Principles and Practice of Endocrinology and Metabolism



Anatomy of the Neurohypophysis

Gross Features

Microscopic Features

Biosynthesis and Release of Vasopressin and Oxytocin

Regulation of Vasopressin Secretion

Regulation of Oxytocin Secretion
Distribution and Clearance of Vasopressin and Oxytocin
Biologic Actions


Thirst Mechanism
Water Homeostasis

Volume, Composition, Distribution, and Balance


Hemodynamic Influences
Chapter References

The neurohypophysis, an extension of the ventral hypothalamus, attaches to the dorsal and caudal surface of the adenohypophysis1 (Fig. 25-1). In adult men and women, it weighs ~100 mg. It is divided by the diaphragma sellae into an upper part, called the infundibulum or median eminence, and a lower part, known as the infundibular process or pars nervosa. The two parts are supplied with blood by branches from the superior and inferior hypophyseal arteries. In the pars nervosa, the arterioles break up into localized capillary networks that drain directly into the jugular vein through the sellar, cavernous, and lateral venous sinuses. In the infundibulum, the primary capillary networks coalesce into another system, the portal veins, which perfuse the adenohypo-physis before discharging into the systemic circulation.

FIGURE 25-1. The neurohypophysis and its principal regulatory afferents are illustrated. (pvn, paraventricular nucleus; or, osmoreceptor; son, supraoptic nucleus; oc, optic chiasm; ds, diaphragma sellae; ah, adenohypophysis; nh, neurohypophysis; br, volume and baroreceptors; ap, area postrema [emetic center]; nts, nucleus tractus solitarii.) (From Robertson GL. Disorders of the posterior pituitary. In: Stein JH, ed. Internal medicine. Boston: Little, Brown and Company, 1983:1728.)

On microscopic examination, the neurohypophysis appears as a densely interwoven network of capillaries, pituicytes, and non-myelinated nerve fibers containing many electrondense neuro-secretory granules. These neurosecretory neurons terminate as bulbous enlargements on capillary networks located at all levels of the neurohypophysis, including the stalk and infundibulum. The vasopressin-containing neurosecretory neurons that form the pars nervosa originate primarily in the supraoptic nuclei2 and probably provide most, if not all, of the vasopressin and oxytocin in the peripheral plasma. Those that terminate in the median eminence originate primarily in the paraventricular or other hypothalamic nuclei,2 probably releasing their hormones into the portal blood supply of the anterior pituitary. Other, smaller groups of vasopressinergic neurons project from the paraventricular nucleus to the medulla, amygdala, spinal cord, and the walls of the lateral and third ventricles.2 The latter may secrete directly into the cerebrospinal fluid (CSF).3
Oxytocinergic cell bodies appear to be less numerous than those containing vasopressin.2 They are found primarily in discrete areas in or around the paraventricular nuclei and, to a lesser extent, the supraoptic nuclei. Most oxytocinergic neurons project to the pars nervosa, but many also terminate in the organum vasculosum or the median eminence. In addition, a relatively large paraventricular division runs parallel to the vasopressinergic fibers that connect to the medulla and spinal cord (see Chap. 8 and Chap. 9).
Vasopressin and oxytocin are the only hormones known to be secreted in significant amounts by the neurohypophysis. As first shown by du Vigneaud and coworkers,4 the two hormones have similar structures (Fig. 25-2), being nonapeptides that contain six-membered disulfide rings and the same amino acid residues in seven of the nine positions. They are stored in neurosecretory granules as insoluble complexes with specific carrier proteins known as neurophysins.5 The neurophysins associated with vasopressin and oxytocin also have similar structures, each having ~100 amino-acid residues with extensive areas of homology. Binding of the hormones to their neurophysins has a pH optima (5.2–5.8) and dissociation constant (Kd) (~5 × 105) that favor association in neurosecretory granules but ensures almost complete dissociation in plasma and other body fluids.

FIGURE 25-2. Structure of oxytocin, vasopressin, and 1-deamino-(8-D-arginine)-vasopressin (DDAVP). (S, sulfur.)

Vasopressin and oxytocin are synthesized through protein precursors encoded by single-copy genes that are located near each other on chromosome 20 in humans6,7,8 and 9 (Fig. 25-3). The gene for the vasopressin precursor, known as propressophysin or vasopressin neurophysin II, is ~2-kb long. It contains three exons that encode, respectively, (a) a signal peptide, vasopressin, and the variable amino-terminal end of neurophysin; (b) the highly conserved middle portion of neurophysin; and (c) the variable, carboxy-terminal end of neurophysin and copeptin, a glycosy-lated peptide of unknown function. The gene for the oxytocin precursor is similar except that exon C is shorter and codes only for the variable carboxy terminus of neurophysin and a single histidine residue. The copeptin moiety is absent.

