Medical Physiology, 3rd Edition

Control of Water Content (Extracellular Osmolality)

Water accounts for half or more of body weight (~60% in men and 50% in women; see p. 102) and is distributed between the ICF and ECF compartments. Changes in total-body water content in the absence of changes in total-body solute content lead to changes in osmolality, to which the CNS is extremely sensitive. Osmolality deviations of ±15% lead to severe disturbances of CNS function. Thus, osmoregulation is critical.

Two elements control water content and thus whole-body osmolality: (1) the kidneys, which control water excretion (see pp. 806–807); and (2) thirst mechanisms, which control the oral intake of water. These two effector mechanisms are part of negative-feedback loops that begin within the hypothalamus. An increase in osmolality stimulates separate osmoreceptors to secrete AVP (which reduces renal excretion of free water) and to trigger thirst (which, if fulfilled, increases intake of free water). As a result, the two complementary feedback loops stabilize osmolality and thus [Na+].

Increased plasma osmolality stimulates hypothalamic osmoreceptors that trigger the release of AVP, inhibiting water excretion

An increase in the osmolality of the ECF is the primary signal for the secretion of AVP from the posterior pituitary gland. An elegant series of animal studies by Verney in the 1940s established that infusing a hyperosmotic NaCl solution into the carotid artery abruptly terminates an established water diuresis (Fig. 40-6A). Infusing the same quantity of hyperosmotic NaCl into the peripheral circulation has little effect because the hyperosmolar solution becomes diluted by the time it reaches the cerebral vessels. Therefore, the osmosensitive site is intracranial. Surgically removing the posterior pituitary abolishes the effect of infusing hyperosmotic NaCl into the carotid artery (see Fig. 40-6B). However, injecting posterior-pituitary extracts into the animal inhibits the diuresis, regardless of whether the posterior pituitary is intact. Later work showed that Verney's posterior-pituitary extract contained an “antidiuretic hormone”—now known to be AVP—that the posterior pituitary secretes in response to increased plasma osmolality. Ingesting large volumes of water causes plasma osmolality to fall, thus leading to reduced AVP secretion.

image

FIGURE 40-6 Sensing of blood osmolality in the dog brain. i.a., intra-arterial (carotid) injection; i.v., intravenous injection; p.o., per os (by mouth). (Data from Verney EG: The antidiuretic hormone and the factors which determine its release. Proc Royal Soc Lond B 135:25–106, 1947.)

In healthy individuals, plasma osmolality is ~290 mOsm. The threshold for AVP release is somewhat lower, ~280 mOsm (Fig. 40-7, red curve). Increasing the osmolality by only 1% higher than this level is sufficient to produce a detectable increase in plasma [AVP], which rises steeply with further increases in osmolality. Thus, hyperosmolality leads to increased levels of AVP, which completes the feedback loop by causing the kidneys to retain free water (see pp. 817–818).

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FIGURE 40-7 Dependence of AVP release on plasma osmolality. (Data from Robertson GL, Aycinena P, Zerbe RL: Neurogenic disorders of osmoregulation. Am J Med 72:339–353, 1982.)

Although changes in plasma [NaCl] are usually responsible for changes in plasma osmolality, other solutes can do the same. For example, hypertonic mannitol resembles NaCl in stimulating AVP release. However, an equivalent increase in extracellular osmolality by urea has little effect on plasma AVP levels. The reason is that urea readily permeates cell membranes and hence exerts a low effective osmolality or tonicity (see pp. 132–133) and is thus poorly effective in shrinking cells.

Hypothalamic neurons synthesize AVP and transport it along their axons to the posterior pituitary, where they store it in nerve terminals prior to release

Osmoreceptors of the CNS appear to be located in two areas that breech the blood-brain barrier: the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO), two of the circumventricular organs (see pp. 284–285). Specific neurons in these regions (Fig. 40-8) are able to sense changes in plasma osmolality. Elevated osmolality increases the activity of mechanosensitive cation channels located in the neuronal membrane, which results in depolarization and thus an increased frequency of action potentials. Hypo-osmolality causes a striking decrease of frequency. The osmosensitive neurons project to large-diameter neurons in the supraoptic and paraventricular nuclei of the anterior hypothalamus (see Fig. 40-8). These neurons synthesize AVP, package it into granules, and transport the granules along their axons to nerve terminals in the posterior lobe of the pituitary, which is part of the brain (see pp. 979–981). When stimulated by the osmosensitive neurons, these magnocellular neurons release the stored AVP into the posterior pituitary—an area that also lacks a blood-brain barrier—and AVP enters the general circulation.

