes in renal blood flow (RBF) and GFR that might otherwise reach deleterious levels. The kidneys and the CV system work cooperatively to ensure that peripheral tissue is sufficiently perfused. An adequate circulating volume is one of the essential requirements for tissue perfusion and it is the kidneys that control this volume. Osmolality is the ratio of solute content to water content. Sodium and chloride together account for 80% of the normal extracellular solute; thus the excretion of sodium and water by the kidneys regulates osmolality in the tight range that is needed for the health of tissue cells. There is a separate goal of regulation that differs from those stated above. Variations in RBF and GFR are major means of regulating sodium excretion. However, the kidney cannot change blood flow and filtration to such extreme values that they compromise the metabolic health of the kidneys or interfere with the excretion of substances other than sodium, particularly organic waste.

Formulas for ECF Volume

There are some formulas showing the relationship between ECF solute content, ECF osmolality, and ECF volume. Since almost all of the ECF solute is accounted for by sodium and an equivalent number of anions (mostly chloride and bicarbonate), the amount of ECF solute is approximately twice the sodium content.

ECF osmolality = ECF solute content / ECF volume (Equation 7-1)

ECF volume = ECF solute content / ECF osmolality (Equation 7-2)

ECF volume ≈ 2 x Na content / ECF osmolality (Equation 7-3)

Therefore, in the face of tightly controlled ECF osmolality, ECF volume varies directly with sodium content. But how do the kidneys know how much sodium there is in the ECF? The detection of sodium content is indirect, based on a combination of assessing sodium concentration and vascular pressures. Glial cells in regions of the brain called the circumventricular organs have sensory Na+ channels that respond to and act as detectors of extracellular sodium concentration. The glial cells modulate the activity of nearby neurons involved  in the control of body sodium. There are also neurons in the hypothalamus contain the sensory Na+ channels that respond to the sodium concentration in the cerebrospinal fluid. Thus cells in or near the hypothalamus monitor extracellular sodium concentration.

The volume affects pressure in different regions of the vasculature. It is the presssure baroreceptors in these regions of the vasculature detect the vascular pressures.

Major Controllers of Sodium Excretion

Sympathetic Stimulation 

Vascular pressures are so important in regard to sodium excretion and because volume affect pressure in different regions of the vasculature, so the changes in ECF affects pressures (arterial and/or venous) and changes in pressure affect sodium excretion (Thread "Regulation of Arterial Pressure" at http://www.tomhsiung.com/wordpress/2016/06/physiology-regulation-of-arterial-pressure/ and thread "Mean Circulatory Filling Pressure and CVP" at http://www.tomhsiung.com/wordpress/2016/06/mean-circulatory-filling-pressure-and-cvp/).

The vasculature and tubules of the kidney are innervated by postganglionic sympathetic neurons that release norepinephrine. In most regions of the kidney, norepinephrine is recognized by alpha-adrenergic receptors. In the renal vasculature activation of alpha1-adrenergic recpetors causes vasoconstriction of afferent and efferent arterioles. This reduces RBF and GFR.

GFR is a crucial determinant of sodium excretion. However, except in body emergencies such as hypovolemic shock, GFR is kept within rather narrow limits due to autoregulatory processes (detail for vascular autoregulatory regulation http://www.tomhsiung.com/wordpress/2015/07/arteriolar-tone-and-its-regulation-local-mechanisms/). Thus although neural control does affect GFR, this component of sympathetic control is probably less important in normal circumstances than its effect on sodium reabsorption. Neural control of the renal vasculature is exerted primarily on blood flow in the cortex, allowing preservation of medullary perfusion even when cortical blood flow is reduced.

The proximal tubule epithelial cells are innervated by alpha1- and alpha2-adrenergic receptors. Stimulation of these receptors in the proximal tubule by norepinephrine activates both components of the main transcellular sodium reabsorptive pathway, that is, the sodium-hydrogen antiporter NHE3 in the apical membrane and the Na-K-ATPase in the basolateral membrane. The effects of sympathetic stimulation on cells in the distal nephron are less straightforward. However, the overall outcome of sympathetic stimulation of the kidney is clearly reduced sodium excretion.

The Renin-Angiotensin System

AII's function

  • Reduces the RBF and GFR
  • Stimulation of sodium tubular reabsorption
  • Stimulation of the CNS: salt appetite, thirst, and sympathetic drive
  • Stimulation of aldosterone secretion

The major determinant of circulating AII is the amount of renin available to form angiotensin I.