FIGURE 25-3. Structure of the vasopressin and oxytocin prohormones and the genes that encode them. (AVP, arginine vasopressin; G, glycosylation.)

In humans and other mammals, the vasopressin and oxytocin genes are expressed in different magnocellular neurons. After transcription and translation in cell bodies within the supraoptic and paraventricular nuclei, the preprohormones are translocated into the endoplasmic reticulum, where the signal peptide is removed and the prohormones fold and self-associate before moving through the Golgi apparatus and on into the neurosecretory granules. There they are transported down the axons and cleaved into the intact hormone, neurophysin, and, in the case of vasopressin, copeptin. This process is critically dependent on correct folding and self-association of the prohormone in the endoplasmic reticulum, because genetic mutations predicted to alter amino acids important for correct folding severely disrupt transport and destroy the neurons, producing the autosomal dominant form of familial neurohypophyseal diabetes insipidus.
Release of the hormones and their associated neurophysins occurs via a calcium-dependent exocytotic process similar to that described for other neurosecretory systems.10 An electrical impulse propagated along the neuron depolarizes the cell membrane, causing an influx of calcium, fusion of secretory granules with the outer cell membranes, and extrusion of their contents.
The secretion of vasopressin is influenced by a number of variables.11,12,13,14 and 15 The most important under physiologic conditions is the effective osmotic pressure of plasma. This influence is mediated by specialized cells called osmoreceptors. These osmoreceptors appear to be concentrated in the anterolateral hypothalamus,16,17 and 18 in an area that is near, but separate from, the supraoptic nuclei (see Fig. 25-1). This area is supplied with blood by small perforating branches of the anterior cerebral or communicating arteries.1
The basic structure, modus operandi, and organization of the individual osmoreceptors have not yet been determined. However, the system as a whole functions like a discontinuous or set-point receptor (Fig. 25-4). Thus, at plasma osmolalities below a certain minimum or threshold level, plasma vasopressin is suppressed to low or undetectable concentrations. Above this set-point, plasma vasopressin rises steeply in direct proportion to plasma osmolality. The slope of the relationship indicates that a change in plasma osmolality of only 1% alters plasma vasopressin by an average of 1 pg/mL, an amount sufficient to significantly affect the urinary concentration and flow (Fig. 25-5).

FIGURE 25-4. The relationship of thirst and plasma vasopressin to plasma osmolality in healthy adults under varying conditions of water balance. (From Robertson GL. Thirst and vasopressin function in normal and disordered states of water balance. J Lab Clin Med 1983; 101:351.)

FIGURE 25-5. The relation of urine osmolality to plasma vasopressin in healthy adults under varying conditions of water balance. (AVP, arginine vasopressin.) (From Robertson GL. Thirst and vasopressin function in normal and disordered states of water balance. J Lab Clin Med 1983; 101:351.)

The sensitivity and “set” of the osmoregulatory system varies considerably among healthy adults. The interindividual differences in sensitivity are large (up to 10-fold), are constant over long periods of time, and appear to be genetically determined.19 However, they can be altered slightly by a variety of pharmacologic or pathologic influences.20 The interindividual differences in setpoint are not as large (275–290 mOsm/kg) or as constant over time but also appear to have a significant genetic component.19 They are more subject to alteration by a variety of physiologic factors, including posture, pregnancy, and the phase of the menstrual cycle,20,21 all of which lower the osmotic threshold or setpoint.
The sensitivity of the osmoregulatory system also varies for different plasma solutes (Fig. 25-6). Sodium and its anions, which normally contribute >95% of the osmotic pressure of plasma, are the most potent solutes known in terms of their capacity to stimulate vasopressin release.20 Certain sugars, such as sucrose and mannitol, appear to be nearly as potent. However, a rise in plasma osmolality secondary to urea or glucose causes little or no increase in plasma vasopressin in healthy adults or animals. These differences in response to various plasma solutes are independent of any recognized nonosmotic influence and probably reflect some property of the osmoregulatory mechanism. Precisely how the osmoreceptor discriminates so effectively between different kinds of plasma solutes still is unresolved. According to current concepts, the signal that stimulates the osmoreceptor is an osmotically induced decrease in the water content of the cell. If this hypothesis is correct, the capacity of a given solute to stimulate vasopressin secretion should be inversely related to the rate at which it passes from plasma into the osmoreceptor. This concept agrees well with the observed inverse relationship between the stimulatory effect of certain solutes, such as sodium, mannitol, and glucose, and the rate at which they penetrate the blood–brain barrier. However, urea is an exception because it penetrates the blood–brain barrier slowly yet is a relatively weak stimulus for thirst and vasopressin. This singular disparity suggests that most, if not all, of the osmoreceptors are located outside of the blood–brain barrier and that another factor (most likely, the permeability of the osmoreceptor cell itself) determines the solute specificity of the system.