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FIGURE 40-8 Control of AVP synthesis and release by osmoreceptors. Osmoreceptors are located in the OVLT and SFO, two areas that breech the blood-brain barrier. Signals from atrial low-pressure baroreceptors travel with the vagus nerve to the nucleus tractus solitarii (NTS); a second neuron carries the signal to the hypothalamus. aa, amino acids.

In humans and most mammals, the antidiuretic hormone is AVP, which is encoded by the messenger RNA for preproneurophysin II. After cleavage of the signal peptide, the resulting prohormone proneurophysin II contains AVP, neurophysin II (NpII), and a glycopeptide (see Fig. 40-8). Cleavage of the prohormone within the secretory granule yields these three components. AVP has nine amino acids, with a disulfide bridge connecting two cysteine residues. Mutations of NpII impair AVP secretion, which suggests that NpII assists in the processing or secretion of AVP.

Levels of circulating AVP depend on both the rate of AVP release from the posterior pituitary and the rate of AVP degradation. The major factor controlling AVP release is plasma osmolality. However, as discussed below, other factors also can modulate AVP secretion.

Two organs, the liver and the kidney, contribute to the breakdown of AVP and the rapid decline of AVP levels when secretion has ceased. The half-life of AVP in the circulation is 18 minutes. Diseases of the liver and kidney may impair AVP degradation and may thereby contribute to water retention. For example, the congestion of the liver and impairment of renal function that accompany heart failure can compromise AVP breakdown, leading to inappropriately high circulating levels of AVP. Conversely, in pregnancy, placental vasopressinase activity can accelerate degradation of AVP.

Increased osmolality stimulates a second group of osmoreceptors that trigger thirst, which promotes water intake

The second efferent pathway of the osmoregulatory system is thirst, which regulates the oral intake of water. Like the osmoreceptors that trigger AVP release, the osmoreceptors that trigger thirst are located in two circumventricular organs, the OVLT and the SFO. Also like the osmoreceptors that trigger AVP release, those that trigger thirst respond to the cell shrinkage that is caused by hyperosmolar solutions. However, these thirst osmoreceptor neurons are distinct from the adjacent AVP osmoreceptor neurons in the OVLT and SFO.

Hyperosmolality triggers two parallel feedback-control mechanisms that have a common end point (Fig. 40-9): an increase in whole-body free water. In response to hyperosmolality, the AVP osmoreceptors in the hypothalamus trigger other neurons to release AVP. The result is the insertion of aquaporin 2 (AQP2) water channels in the collecting duct of the kidney, an increase in the reabsorption of water, and, therefore, a reduced excretion of free water. In response to hyperosmolality, the thirst osmoreceptors stimulate an appetite for water that leads to the increased intake of free water. The net effect is an increase in whole-body free water and, therefore, a reduction in osmolality.

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FIGURE 40-9 Feedback systems involved in the control of osmolality. PVN, paraventricular nucleus; SON, supraoptic nucleus of the hypothalamus.

Several nonosmotic stimuli also enhance AVP secretion

Although an increase in plasma osmolality is the primary trigger for AVP release, several other stimuli increase AVP release, including a decrease in effective circulating volume or arterial pressure and pregnancy. Conversely, volume expansion diminishes AVP release.