PS: "Control of the Circulating RAAS" is ready at http://www.tomhsiung.com/wordpress/2016/06/control-of-the-circulating-raas/

AII is a potent vasoconstrictor, acting on the vasculature of many peripheral tissues, the effect of which is to raise arterial pressure. It also vasoconstricts both cortical and medullary vessels in the kidney. This reduces total RBF and reduces GFR, thus decreasing the filtered load of sodium.

AII stimulates sodium reabsorption in both the proximal tubule and distal nephron. In the proximal tubule it stimulates the same transcellular transport pathway as does norepinephrine, namely NHE3 sodium/hydrogen antiporter in the apical membrane and the Na-K-ATPase in the basolateral membrane. In the distal tubule and connecting tubule, it stimulates the activity of sodium/chloride symporters and sodium channels (ENaC) that reabsorb sodium.

AII stimulates behavioral actions in response to fluid loss that increase salt appetite and thirst. AII acts on the circumventricular organs in the brain. These function as detectors of many substances in the blood and convey information to various areas of the brain. In situations of volume depletion and low blood pressure, when circulating levels of AII are high, a key effect, in addition to vascular and tubular actions is increased thirst and salt appetite. These pathways also increase sympathetic drive.

Aldosterone is a major stimulator of sodium reabsorption in the distal nephron, that is, regions of the tubule beyond the proximal tubule and loop of Henle. We focus here on the role of aldosterone in sodium reabsorption, but aldosterone has many other important actions, including stimulation of potassium excretion and acid excretion. The most important physiological factor controlling secretion of aldosterone is the circulating level of AII, which stimulates the adrenal cortex to produce aldosterone. But keep in mind that elevated plasma potassium concentration, atrial natriuretic factors are other stimulators of aldosterone secretion. The aldosterone has enough lipid character to freely cross principal cell membrane in the collecting ducts, after which it combines with mineralocorticoid receptors (aldosterone receptors) in the cytoplasm. After being transported to the nucleus, the receptor acts as a transcription factor that promotes gene expression of specific proteins. The effect of these proteins is to increase the activity or number of luminal membrane sodium channels (ENaCs) and basolateral membrane Na-K-ATPase pumps.

Dopamine

Dopaimine inhibits sodium reabsorption in the kidney. The dopamine that acts in the kidney is not released from neurons; rather it is synthesized in proximal tubule cells from the precursor l-DOPA. l-DOPA is taken up from the renal circulation and glomerular filtrate and converted to dopamine in the proximal tubule epithelium, and then released to act in a paracrine manner on nearby cells. Although the signaling path is not clear, it is known that increases in sodium intake lead to increased production of intrarenal dopamine. Dopamine has 2 actions, both of which reduce sodium reabsorption. First, it causes retraction of NHE antiporters and Na-K-ATPase pumps into intracellular vesicles, thereby reducing transcellular sodium reabsorption. Second, it reduces the expression of AII receptors, thereby decreasing the ability of AII to stimulate sodium reabsorption.

Other Controllers of Sodium Excretion

ADH

When ADH binds to V2 reecptors in tubular cells, it increases the production of c-AMP. This results in increased activity of the NKCC multiporter in the thick ascending limb and increased sodium channel (ENaC) presence in principal cells of the distal nephron, thereby increasing the uptake of sodium that, in both regions, is actively transported into the interstitium by the Na-K-ATPase. Interestingly, in the distal nephron the mechanism proceeds, not by moving ENaCs into the membrane, but rather by decreasing their removal and degradation.

Glomerulotubular Balance

Glomerulotubular balance (not to be confused with TG feedback described previously) refers to the phenomenon whereby sodium reabsorption in the proximal tubule varies in parallel with the filtered load, such that approximately two thirds of the filtered sodium is reabsorbed even when GFR varies. The mechanism by which reabsorption varies with filtered load appears to be via mechanotransduction by the microvilli on the apical surface of the proximal tubule cells, similar in principle to mechanotransduction by primary cilia in the macula densa. As flow changes, the amount of bending of the microvilli changes, and this is converted by cellular mechanisms into changes in transport.