FIGURE 25-6. The relationship of plasma vasopressin to plasma osmolality in healthy adults during the infusion of hypertonic solutions of different solutes. (From Robertson GL. Disorders of the posterior pituitary. In: Stein JH, ed. Internal medicine. Boston: Little, Brown and Company, 1983:1728.)

The solute specificity of the osmoregulatory system is also subject to change. Thus, its sensitivity to stimulation by glucose increases when insulin is deficient.20 This change probably results from decreased permeability of the osmoreceptors to glucose and indicates that these cells are insulin dependent. It may also explain the hyperdipsia and at least part of the hyper-vasopressinemia that occurs in many patients with uncontrolled type 1 diabetes mellitus.
The secretion of vasopressin is also affected by changes in blood volume, pressure, or both.11,12,14,15,22 These hemodynamic influences are mediated largely, if not exclusively, by neurogenic afferents that arise in pressure-sensitive receptors in the heart and large arteries and that travel by way of the vagal and glos-sopharyngeal nerves to primary synapses in the nucleus tractus solitarius in the brainstem (see Fig. 25-1). From there, postsyn-aptic pathways project to the region of the paraventricular and supraoptic nuclei. At least one of the links in the afferent chain for volume control involves opioid receptors in the lateral parabrachial nucleus, because administration of selective as well as nonselective antagonists in this area almost totally inhibits the vasopressin response to an acute hypovolemic stimulus.23,24 and 25
The functional properties of the baroregulatory system also differ from those of the osmoregulatory mechanism (Fig. 25-7). In healthy adults and animals, acutely lowering blood pressure increases plasma vasopressin in proportion to the degree of hypotension achieved. However, this stimulus-response relationship follows a distinctly exponential pattern. Thus, small decreases in blood pressure of 5% to 10% usually have little effect on plasma vasopressin, whereas decreases in blood pressure of 20% to 30% result in hormone levels many times those required to produce maximal antidiuresis. The vasopressin response to changes in blood volume has not been well defined but appears to be quantitatively and qualitatively similar to the vasopressin response to changes in blood pressure. An acute rise in blood volume or pressure appears to suppress vasopressin secretion.

FIGURE 25-7. Schematic representation of the relationship between plasma vasopressin and percentage of change in plasma osmolality, blood volume, or blood pressure in healthy adults. (From Robertson GL. Diseases of the posterior pituitary. In: Felig P, Baxter J, Brodus A, Frohman L, eds. Endocrinology and metabolism. New York: McGraw-Hill, 1981:251.)

The failure of small changes in blood volume and pressure to alter vasopressin secretion contrasts markedly with the extraordinary sensitivity of the osmoregulatory system (see Fig. 25-7). The recognition of this difference is essential for understanding the relative contribution of each system to the control of the hormone under both physiologic and pathologic conditions. Because day-to-day variations of total body water rarely exceed 2% to 3%, their effect on vasopressin secretion must be mediated largely, if not exclusively, by the osmoregulatory system. For this reason, patients with destruction of the osmoreceptor exhibit a markedly subnormal vasopressin response to changes in water balance, even though baroregulatory mechanisms are completely intact. On the other hand, baroregulatory input appears to mediate the effects of a large number of pharmacologic agents and pathologic conditions (Table 25-1). Among these are diuretics, isoproterenol, nicotine, prostaglandins, nitroprusside, trimethaphan camsylate, histamine, morphine, and bradykinin, all of which stimulate vasopressin secretion, at least in part, by lowering blood volume or pressure. In addition, norepinephrine and aldosterone suppress vasopressin secretion by raising blood volume, pressure, or both. In addition, upright posture, sodium depletion, congestive failure, cirrhosis, and nephrosis stimulate vasopressin secretion, probably by reducing total or effective blood volume, whereas orthostatic hypotension, vasovagal reactions, and other forms of syncope markedly stimulate secretion of the hormone by reducing blood pressure. This list probably could be extended to include almost every other hormone, drug, and condition known to affect blood volume or pressure. The only recognized exception is a form of orthostatic hypotension associated with the loss of afferent baroregulatory function.26

TABLE 25-1. Variables That Influence Vasopressin Secretion

Changes in blood volume or pressure that are large enough to affect vasopressin secretion do not necessarily interfere with osmoregulation of the hormone.12,13,14 and 15 Instead, they appear to act by shifting the setpoint of the system in such a way as to increase or decrease the effect on vasopressin of a given osmotic stimulus (Fig. 25-8). This kind of interaction ensures that, even in the presence of hemodynamic stimuli, the capacity to osmoregulate is not lost. How this integration occurs is unknown, but it probably involves one or more interneurons that link the osmoreceptor to neurosecretory neurons.