Reduced Effective Circulating Volume

As noted above on page 846, a mere 1% rise in plasma osmolality stimulates AVP release by a detectable amount. However, fairly large reductions in effective circulating volume (5% to 10%) are required to stimulate AVP release of similar amounts. Nevertheless, once the rather high threshold for nonosmotic release of AVP is exceeded, AVP release rises steeply with further volume depletion. The interaction between osmotic and volume stimuli on AVP release is illustrated in Figure 40-7, which shows that the effective circulating volume modifies the slope of the relationship between plasma AVP levels and osmolality, as well as the osmotic threshold for AVP release. At a fixed osmolality, volume contraction (see Fig. 40-7, green curve) increases the rate of AVP release. Therefore, during volume depletion, a low plasma osmolality (e.g., 280 mOsm) that would normally suppress AVP release allows AVP secretion to continue (see Fig. 40-7, green dot). This leftward shift of the osmolality threshold for AVP release is accompanied by an increased slope, reflecting an increased sensitivity of the osmoreceptors to changes in osmolality.

Figure 40-9 summarizes the three pathways by which decreased effective circulating volume and low arterial pressure enhance AVP release: (1) A reduction in left atrial pressure—produced by volume depletion—via low-pressure receptors in the left atrium decreases the firing rate of vagal afferents (see p. 547). These afferents signal brainstem neurons in the nucleus tractus solitarii, causing magnocellular neurons in the hypothalamus to release AVP (see Fig. 40-8). Indeed, at constant osmolality, AVP secretion varies inversely with left atrial pressure. (2) Low effective circulating volume triggers granular cells in the JGA to release renin. This leads to the formation of ANG II, which acts on receptors in the OVLT and the SFO to stimulate AVP release. (3) More importantly, a fall in the arterial pressure similarly causes high-pressure carotid sinus baroreceptors to stimulate AVP release (see pp. 534–536).

Two clinical examples in which reduced effective circulating volume leads to increases in AVP are severe hemorrhagic shock and hypovolemic shock (e.g., shock resulting from excessive loss of ECF, as in cholera). In both cases, the water retention caused by AVP release accounts for the accompanying hyponatremia. In the first part of this chapter, we said that the appropriate renal response to decreased effective circulating volume is to retain Na+ (i.e., isotonic saline). Why is it that, in response to shock, the body also retains free water? Compared with isotonic saline, free water is less effective as an expander of the ECF volume (see p. 135). Nevertheless, in times of profound need, the body uses free-water retention to help expand extracellular (and plasma) volume. Clearly, the body is willing to tolerate some hypo-osmolality of the body fluids as the price for maintaining an adequate blood volume.

A clinical example in which reduced effective circulating volume can lead to an inappropriate increase in AVP levels is congestive heart failure (see p. 838). In this situation, the water retention may be so severe that the patient develops hyponatremia (i.e., hypo-osmolality).

Volume Expansion

In contrast to volume contraction, chronic volume expansion reduces AVP secretion, as a consequence of the rightward shift of the threshold to higher osmolalities and of a decline in the slope (see Fig. 40-7, blue curve). In other words, volume expansion decreases the sensitivity of the central osmoreceptors to changes in plasma osmolality. A clinical example is hyperaldosteronism. With normal thirst and water excretion, the chronic Na+ retention resulting from the hyperaldosteronism would expand the ECF volume isotonically, thus leaving plasma [Na+] unchanged. However, because chronic volume expansion downregulates AVP release, the kidneys do not retain adequate water, which results in slight hypernatremia (i.e., elevated plasma [Na+]) and very modest hyperosmolality (Box 40-3).

Box 40-3

Diuretics

Diuretics reversibly inhibit Na+ reabsorption at specific sites along the nephron, increasing the excretion of Na+ and water, creating a state of negative Na+ balance, and thereby contracting ECF volume. Properly speaking, these agents should be called natriuretic to emphasize this use to promote Na+ excretion. This is in contrast to aquaretic agents (e.g., vasopressin receptor antagonists, or VRAs) that promote water excretion with little or no effect on Na+ excretion. Nevertheless, it has been customary to refer to natriuretics as diuretics.