Pressure Natriuresis and Diuresis

Because the kidneys are responsive to arterial pressure, there are situations in which elevated blood pressure can lead directly to increased excretion of sodium. This phenomenon is called pressure natriuresis, and because natriuresis is usually accompanied by water, it is often called pressure diuresis. This is an intrarenal phenomenon, not requiring external signaling. However, external signals normally override pressure natriuresis.

Natriuretic Peptides

Several tissues in the body synthesize members of a hormone family called natriuretic peptides. Key among these are atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). The main source of both natriuretic peptides is the heart. The natriuretic peptides have both vascular and tubular actions. The relax the afferent arteriole, thereby promoting increased filtration, and act at several sites in the tubule. They inhibit release of renin, inhibit the actions of AII that normally promote reabsorption of sodium, and act in the medullary collecting duct to inhibit sodium absorption. The major stimulus for increased secretion of the natriuretic peptides is distention of the atria, which occurs during plasma volume expansion. This is probably the stimulus for the increased natriuretic peptides that occurs in persons on a high salt diet.

Urinary Concentration – The Medullary Osmotic Gradient

June 22, 2016 Anatomy, Critical Care, Hemodynamics, Histology, Nephrology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , ,

The kidneys can produce a range of urine osmolalities depending on the levels of ADH. The production of hypo-osmotic urine is an understandable process: The tubules (particularly the thick ascending limb of Henle's loop) reabsorb relatively more solute than water, and the dilute fluid that remains in the lumen is excreted. The production of hyperosmotic urine is also straightfoward in that reabsorption of water from the lumen into a hyperosmotic interstitium concentrates that luminal fluid, leaving concentrated urine to be excreted.

The Mechanism to Generate Medullary Osmotic Gradient

There is a gradient of osmolality (hyperosmotic), increasing from a nearly iso-osmotic value at the corticomedullary border to a maximum of greater than 1000 mOsm/kg at the papilla. The peak osmolality is variable depending on dehydration or overhydration, where highest during periods of dehydration and lowest (approximately half of that during excess hydration) during excess hydration.

In the steady state there must be mass balance, that is, every substance that enters the medulla via tubule or blood vessel must leave the medulla via tubule or blood vessels. However, during development of the gradient there are transient accumulations of solute, and during washout of the gradient there are losses. To develop the osmotic gradient in the medullary interstitium, there must be deposition of solute in excess of water. It is reabsorption of sodium and chloride by the thick ascending limb in excess of water reabsorbed in the thin descending limbs that accomplishes this task. At the junction between the inner and outer medulla, the ascending limbs of all loops of Henle, whether long or short, turn into thick regions and remain thick all the way back until they reach the original Bowman's capsules. As they reabsorb solute without water and dilute the luminal fluid, they simultaneously add solute without water to the surrounding interstitium. This action of the thick ascending limb is absolutely essential and is the key to everything else that happens. If transport in the thick ascending limb is innhibited, the lumen is not diluted and the interstitium is not concentrated, and the urine becomes iso-osmotic.

Solutes

  • For thick ascending limbs in the cortex, reabsorbed solute is taken up by abundant cortex blood flow so intersititum osmolality in the cortex approximately equal plasma
  • High concentratiion sodium level in outer medulla interstitium makes them diffuse into DVR and AVR
  • Hyperosmotic sodium in AVR can diffuse into nearby DVR – the countercurrent exchange

For those portions of the thick ascending limbs in the cortex, the reabsorbed solute simply mixes with material reabsorbed by the nearby proximal convoluted tubules. Because the cortex contains abundant peritubular capillaries and a hight blood flow, the reabsorbed material immediately moves into the vasculature and returns to the general circulation. However, in the medulla, the vascular anatomy is arranged differently and total blood flow is much lower. Solute that is reabsorbed and deposited in the outer medullary interstitium during the establishment of the osmotic gradient is not immediately removed, that is, it accumulates. The degree of accumulation before a steady state is reached is a function of the arrangement of the vasa recta, their permeability properties and the volume of blood flowing within them.

Imagine first a hypothetical situation of no blood flow. Sodium would accumulate in the outer medulla without limit, because there would be no way to remove it. But, of course the outer medulla is perfused with blood, as are all tissues. Blood enters and leaves the outer medulla through parallel bundles of descending and ascending vasa recta (DVR and AVR). These vessels are permeable to sodium. Therefore sodium enters the vasa recta driven by the rise in concentration in the surrounding interstitium. Sodium entering the ascending vessels returns to the general circulation, but sodium in the descending vessels is distributed deeper into the medulla, where it diffuses out across the endothelia of the vassa recta and the interbundle capillaries that they feed, thereby raising the sodim content throughout the medulla.