FIGURE 25-8. The relationship between plasma vasopressin and plasma osmolality in the presence of different states of blood volume or pressure. The oblique heavy line, labeled N, represents normovolemic, normotensive conditions. Lines labeled with negative numbers (to the left) or positive numbers (to the right) indicate, respectively, the percentage of decrease or increase in blood volume or pressure. (From Robert-son GL. Disorders of the posterior pituitary. In: Stein JH, ed. Internal medicine. Boston: Little, Brown and Company, 1983:1728.)

Nausea is an extremely potent stimulus for vasopressin secretion in humans.15 The pathway that mediates this effect probably involves the chemoreceptor trigger zone in the area postrema of the medulla (see Fig. 25-1). It can be activated by a variety of drugs and conditions, including apomorphine, morphine, nicotine, alcohol, and motion sickness.15 Its effect on vasopressin secretion is instantaneous and extremely potent (Fig. 25-9). Increases in vasopressin of 100 to 1000 times basal levels are not unusual, even when the nausea is transient and unaccompanied by vomiting or changes in blood pressure. Pretreatment with fluphenazine, haloperidol, or promethazine in doses sufficient to prevent nausea completely abolishes the vasopressin response.27 The inhibitory effect of these dopamine antagonists is specific for emetic stimuli because they do not alter the vasopressin response to hyperosmolality, hypovolemia, or hypotension.

FIGURE 25-9. Effect of nausea on plasma vasopressin in a healthy adult. (APO, apomorphine; PRA, plasma renin activity.) (From Robert-son GL. The regulation of vasopressin function in health and disease. Recent Prog Horm Res 1977; 33:333.)