Clinicians use diuretics to treat hypertension as well as edema (see Box 20-1) caused by heart failure, cirrhosis of the liver, or nephrotic syndrome. Common to these latter edematous diseases is an abnormal shift of ECF away from the effective circulating volume, which thereby activates the feedback pathways. The results are Na+ retention and expansion of total extracellular volume. However, this expansion, which results in edema formation, falls short of correcting the underlying decrease in the effective circulating volume. The reason that most of this added extracellular volume remains ineffective—and does not restore the effective circulating volume—is not intuitive but reflects the underlying pathologic condition that initiated the edema in the first place. Thus, treating these edematous diseases requires generating a negative Na+ balance, which can often be achieved by rigid dietary Na+ restriction or the use of diuretics. Diuretics are also useful in treating hypertension. Even though the primary cause of the hypertension may not always be an increase in the effective circulating volume, enhanced Na+ excretion is frequently effective in lowering blood pressure.

Classification

The site and mechanism of a diuretic's action determine the magnitude and nature of the response (Table 40-3). Both chemically and functionally, diuretics are very heterogeneous. For example, acetazolamide produces diuresis by inhibiting carbonic anhydrase and thus the component of proximal-tubule Na+ reabsorption that is coupled to image reabsorption. The diuretic effect of hydrochlorothiazide is largely the result of its ability to inhibit Na/Cl cotransport in the distal convoluted tubule. Spironolactone (which resembles aldosterone) competitively inhibits mineralocorticoid receptors in principal cells of the initial and cortical collecting tubule. Mannitol (reduced fructose) is a powerful osmotic diuretic (see Box 35-1) that reduces net Na+ transport in the proximal tubule and TAL by causing retention of water in the lumen and reduction in luminal [Na+].

TABLE 40-3

Action of Diuretics

SITE

DRUG

FINAL MOLECULAR “TARGET”

PHYSIOLOGICAL REGULATION OF “TARGET”

PAGE REFERENCE FOR TARGET

STIMULATOR

INHIBITOR

PCT

Acetazolamide

Carbonic anhydrase

   

pp. 828–829

PCT

Dopamine

Na-H exchanger (NHE3)

ANG II, sympathetic nerve activity, α-adrenergic agonists

Dopamine

p. 827

TAL

Loop diuretics:
Furosemide
Bumetanide
Ethacrynic acid

Na/K/Cl cotransporter (NKCC2)

Aldosterone

PGE2

p. 757

DCT

Thiazides
Metolazone

Na/Cl cotransporter (NCC)

ANG II
Aldosterone

 

p. 758

CCT

Amiloride
Triamterene

Na+ channel (ENaC)

ANG II

PGE2

pp. 758–759

CCT

Spironolactone

Mineralocorticoid receptor

Aldosterone

 

p. 766

IMCD

Amiloride

cGMP-gated cation channel

Aldosterone

ANP

p. 768

Water-permeable segments

Osmotic diuretics (mannitol)

       

CCT, cortical collecting tubule; DCT, distal convoluted tubule; IMCD, inner medullary collecting duct; PCT, proximal convoluted tubule; PGE2, prostaglandin E2.

An ideal diuretic should promote the excretion of urine whose composition resembles that of the ECF. Such diuretics do not exist. In reality, diuretics not only inhibit the reabsorption of Na+ and its osmotically obligated water, but also interfere with the renal handling of Cl, H+, K+, and Ca2+, as well as with urinary concentrating ability. imageN40-7 Thus, many diuretics disturb the normal plasma electrolyte pattern. Table 40-4 summarizes the most frequent side effects of diuretic use on the electrolyte composition of the ECF. These electrolyte derangements are the predictable consequences of the mechanism of action of individual diuretics at specific tubule sites.