Later, the interbundle capillaries drain into ascending vasa recta that lie near descending vasa recta. The walls of the ascending vasa recta are fenestrated, allowing movment of water and small solutes between plasma and interstitium. As the sodium concentration of the medullary interstitium rises, blood in the ascending vessels also takes on an increasingly higher sodium concentration. However, blood entering the medulla always has a normal sodium concentration (approximtely 140 mEq/L). Accordingly, some of the sodium begins to re-circulate, diffusing out of ascending vessels and reentering nearbydescending vessels that contain less sodium (countercurrent exchange). So sodium is entering descending vasa recta from 2 sources – re-circulated sodium from the ascending vasa recta, and new sodium from the thick ascending limbs. Over time, everything reaches a steady state in which the amount of new sodium entering the interstitium from thick ascending limbs matches the amount of sodium leaving the interstitium in ascending vasa recta. At its peak, the concentration of sodium in the medulla may reach 300 mEq/L, more than double its value in the general circulation. Since sodium is accompanied by an anion, mostly chloride, the contribution of salt to the medullary osmolality is approximately 600 mOsm/kg.

Water

  • While solute can accumulate without a major effect on renal volume, the amount of water in the medullary interstitium must remain nearly constant; otherwise the medulla would undergo significiant swelling or shrinking.
  • Because water is always being reabsorbed from the medullary tubules into the interstitium (from descending thin limbs and medullary colelcting ducts), that water movement must be matched by equal water movement from the interstitium to the vasculature.
  • Blood entering the medulla has passed through glomeruli, thereby concentrating the plasma proteins. While the overall osmotic content (osmolality) of this blood is essentially isosmotic with systemic plasma, its oncotic pressure is considerably higher.

The challenge for the kidneys is to prevent dilution of the hyperosmotic interstitium by water reabsorbed from the tubules and by water diffusing out of the iso-osmotic blood entering the medulla. The endotheial cells of descending vasa recta contain aquaporins. So water is drawn osmotically into the outer medullary interstitium by the high salt content in a manner similar to water being drawn out of tubular elements. At first glance it seems that this allows the undesired diluting effect to actually take place. But, of course, solute is also constantly being added from the nearby thick ascending limbs. The loss of water from descending vasa recta in the outer medulla serves the useful purpose of raising the osmolality of blood penetrating the inner medulla and decreasing its volume, thereby reducing the tendency to dilute the inner medullary interstitium. The ascending vasa recta have a fenestrated endothelium, allowing free movement of water and small solutes. Since the oncotic pressure is high, water entering the interstitium of the outer medulla from descending vasa recta is taken up by ascending vasa recta and removed from the medulla. In addition, water reabsorbed from tubular elements (descending thin limbs and collecting ducts) is also taken up by ascending vasa recta and removed, thereby preserving constancy of total medullary water content.

The magnitude of blood flow in the vasa recta is a crucial variable. The peak osmolality in the interstitium depends on the ratio of sodium pumping by the thick ascending limbs to blood flow in the vasa recta. If this ratio is high (meaning low blood flow), water from the isosmotic plasma entering the medulla in descending vasa recta does not dilute the hyperosmotic interstitium. In effect the "salt wins" and osmolality remains at a maximum. But in conditions of water excess, this ratio is very low (high blood flow) and the diluting effect of water diffusing out of descending vasa recta is considerable. In part the tendency to diulte is controlled by ADH (due to its vasoconstriction effect to limit the blood flow of DVR).

Urea

The peak osmolality in the renal papilla reaches over 1000 mOsm/kg. Approximately half of this is accounted for by sodium and chloride, and most of the rest is (500-600 mOsm/kg) accounted for by urea. Urea is a very special substance for the kidney. It is an end product of protein metabolism, waste to be excreted, and also an important component for the regulation of water excretion. For the handle of urea in the kidneys: 

1.There are no membrane transport mechanisms in the proximal tubule; instead, it easily permeates the tight junctions of the proximal tubule where it is reabsorbed paracellularly.

2.Tubular elements beyond the proximal tubule express urea transporters and handle urea in a complex, regulated manner.