Water loading blunts, but does not abolish, the effect of nausea on vasopressin release, a finding which suggests that osmotic and emetic influences interact in a manner similar to osmotic and hemodynamic pathways.27 Emetic stimuli probably mediate many pharmacologic and pathologic effects on vasopressin secretion. For example, emetic stimulation may be at least partially responsible for the increase in vasopressin secretion that has been observed with intravenous administration of cyclophosphamide, vasovagal reactions, ketoacidosis, acute hypoxia, and motion sickness. Because nausea and vomiting are frequent side effects of many other drugs and diseases, additional examples of emetically mediated vasopressin secretion doubtlessly could be demonstrated.
Hypoglycemia. Acute hypoglycemia is a relatively weak stimulus for vasopressin release.28 The receptor and pathway that mediate this effect are unknown but must be separate from those of other recognized stimuli because hypoglycemia stimulates vasopressin secretion in patients who have lost the capacity to respond selectively to osmotic, hemodynamic, or emetic stimuli. However, the vasopressin response to hypoglycemia is accentuated by dehydration and is abolished by water loading. Thus, glucopenic stimuli probably act in concert with osmotic influences, even though the osmoreceptors are unnecessary for the response. Vasopressin release may be triggered by an intracellular deficiency of glucose or one of its metabolites because 2-deoxyglucose is also an effective stimulus.29
Angiotensin. The renin angiotensin system has also been implicated in the control of vasopressin secretion.30 The precise site and mechanism of action have not been defined, but central receptors are likely to be involved because angiotensin is most effective when injected directly into brain ventricles or cranial arteries. The levels of plasma renin or angiotensin required to stimulate vasopressin release have not been determined but probably are high. When administered intravenously, pressor doses of angiotensin increase plasma vasopressin twofold to fourfold. The magnitude of the vasopressin response may depend on the concurrent osmotic stimulus, because angiotensin increases the sensitivity of the osmoregulatory system.31 This dependency on osmotic influences resembles that seen with glucopenic stimuli and may account for the inconsistency of the vasopressin response to exogenous angiotensin.
Nonspecific stress caused by pain, emotion, or physical exercise has long been thought to cause the release of vasopressin.32 However, this effect now appears likely to be secondary to other stimuli, such as hypotension or nausea, which usually accompanies stress-induced vasovagal reactions. In the absence of hypotension or nausea, pain sufficient to stimulate the pituitary-adrenal axis has no effect on vasopressin secretion in humans.33
Acute hypoxia or hypercapnia also stimulates vasopressin release.34 In conscious humans, however, the stimulatory effect of moderate hypoxia is inconsistent and appears to occur only in subjects who develop nausea or hypotension.35 Severe hypoxia probably has a greater effect on vasopressin secretion and may be responsible for the osmotically inappropriate hormonal elevations noted in some patients with acute respiratory failure. Whether or not hypercapnia has similar effects on vasopressin secretion in conscious persons is not known.
Vasopressin secretion is inhibited by drinking before any detectable decrease in plasma osmolality is seen.36 This inhibition can override a moderately strong osmotic stimulus but is not sustained unless it is followed by a prompt decline in plasma osmolality. The mechanism has not been determined, but it probably involves some kind of oropharyngeal receptor.
Many hormones and drugs influence vasopressin secretion.37 Those that have a stimulatory effect include acetylcholine, nicotine, apomorphine, morphine (high doses), epinephrine, isoproterenol, histamine, bradykinin, prostaglandins, b-endorphin, intravenous cyclophosphamide, vincristine, insulin, 2-deoxy-glucose, angiotensin, lithium, and possibly chlorpropamide and clofibrate. Those that have an inhibitory effect include norepinephrine, fluphenazine, haloperidol, promethazine, oxilorphan, butorphanol, morphine (low doses), alcohol, carbamazepine, glucocorticoids, clonidine hydrochloride, muscimol, and possibly phenytoin. Many stimulants, such as isoproterenol, nicotine, and high doses of morphine, undoubtedly act by lowering blood pressure or producing nausea. Others, such as substance P, prostaglandin, endorphin, and other opioids, also probably exert their influence by one or both of the same mechanisms. Insulin and 2-deoxyglucose appear to act by producing intracellular glucopenia, whereas angiotensin has an undefined but probably independent central effect. Vincristine may act by exerting a direct effect on the neurohypophysis or on peripheral neurons involved in the regulation of vasopressin secretion. Lithium, which antagonizes the antidiuretic effect of vasopressin, also increases secretion of the hormone. This effect is independent of changes in water balance and appears to result from an increase in sensitivity of the osmoregulatory system. The stimulatory effects of chlorpropamide and clofibrate are still controversial. Carbamazepine inhibits vasopressin secretion by diminishing the sensitivity of the osmoregulatory system. This effect occurs independently of changes in blood volume, blood pressure, or blood glucose levels and suggests that the ability of carbamazepine to produce antidiuresis in patients with neurogenic diabetes insipidus is the result of action on the kidney.