TABLE 40-4

Complications of Diuretic Therapy

COMPLICATION

CAUSATIVE DIURETICS

SYMPTOMS

CAUSATIVE FACTORS

ECF volume depletion

Loop diuretics and thiazides

Lassitude, thirst, muscle cramps, hypotension

Rapid reduction of plasma volume

K+ depletion

Acetazolamide, loop diuretics, thiazides

Muscle weakness, paralysis, cardiac arrhythmias

Flow and Na+-related stimulation of distal K+ secretion

K+ retention

Amiloride, triamterene, spironolactone

Cardiac arrhythmias, muscle cramps, paralysis

Block of ENaC in the collecting duct

Hyponatremia

Thiazides, furosemide

CNS symptoms, coma

Block of Na+ transport in water-impermeable nephron segment

Metabolic alkalosis

Loop diuretics, thiazides

Cardiac arrhythmias, CNS symptoms

Excessive Cl excretion, secondary volume contraction

Metabolic acidosis

Acetazolamide, amiloride, triamterene

Hyperventilation, muscular and neurological disturbances

Interference with H+ secretion

Hypercalcemia

Thiazides

Abnormal tissue calcification, disturbances of nerve and muscle function

Increased Ca2+ reabsorption in distal convoluted tubule

Hyperuricemia

Thiazides, loop diuretics

Gout

Decreased ECF volume, which activates proximal fluid and uric acid reabsorption

ENaC, epithelial Na+ channel.

Delivery of Diuretics to Their Sites of Action

Diuretics generally inhibit transporters or channels at the apical membranes of tubule cells. How do the diuretics get there? Plasma proteins bind many diuretics so that the free concentration of the diuretic in plasma water may be fairly low. Thus, glomerular filtration may deliver only a modest amount to the tubule fluid. However, organic anion or organic cation transporters in the S3 segment of the proximal tubule can secrete diuretics and can thereby produce high luminal concentrations. For example, the basolateral organic anion transporter system that carries para-aminohippurate (see pp. 779–781) also secretes thiazide diuretics, furosemide, and ethacrynic acid. Organic cation transporters (see pp. 783–784) secrete amiloride. The subsequent reabsorption of fluid along the nephron further concentrates diuretics in the tubule lumen. Not surprisingly, renal disease may compromise the delivery of diuretics and cause resistance to the actions of diuretics. imageN40-8

Response of Nephron Segments Downstream from a Diuretic's Site of Action

The proximal tubule reabsorbs the largest fraction of filtered Na+; the loop of Henle, the distal convoluted tubule, and the collecting ducts retrieve smaller fractions. Thus, intuition could suggest that the proximal tubule would be the best target for diuretics. However, secondary effects in downstream nephron segments can substantially mitigate the primary effect of a diuretic. Inhibiting Na+ transport by the proximal tubule raises Na+ delivery to downstream segments and almost always stimulates Na+ reabsorption there (see p. 765). As a result of this downstream Na+ reclamation, the overall diuretic action of proximally acting diuretics (e.g., acetazolamide) is relatively weak.

A diuretic is most potent if it acts downstream of the proximal tubule, a condition met by loop diuretics, which inhibit Na+ transport along the TAL. Although the TAL normally reabsorbs only 15% to 25% of the filtered load of Na+, the reabsorptive capacity of the more distal nephron segments is limited. Thus, the loop diuretics are currently the most powerful diuretic agents. Because nephron segments distal to the TAL have only modest rates of Na+ reabsorption, diuretics that target these segments are not as potent as loop diuretics. Nevertheless, distally acting diuretics are important because their effects are long lasting. Moreover, agents acting on the connecting and collecting tubules are K+ sparing (i.e., they tend to conserve body K+).

It is sometimes advantageous to use two diuretics that act at different sites along the nephron, generating a synergistic effect. Thus, if a loop diuretic alone is providing inadequate diuresis, one could complement its action by adding a thiazide, which will block the compensating effect of the distal convoluted tubule to reabsorb Na+.

Blunting of Diuretic Action with Long-Term Use

The prolonged administration of a diuretic may lead to a sustained loss of body weight but only transient natriuresis. imageN40-9 Most of the decline in Na+ excretion occurs because the drug-induced fall in effective circulating volume triggers Na+ retention mediated by increased sympathetic outflow to the kidneys (which lowers GFR), increased secretion of ANG II and aldosterone, and decreased secretion of ANP. Hypertrophy or increased activity of tubule segments downstream of the main site of action of the diuretic can also contribute to the diminished efficacy of the drug during long-term administration.