The gist of the renal handling of urea is the following: it is freely filtered. About half is reabsorbed passively in the proximal tubule. Then an amount equal to that reabsorbed is secreted back into the loop of Henle. Finally, about half is reabsorbed a second time in the medullary collecting duct. The net result is that about half the filtered load is excreted.

Urea does not permeate lipid layer because of its highly polar nature, but a set of uniporters transport urea in various places beyond the proximal tubule and in other sites within the body. Because urea is freely filtered, the filtrate contains urea at a concentration identical to that in plasma. In the proximal tubule when water is reabsorbed, the urea concentation rises well above the plasma urea concentration, driving diffusion through the leaky tight junctions. Roughly, half the filtered load is reabsorbed in the proximal tubule by the by the paracellular route. As the tubular fluid enters the loop of Henle, about half the filtered urea remains, but the urea concentration has increased somewhat above its level in the filtrate because proportionally, more water than urea was reabsorbed. At this point, the process becomes fairly complicated.

The interstitium of the medulla has a considerably higher urea concentration than does plasma. The concentration increases from the outer to the inner medulla. Since the medullary interstitial urea concentration is greater than that in the tubular fluid entering the loop of Henle, there is a concentration gradient favoring secretion into the lumen. The tight junctions in the loop of Henle are no longer permeable, but the epithelial membranes of the thin regions of the Henle's loops express urea uniporters, members of the UT family. This permits secretion of urea into the tubule. In fact, the urea secreted from the medullary interstitium into the thin regions of the loop of Henle replaces the urea previously reabsorbed in the proximal tubule. Thus, when tubular fluid enters the thick ascending limb, the amount of urea in the lumen is at least as large as the filtered load. However, because about 80% of the filtered water has now been reabsorbed, the luminal urea concentration is now several times greater than in the plasma. Beginning with the thick ascending limb and continuing all the way to the inner medullary collecting ducts (through the distal tubule and cortical collecting ducts), the apical membrane urea permeability (and the tight junction permeability) is essentially zero. Therefore, an amount of urea roughly equal to the filtered load remains within the tubular lumen and flows from the cortical into the medullary collecting ducts.

During the transit through the cortical collecting ducts variable amounts of water are reabsorbed, significantly concentrating the urea.We indicated eariler that the urea concentration in the medullary interstitium is much greater than in plasma, but the luminal concentration in the medullary collecting ducts is even higher (up to 50 times its plasma value), so in the inner medulla the gradient now favors reabsorption and urea is reabsorbed a second time via another isoform of UT urea uniporter. It is this urea reabsorbed in the inner medulla that leads to the high medullary interstitial concentration, driving urea secretion into the thin regions of the loop of Henle.

Physiologic Adapations and Maladaptations in Heart Failure

October 20, 2015 Cardiology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , ,

Basic Concepts

Preload

The concept of preload in the intact heart was described by physiologists Frank and Starling a century ago. The preload can be though of as the amount of myocardial stretch at the end of diastole, just before contraction. Measurements that correlate with myocardial stretch, and that are often used to indicate the preload on the horizontal axis, are the ventricular end-diastolic volume (EDV).

Afterload

Afterload in the intact heart reflects the resistance that the ventricle must overcome to empty its contents. It is more formally defined as the ventricular wall stress that develops during systolic ejection. Wall stress (σ), like pressure, is expressed as force per unit area and, for the left ventricle, may be estimated from Laplace relationship:

σ = (P x r)/(2 x h)

where P is ventricular pressure, r is ventricular chamber radius, and h is ventricular wall thickness. Thus, ventricular wall stress rises in response to a higher pressure load (e.g., hypertension) or an increased chamber size (e.g., a dilated left ventricle). Conversely, as would be expected from Laplace relationship, an increase in wall thickness (h) serves a compensatory role in reducing wall stress, because the force is distributed over a greater mass per unit surface area of ventricular muscle.


Pathophysiology of Heart Failure

The pathophysiology of heart failure is complex and must be understood at multiple levels. Traditionally, research has focused on the hemodynamic changes of the failing heart, considering the heart as an isolated organ. However, studies of the failing heart have emphasized the importance of understanding changes at the cellular level and the neuro-hormonal interactions between the heart and other organs of the body.

Hemodynamic Changes

From a hemodynamic standpoint, heart failure can arise from worsening systolic or diastolic function or, more frequently, a combination of both.