Vasopressor drugs, such as norepinephrine, inhibit vasopressin secretion indirectly by raising arterial pressure. Dopaminergic antagonists, such as fluphenazine, haloperidol, and promethazine, probably act by suppressing the emetic center because they inhibit the vasopressin response to emetic stimuli only, not to osmotic or hemodynamic stimuli. In low doses, a variety of opioids, including morphine, butorphanol, and oxilorphan, inhibit vasopressin secretion, apparently by increasing the osmotic threshold for vasopressin release. The inhibitory effect of alcohol may be mediated by endogenous opiates; this effect also may be attributable to an elevation in the osmotic threshold for vasopressin release and can be blocked in part by treatment with naloxone hydrochloride. Other drugs that can inhibit vasopressin secretion include clonidine, which appears to act through both central and peripheral adrenoreceptors, and muscimol, which is postulated to act as a g-aminobutyric acid antagonist. Vasopressin and oxytocin may also exert a feedback effect, inhibiting or facilitating their own secretion. In the case of vasopressin, feedback inhibition occurs after systemic or central administration of relatively large doses of the hormone.
In humans, the only stimulus known to reproducibly increase plasma oxytocin is suckling or other stimulation of the nipple in lactating women.38 This stimulus may also cause the release of oxytocin in nonlactating women, but the effect is less consistent. No recognized stimulus has been found for oxytocin secretion in men. In rats, but not in humans, oxytocin secretion is induced by osmotic, hemodynamic, and emetic stimuli, which indicates that this hormone is regulated quite differently in the two species.
In healthy adults, vasopressin and oxytocin distribute rapidly into a space roughly equivalent in volume to the extracellular compartment.12,39 This initial mixing phase has a half-time of 4 to 8 minutes and is virtually complete in 10 to 15 minutes. This rapid mixing phase is followed by a second, slower decline that probably corresponds to the metabolic or irreversible phase of clearance. The half-time of the metabolic phase varies considerably from person to person but is in the range of 10 to 20 minutes. The metabolic clearance rate determined by steady-state as well as non–steady-state methods is largely independent of the plasma concentration within the physiologic range (ranging from 5 to 20 mL/kg per minute for vasopressin12,39 and from 10 to 23 mL/kg per minute for oxytocin).40 In pregnant women, the metabolic clearance rate of vasopressin is increased threefold to fourfold.21
Many tissues have the capacity to inactivate vasopressin in vitro, but most metabolism in vivo probably occurs in the liver and kidney. The plasma of pregnant women contains an enzyme that is capable of rapidly degrading the hormones in vitro, and it may also be active in vivo.21
Vasopressin and oxytocin are also excreted in urine, but the amounts are generally <10% of the total clearance.12,40,41 The mechanisms involved in the excretion of vasopressin probably involve filtration at the glomerulus and variable reabsorption at one or more sites along the tubule. The latter process may be linked in some way to the handling of sodium in the proximal nephron because the urinary clearance of vasopressin varies by as much as 20-fold in a direct relationship with solute clearance. Consequently, measurements of urinary vasopressin do not provide a reliable index of changes in plasma vasopressin unless glomerular filtration and solute clearance are normal. The dependence of urinary oxytocin excretion on solute clearance has not been determined but is probably similar.
Vasopressin is also secreted into CSF3 and the portal venous system of the anterior pituitary.2 The concentration of vasopressin in the lumbar cistern is usually lower than that in plasma, but the two values tend to change in a parallel manner, a finding that suggests that they are subject to most, if not all, of the same regulatory influences. The two compartments must receive the hormone from different groups of neurons, however, because patients with neurogenic diabetes insipidus often have normal or increased CSF concentrations of vasopressin. The concentration of vasopressin in adenohypophyseal portal blood is much higher than that in peripheral veins but appears to be subject to some of the same regulatory influences (e.g., hypotension and hypovolemia).
The most important action of vasopressin is to conserve body water by reducing the rate of urinary, solute-free water excretion.39 This antidiuretic effect is achieved by promoting the reabsorption of solute-free water from urine as it passes through the distal or collecting tubules of the kidney (Fig. 25-10) (see Chap. 206). In the absence of vasopressin, the membranes lining this portion of the nephron are impermeable to water as well as to solutes. Hence, hypotonic filtrate formed in the more proximal part of the neph-ron passes unmodified through the distal tubule and collecting duct. In this condition, which is known as water diuresis, urine osmolality and flow in a healthy adult usually approximate 40 to 60 mOsm/kg and 15 to 20 mL per minute, respectively. In the presence of vasopressin, the hydroosmotic permeability of the distal and collecting tubules increases, which allows water to back-diffuse down the osmotic gradient that normally exists between tubular fluid and the isotonic or hypertonic milieu of the renal cortex and medulla. Because water is reabsorbed without solute, the urine that remains has an increased osmotic pressure as well as a decreased volume or flow rate. The degree of urinary concentration is proportional to the plasma vasopressin concentration, and in healthy adults, it is usually maximal at hormone concentrations of 5 pg/mL or less (see Fig. 25-5).