N40-7

Secondary Effects of Diuretic Drugs

Contributed by Erich Windhager, Gerhard Giebisch

As noted in the text, the perfect diuretic—which does not exist—would produce an increase in the urinary excretion of protein-free fluid with a composition otherwise identical to that of the ECL. However, diuretics not only inhibit the reabsorption of Na+ and the osmotically obligated water, but also interfere with the renal handling of Cl, H+, K+, and Ca2+, as well as with urinary concentrating ability.

1. Urine [Cl]. With the exception of carbonic anhydrase inhibitors, all diuretics promote the excretion of urine having a high [Cl]. The ratio [Cl]/[Na+] is greater in the urine than in the plasma.

2. Urine pH. Because of its inhibition of proximal-tubule image reabsorption, acetazolamide leads to excretion of a relatively alkaline urine. Thus, acetazolamide produces a mild metabolic acidosis. In contrast, the loop diuretics and thiazides cause the excretion of a Cl-rich, image-poor urine, which tends to induce a metabolic alkalosis.

3. Urine [K+]. Some diuretics are called K+-sparing because they tend to conserve body K+. These diuretics—which include amiloride, triamterene, and spironolactone—block only a small fraction of Na+reabsorption, but reduce K+ secretion through apical K+ channels by hyperpolarizing the apical cell membrane. By inhibiting passive cation movement, they may induce hyperkalemia. This hyperkalemia may lead to metabolic acidosis (see p. 835).

4. Urine [Ca2+]. With the exception of the chlorothiazides, most diuretics enhance Ca2+ excretion. They interfere with the passive reabsorption of Ca2+ through the paracellular pathway in both the proximal tubule and TAL (see p. 787). In the proximal tubule, the high luminal flow rate produced by the diuresis reduces the reabsorption of Ca2+ via solvent drag. In the TAL, loop diuretics diminish the lumen-positive potential that normally drives the passive reabsorption of Ca2+.

5. Urine osmolality. Loop diuretics diminish the urinary concentrating ability by inhibiting Na+ transport in the TAL (see p. 811).

Clinical side effects of diuretic therapy are summarized in Table 40-4.

N40-8

Reduced Delivery of Diuretics in Renal Disease

Contributed by Erich Windhager, Gerhard Giebisch

As noted in the text, diuretics cannot have their intended effects unless they have appropriate access to their protein targets in the tubule cells. The two access routes are filtration and secretion, of which secretion is usually the most important.

Not surprisingly, renal disease may compromise the net secretion of diuretics in three ways. First, the capability of the diseased cells to secrete diuretics may be impaired (i.e., decreased transport). Second, renal failure leads to a buildup in the blood of organic anions that would otherwise be secreted. These organic anions may competitively inhibit the transport of diuretics by the proximal tubule (i.e., competition). Third, in renal diseases in which breakdown of the glomerular filtration barrier leads to proteinuria, albumin and other proteins not normally present in the tubule lumen bind the diuretics and greatly reduce the concentration of unbound drug (i.e., binding).

N40-9

Blunting of Diuretic Action

Contributed by Erich Windhager, Gerhard Giebisch

Let us assume that a patient has a fixed daily intake of Na+. As noted in the text, the administration of a diuretic will cause an initial period of increased Na+ excretion (negative Na+ balance), peaking within a few days, that leads to a loss in weight. During prolonged administration of the diuretic, urinary Na+ excretion will fall back toward normal over a period of many days, and the patient will reach a steady state (neutral Na+ balance) in which Na+ intake and excretion are equal, and in which the initial weight loss is maintained.

When the drug is discontinued, the patient will experience a transient period of diminished urinary Na+ excretion, reaching a nadir after a few days. During this time he or she is in positive Na+ balance. As a result, the patient will regain the weight that was lost during the initial phase of the diuretic treatment. However, over a period of many days, the Na+ excretion eventually rises back to a normal level as the patient achieves a new steady state (neutral Na+ balance) in which Na+ intake and excretion are again equal, and the patient maintains a prediuretic weight.

Pregnancy

Leftward shifts in the threshold for AVP release and thirst often occur during pregnancy. These changes probably reflect the action of chorionic gonadotropin on the sensitivity of the osmoreceptors. Pregnancy is therefore often associated with a decrease of 8 to 10 mOsm in plasma osmolality. A similar but smaller change may also occur in the late phase of the menstrual cycle.