Systolic Dysfunction

In systolic dysfunction, the isovolumic systolic pressure curve of the pressure-volume relationship is shifted downward (A). This reduce the stroke volume of the heart with a concomitant decrease in cardiac output. To maintain cardiac output, the heart can respond with three compensatory mechanisms:

1.Increased return of blood to the heart (preload) can lead to increased contraction of sarcomeres. In the pressure-volume relationship, the heart operates at a' instead of a, and stroke volume increases, but at the cost of increased end-diastolic pressure (D).

2.Second, increase release of catecholamines can increase cardiac output by both increasing the heart rate and shifting the systolic isovolumetric curve to the left (C).

3.Cardiac muscle can hypertrophy and ventricular volume can increase, which shifts the diastolic curve to the right (B).

Screen Shot 2015-10-18 at 7.15.43 PMAlthough each of these compensatory mechanisms can temporarily maintain cardiac output, each is limited in its ability to do so, and if the underlying reason for systolic dysfunction remains untreated, the heart ultimately fails.

Diastolic Dysfunction

Screen Shot 2015-10-18 at 8.49.51 PMIn diastolic dysfunction, the position of the systolic isovolumic curve remains unchanged (contractility of the myocytes is preserved). However, the diastolic pressure-volume curve is shift to the left, with an accompanying increase in left ventricular end-diastolic pressure and symptoms of heart failure. Diastolic dysfunction can be present in any disease that causes decreased relaxation, decreased elastic recoil, or increased stiffness of the ventricle.

Neurohormonal Changes

After an injury to the heart, increased secretion of endogenous neurohormones and cytokines is observed. Initially, increased activity of the adrenergic system and the renin-angiotensin system provides a compensatory response that maintains perfusion of vital organs. However, over time these changes can lead to progressive deterioration of cardiac function.

Sympathetic Nervous System

Increased sympathetic activity occurs early in the development of heart failure. Elevated plasma norepinephrine levels cause increased cardiac contractility and an increased heart rate that initially help maintain cardiac output. However, continued increases lead to increased preload (as a result of venous vasoconstriction) and afterload (from arterial vasoconstriction), which can worsen heart failure. In addition, sympathetic hyperactivity causes deleterious cellular changes.

RAAS

Reduced renal blood pressure stimulates the release of renin and increases the production of angiotensin II. Both angiotensin II and sympathetic activation cause efferent glomerular arteriolar vasoconstriction, which helps maintain the glomerular filtration rate despite a reduced cardiac output. Angiotensin II stimulates aldosterone synthesis, which leads to sodium resorption and potassium excretion by the kidneys. However, a vicious circle is initiated as continued hyperactivity of the renin-angiotensin system leads to severe vasoconstriction, increased afterload, and further reduction in cardiac output and glomerular filtration rate.

ADH

Heart failure is associated with increases release of vasopressin from the posterior pituitary gland. Vasopressin is another powerful vasoconstrictor that also promotes reabsorption of water in the renal tubules (collecting ducts).

Cytokines and Others

Heart failure is associated with the release of cytokines and other circulating peptides. Cytokines are a heterogeneous family of proteins that are secreted by macrophages, lymphocytes, monocytes, and endothelial cells in response to injury. The interleukins (ILs) and tumor necrosis factor (TNF) are the two major groups of cytokines that may have an important pathophysiologic role in heart failure. Upregulation of the gene responsible for TNF with an acompanying increase in circulating plasma levels of TNF has been found in patients with hear failure. TNF appears to have an important role in the cycle of myocyte hypertrophy and cell death (apoptosis). Preliminary in vitro data suggest that IL-1 may accelerate myoctye hypertrophy. Another peptide important for mediating some of the pathophysiologic effects observed in heart failure is the potent vasoconstrictor endothelin, which is released from endothelial cells. Preliminary data have suggested that excessive endothelin release may be responsible for hypertension in the pulmonary arteries observed in patients with left ventricular heart failure. Endothelin is also associated with myocyte growth and deposition of collagen in the interstitial matrix.

Cellular Changes

Pathophysiologic chanages at the cellular level are very complex and include changes in Ca2+ handling, adrenergic receptros, contractile apparatus, and myocyte structure.

Ca2+ Handling

In heart failure, both delivery of Ca2+ to the contractle apparatus and reuptake of Ca2+ by the sarcoplasmic reticulum are slowed. Decreased levels of messenger ribonucleic acid (mRNA) for the specialized Ca2+ release channels have been reported by some investigators. Similarly, myocytes from failing hearts have reduced levels of mRNA for the two sarcoplasmic reticulum proteins phospholamban and Ca2+-ATPase.