FIGURE 25-10. Schematic representation of the effect of vasopressin (AVP) on the formation of urine by the nephron. The osmotic pressure of tissue and tubular fluid is indicated by the density of the shading. The numbers within the lumen of the nephron indicate typical rates of flow in milliliters per minute. Arrows indicate reabsorption of sodium (Na) or water (H2O) by active (solid) or passive (broken) processes. Note that vasopressin acts only on the distal nephron, where it increases the hydroosmotic permeability of tubular membranes. The fluid that reaches this part of the nephron normally amounts to 10% to 15% of the total filtrate and is hypotonic, owing to selective reabsorption of sodium in the ascending limb of the Henle loop. In the absence of vasopressin, the membranes of the distal nephron remain relatively impermeable to water as well as to solute, and the fluid issuing from the Henle loop is excreted essentially unmodified as urine. With maximum vasopressin action, all but 5% to 10% of the water in this fluid is reabsorbed passively down the osmotic gradient that normally exists with the surrounding tissue. (From Robertson GL. Diseases of the posterior pituitary. In: Felig P, Baxter J, Brodus A, Frohman L, eds. Endocrinology and metabolism. New York: McGraw-Hill, 1986:351.)

The effect of vasopressin on urinary concentration and flow can be influenced markedly by changes in the volume of filtrate presented to the distal tubule. If the intake of salt is high, or if a poorly reabsorbed solute, such as mannitol, urea, or glucose, is filtered in increased amounts, the resultant decreased reabsorption in the proximal tubule may overwhelm the limited capacity of the distal nephron to reabsorb water and electrolytes. As a consequence, urine osmolality decreases, and the rate of flow rises, even in the presence of supranormal levels of vasopressin. This type of polyuria is referred to as solute diuresis to distinguish it from that resulting from a deficiency of vasopressin action. Conversely, in clinical conditions, such as congestive failure, in which the proximal nephron reabsorbs increased amounts of filtrate, the capacity to excrete solute-free water is greatly reduced, even in the absence of vasopressin.
The antidiuretic effect of vasopressin also may be inhibited by the dissipation of the medullary concentration gradient. The latter may result from such diverse causes as chronic water diuresis, reduced medullary blood flow, or protein deficiency. However, probably because the bulk of the fluid issuing from the Henle loop can still be reabsorbed isotonically in the distal convoluted tubule or proximal collecting duct, the loss of the medullary concentration gradient alone rarely results in marked polyuria.
The cellular receptors that mediate the antidiuretic effect of vasopressin are located on the serosal surface of renal tubular epithelia in the collecting ducts. They are known as V2 receptors and have a structure similar to that of other G protein–coupled receptors.42 Binding of these receptors activates adenylate cyclase, which in turn increases the hydroosmotic permeability of the mucosal surface by inserting preformed water channels composed of a protein known as aquaporin-2,43 a nonpeptide antagonist that binds selectively to V2 receptors and blocks the antidiuretic action of vasopressin in humans that has been developed44a,44b and may prove useful in treating clinical disorders of water balance resulting from osmotically inappropriate secretion of vasopressin (see Chap. 27). A number of different mutations in the genes that encode the V2 receptor protein or the aquaporin-2 proteins impair the urinary concentration and results in the clinical syndrome of congenital nephrogenic diabetes insipidus.45
Vasopressin has been implicated in the control of other physiologic functions such as blood pressure, temperature, insensible water loss, adrenocorticotropic hormone (ACTH) secretion, glycogenolysis, platelet function, CSF formation, and memory. Most of these effects are thought to be mediated by different receptors, known as V1a and V1b46,47 which are present in several parts of the body, including the brain.48,49 For the most part, however, these extrarenal effects of vasopressin have been demonstrated only at relatively high concentrations of the hormone in experimental animals, and their putative role in human physiology or pathophysiology is still uncertain.
The major physiologic action of oxytocin is to facilitate nursing by stimulating the contraction of myoepithelial cells in the lactating mammary gland (see Chap. 106). Oxytocin may also aid in parturition by stimulating contraction of the uterus (see Chap. 109).49a These effects are mediated via a specific oxytocin receptor,50 which may be up-regulated during pregnancy. Whether the hormone has any significant physiologic role in men is unknown. At supraphysiologic concentrations approaching those achieved during the infusion of Pitocin (oxytocin) to induce labor, oxytocin exerts a significant antidiuretic effect51 in humans, probably by stimulating vasopressin V2 receptors.52
The thirst mechanism provides an indispensable adjunct to the antidiuretic control of water balance in humans (see Chap. 26 and Chap. 27). Thirst is stimulated by many of the same variables that cause vasopressin release,53 the most potent of which appears to be hypertonicity. In healthy adults, a rise in effective plasma osmolality to 2% to 3% above basal levels produces a strong desire to drink. The absolute level of plasma osmolality at which a desire for water is first perceived may be termed the osmotic threshold for thirst. This threshold varies appreciably, but among healthy adults, it averages ~295 mOsm/kg (see Fig. 25-4). This level is higher than the osmotic threshold for vasopressin release and closely approximates the level at which the amount of hormone secreted is sufficient to produce maximal concentration of the urine (see Fig. 25-5). The osmoreceptors that regulate thirst appear to be located in the anterolateral hypothalamus near, but not totally coincident with, those responsible for vasopressin release.54 The sensitivity and solute specificity of the thirst and vasopressin osmoreceptors also appear to be similar. Thus, the intensity of thirst and the amount of water ingested increase rapidly in direct proportion to plasma sodium or osmolality. As with vasopressin secretion, thirst is not stimulated in healthy adults when the rise in plasma osmolality is secondary to urea or glucose. However, thirst, as well as vasopressin release, is stimulated by hypergly-cemia in insulin-deficient diabetics, probably because insulin is necessary for uptake of glucose by both types of osmoreceptor.
Hypovolemia and hypotension are also dipsogenic.55 The degree of hypovolemia or hypotension required to produce thirst appears to be greater than the degree at which vasopressin release is affected. The pathways by which hypovolemia and hypotension produce thirst are uncertain, but they probably are similar, if not identical, to those that mediate the baroregulation of vasopressin. Hemodynamic stimuli also reset the osmotic threshold for thirst, just as they do for vasopressin.56
Water is by far the largest constituent of the human body. In lean, healthy adults, it constitutes 55% to 65% of body weight, and in infants and young children, it represents an even larger proportion.57 Approximately two-thirds of body water is intracellular. The rest is extracellular and is divided further into the intravascular (plasma) and extravascular (interstitial) compartments. Plasma is much the smaller of the two, constituting only approximately one-fourth of the total extracellular volume.
The solute composition of intracellular and extracellular fluid differs markedly because most cell membranes possess an array of transport systems that actively accumulate or expel specific solutes.58 However, the total solute concentration of the extracellular and the intracellular fluid is always the same because most cell membranes are freely permeable to water. Thus, distribution of water between the intracellular and extracellular compartments is determined by osmotic pressure resulting from differences in the solute content of the two compartments. If the total solute concentration of one compartment changes, the difference in osmotic pressure induces a rapid efflux or influx of water from the neighboring compartments until osmotic equilibrium is restored.59,60 Similarly, the distribution of extracellular water between the intravascular and interstitial compartments is determined largely by the balance of hemodynamic and oncotic pressure.
The total amount of water in the body is determined by the balance between intake and loss to the environment. The latter occurs via two routes; urination and evaporation, mostly from skin and lungs. The amounts lost via either route can vary markedly depending on antidiuretic function, solute load, physical activity, and temperature. However, even when conservation is maximum, the total amount of water lost by a healthy 70-kg adult cannot be reduced below ~1000 mL a day. Part of this obligatory loss can be replaced by the metabolism of fat (~300 mL per day in the average adult). The rest must come from the ingestion of water either as food or beverage. Thus, the mechanisms for ensuring an adequate intake of water are the most important for maintaining normal hydration.
Despite large daily variations in sodium intake and water output, plasma osmolality and its principal determinant—plasma sodium concentration—normally are maintained within a remarkably narrow range (Fig. 25-11). The only perceptible changes occur after meals when plasma osmolality rises transiently as a result of the absorption of sodium, glucose, and other solutes. This stability is achieved largely by keeping total body water in balance with sodium through the osmoregulation of thirst and vasopressin secretion. Thus, a reduction in osmotic pressure of only 1% or 2% inhibits vasopressin secretion, thereby decreasing the urine concentration and increasing the urine flow. Concomitantly, fluid intake is reduced,53 apparently because a sense of satiety develops. Conversely, a rise in the osmotic pressure of body fluids of 1% to 2% stimulates vasopressin secretion and thirst, thereby decreasing urinary water excretion and increasing oral water intake.