Other Factors

Pain, nausea, and several drugs (e.g., morphine, nicotine, and high doses of barbiturates) stimulate AVP secretion. In contrast, alcohol and drugs that block the effect of morphine (opiate antagonists) inhibit AVP secretion and thus promote diuresis. Of great clinical importance is the hypersecretion of AVP that may occur postoperatively. In addition, some malignant tumors secrete large amounts of AVP. Such secretion of inappropriate amounts of “antidiuretic hormone” leads to pathological retention of water with dilution of the plasma electrolytes, particularly Na+. If progressive and uncorrected, this condition may lead to life-threatening deterioration of cerebral function (see Box 38-3).

Decreased effective circulating volume and low arterial pressure also trigger thirst

Large decreases in effective circulating volume and blood pressure not only stimulate the release of AVP, they also profoundly stimulate the sensation of thirst. In fact, hemorrhage is one of the most powerful stimuli of hypovolemic thirst: “Thirst among the wounded on the battlefield is legendary” (Fitzsimons). Therefore, three distinct stimuli—hyperosmolality, profound volume contraction, and large decreases in blood pressure—lead to the sensation of thirst. Low effective circulating volume and low blood pressure stimulate thirst centers in the hypothalamus via the same pathways by which they stimulate AVP release (see Fig. 40-9).

In addition to stimulating thirst, some of these hypothalamic areas are also involved in stimulating the desire to ingest salt (i.e., Na+ appetite). We discuss the role of the hypothalamus in the control of appetite on page 1001.

Defense of the effective circulating volume usually has priority over defense of osmolality

Under physiological conditions, the body regulates plasma volume and plasma osmolality independently. However, as discussed on page 847, this clear separation of defense mechanisms against volume and osmotic challenges breaks down when more dramatic derangements of fluid or salt metabolism occur. In general, the body defends volume at the expense of osmolality. Examples include severe reductions in absolute blood volume (e.g., hemorrhage) and decreases in effective circulating volume even when absolute ECF volume may be expanded (e.g., congestive heart failure, nephrotic syndrome, and liver cirrhosis). All are conditions that strongly stimulate both Na+and water-retaining mechanisms. However, hyponatremia can be the consequence. imageN40-10

N40-10

Defense of Osmolality at the Expense of Effective Circulating Volume During Dehydration

Contributed by Gerhard Giebisch, Erich Windhager, Emile Boulpaep, Walter Boron

An exception to the rule of defending volume over osmolality occurs during severe water loss (i.e., dehydration; see p. 1215). In this case, the hyperosmolality that accompanies the dehydration maximally stimulates AVP secretion and thirst (see Fig. 40-9). Of course, severe dehydration also reduces total-body volume. However, this loss of free water occurs at the expense of both intracellular water (~60%) and extracellular water (~40%). Thus, dehydration does not put the effective circulating volume at as great a risk as the acute loss of an equivalent volume of blood. Because dehydration reduces effective circulating volume, one might think that the renin-angiotensin-aldosterone axis would lead to Na+ retention during dehydration. However, the opposite effect may occur, possibly because hyperosmolality makes the glomerulosa cells of the adrenal medulla less sensitive to ANG II and thereby reduces the release of aldosterone. Thus, the kidneys fail to retain Na+ appropriately. Accordingly, in severe dehydration, the net effect is an attempt to correct hyperosmolality by both water intake and retention, as well as by the loss of Na+ (i.e., natriuresis) that occurs because aldosterone levels are inappropriately low for the effective circulating volume. Therefore, in severe dehydration, the body violates the principle of defending volume over osmolality.

If the dehydration occurs during exercise, the drive to preserve effective circulating volume will trump temperature regulation (see p. 1215), offsetting the earlier vasodilation of the skin and active muscle. We can infer that the exercise-induced dehydration, by triggering thirst and AVP secretion (see previous paragraph), leads to a correction of the hyperosmolality and an increase in effective circulating volume that, once again, allows the individual to sweat and effectively regulate whole-body temperature.