Changes of Adrenergic Receptors

Two major classes of adrengeric receptors are found in the human heart. Alpha1-adrenergic receptors are important for induction of myocardial hypertrophy; levels of alpha1 receptors are slightly increased in heart failure. Heart failure is associated with significant beta-adrenergic receptor desensitization as a result of chronic sympathetic activation. This effect is mediated by downregulation of beta1-adrenergic receptors, downstream uncoupling of the signal transducton pathway, and upregulation of inhibitory G proteins. All of these changes lead to a further reduction in myocyte contractility.

Contractile Apparatus

Cardiac myocytes cannot proliferate once they have matured to their adult form. However, these is a constant turnover of the contractile proteins that make up the sarcomere. In response to the hemodynamic stresss associated with heart failure, angiotensin II, TNF, norepinephrine, and other molecules induce protein synthesis via intranuclear mediators of gene activity. This causes myoctye hypertrophy with an increase in sarcomere numbers and a re-expression of tetal and neonatal forms of myosin and troponin. Activation of this primitive program results in the development of large myocytes that do not contract normally and have decreased ATPase activity.

Myocyte Structure Changes

The heart enarges in response to continued hemodynamic stress. Changes in myocardial size and shape associated with heart failure are collectively referred to as left ventricular remodeling. Several tissue is associated with myocyte loss via a process of necrosis, apoptosis (programmed cell death). Unlike the process of necrosis, apoptotic cells initially demonstrate decreased cell volume without disrutpion of the cell membrane. However, as the apoptotic process continues, the myocyte ultimately dies, and "holes" are left in the myocardium. Loss of myocytes places increased stress on the remaining myoctes. The process of apoptosis is accelerated by the proliferative signals that stimulate myocyte hypertrophy such as TNF. Although apoptosis is a normal process that is essential in organs made up of proliferating cells, in the heart apoptosis initiates a vicious circle whereby cell death causes increased stress that leads to hypertrophy and further acceleraton of apoptosis.

A second tissue change observed in heart failure is an increased amount of fibrous tissue in the interstitial spaces of the heart. Collagen deposition is due to activation of fibroblasts and myocyte death. Endothelin release leads to interstitial collagen deposition. The increase in connective tissue increase chamber siffness and shifts the diastolic pressure-volume curve to the left.

Finally, heart failure is associated with gradual dilation of the ventricle. Myocyte "slippage" as a result of activation of collagenases that disrupt the collagen network may be responsible for this process.

The Regular of Extracellular Fluids – ADH Secretion and Renin-Angiotensin System

March 9, 2014 Physiology and Pathophysiology 3 comments , , ,

CaduceusThe volume of ECF is determined primarily by the total amount of osmotically active solute in the ECF. Excessive loss of Na+ in the stools (diarrhea), urine (severe acidosis, adrenal insufficiency), or sweat (heat prostration) decreases ECF volume markedly and eventually leads to shock.

The regular of extracellular fluids is based on vasopressin (ADH) and renin-angiotensin system. The homeostatic mechanisms for controlling blood volume are focused on controlling sodium balance. In contrast, the homeostatic mechanisms for controlling plasma osmolality, which is largely determined by serum sodium concentration, are focused on controlling water balance.

The extracellular and intracellular concentration of sodium and potassium are maintained by Na+-K+-ATPase (although solutes generally cannot freely cross cell membranes) and these maintained concentration determine the osmolality of extracellular and intracellular fluids. Most cell membranes are freely permeable to water, and thus the osmolality of intra- and extracellular body fluids is the same. Otherwise, water will move from the hypotonic compartments to hypertonic compartments.

The Genesis of Osmosis

When a substance is dissolved in water, the concentration of water molecules in the solution is less than that in pure water, because the addition of solute to water results in a solution that occupies a greater volume than dose the water alone. If the solution is placed on one side of a membrane that is permeable to water but not to the solute, and an equal volume of water is placed on the other, water molecules diffuse down their concentration (chemical) gradient into the solution. This process – the diffusion of solvent molecules into a region in which the membrane is impermeable – is called osmosis.

The tendency for movement of solvent molecules to a region of greater solute concentration can be prevented by applying pressure to the more concentrated solution. The pressure necessary to prevent solvent migration is the osmotic pressure of the solution. Just like shown in picture below.

Screen Shot 2014-10-26 at 3.00.36 PM

Control of Vasopressin Secretion

Plasma osmolality and ECF volume can affect the secretion of ADH.

ADH increases the permeability of the collecting ducts of the kidney, so that more water enters the hypertonic interstitium of the renal pyramids and the urine becomes concentrated and its volume decreases (the hypertonic status of renal pyramid interstitium is caused by the “countercurrent mechanism”. The thin descending limb is only permeable to water. And the thick ascending limb has active transport of Na+ and Clwhich makes the intersitium hypertonic).

The overall effect of ADH is retention of water in excess of solute; consequently, the effective osmotic pressure of the body fluids is decreased. In the absence of vasopressin, the urine is hypotonic to plasma, urine volume is increased, and there is a net water loss; consequently, the osmolality of the body fluid rises.

The secretion of ADH is controlled by mechanisms of osmotic stimuli and volume feedback effect.

When effective osmotic pressure of the plasma is increased above 285 mOsm/kg, the rate of discharge of neurons containing vasopressin increases and vasopressin secretion occurs. Generally, at 285 mOsm/kg, plasma vasopressin is at or near the limits of detection by available assays.

Meanwhile, as plasma osmolality increases, the feeling of thirst gets stronger and people will take more water. The osmotic threshold for thirst is the same as or slightly greater than the threshold for increased vasopressin secretion.

A decreased extracellular volume or major decrease in arterial pressure reflexively activates increased ADH secretion. To say strictly, the effective circulating blood volume affeccts ADH secretion via volume receptors. These receptors are located in low- and high-pressure portions of the vascular system. The response is mediated by neural pathways originating in cardiopulmonary baroreceptors, and if arterial pressure decreases, from arterial baroreceptors. There is an inverse relationship between the rate of ADH secretion and the rate of discharge in afferents from stretch receptors. AngII reinforces the response to hypovolemia and hypotension by acting on the circumventricular organs to increase ADH secretion (but it is not certain which of the circumventricular organs are responsible for the increases in ADH secretion).

Also, volume effects have an inverse relationship with the feeling of thirst (probably by the increased level of ang II).

Some other factors such as pain, nausea, surgical stress, and emotions would affect the secretion of ADH. Alcohol decreases ADH secretion.

Control of Renin-Angiotensin System

The most important angiotensin is ang II. In physiology,

angiotensin II produces arteriolar constriction and a rise in systolic and diastolic blood pressure.

Ang II also acts directly on the adrenal cortex to increase the secretion of aldosterone.

Besides, ang II acts on the brain to decrease the sensitivity of the baroreflex, which potentiates the pressor effect of ang II.

Ang II acts on the brain to increase water intake and increase the secretion of ADH.

In general, four factors regulate the secretion of rennin and the resultant ang II and aldosterone. When arteriolar pressure at the level of the JG cells falls, renin secretion is enhanced. Renin secretion is inversely proportional to the amount of Na+ and Cl entering the distal renal tubules from the loop of Henle. Besides, ang II fees back to inhibit renin secretion by a direct action on the JG cells. Finally, increased activity of the sympathetic nervous system increases renin secretion.

Additional Information (updated on Jun 12th 2014)

Thirst

Water intake is increased by increased effective osmotic pressure of the plasma and by decrease in ECF volume (to say strictly, the effective circulating blood volume) and the impact of effective circulating blood volume >the one of effective osmotic pressure (and the Plasma Osmolality – ADH Secretion cluve shifts to the left by decreased effective circulating blood volume).

Osmolality acts via osmoreceptors, receptors that sense the osmolality of the body fluids (more accurately, the plasma). These osmoreceptors are located in the anterior hypothalamus. Decrease in ECF volume stimulate thirst by a pathway independent of that mediating thirst in response to increased plasma osmolality. Generally, the effect of ECF volume depletion on thirst is mediated in part via the rennin-angiotensin system. The angII acts on the subfornical organ (one of the circumventricular organs of the brain), a specialized receptor area in the diencephalon, to stimulate the neural area concerned with thirst. Some evidence suggests that it acts on the OVLT (no BBB) as well.

However, drugs that block the action of angII do not completely block the thirst response to hypovolemia (and decreased effective circulatory pressure).