FIGURE 25-11. Circadian pattern of urine output, plasma vasopressin, and its recognized influences in healthy young adults. Each value represents the mean ± standard error of the mean of nine subjects. Note that urine volume decreases by ~50% during sleep, owing largely to a decrease in the rate of solute excretion and a resultant rise in urine osmolality. Plasma vasopressin changes relatively little throughout the day except for transient small increases that occur after meals, coincident with small increases in plasma osmolality and sodium. The 15% to 20% fall in mean arterial pressure that occurs during sleep has no appreciable effect on vasopressin secretion, possibly because this stimulus is counteracted by an increase in plasma volume that results from a net influx of fluid from the interstitial space. (From Robertson GL. The regulation of vasopressin secretion. In: Seldin DW, Giebisch G, ed. The kidney: physiology and pathophysiology. Philadelphia: Lippincott–Raven, 2000; in press.)

The ability of the thirst or vasopressin mechanisms to effect very large changes in the rate of water intake or excretion provides almost insurmountable barriers to excessive overhydration or underhydration even in certain conditions in which one or the other control mechanism malfunctions. Thus, if plasma osmolality falls enough to maximally inhibit vasopressin secretion (and renal function and solute excretion are normal), the rate of water excretion rises to levels that can equal or surpass all but the most pathologically excessive rates of water intake (as in many patients with severe primary polydipsia). In this situation, the osmotic threshold for vasopressin secretion effectively determines the lower limit to which the osmotic pressure of body fluids can be depressed. If the diuretic control system is inoperable (as in patients treated with antidiuretic hormone), the thirst mechanism can compensate by down-regulating water intake to keep it in balance with even minimal rates of urine output. On the other hand, if plasma osmolality rises sufficiently to stimulate thirst (and access to fresh water is unrestricted), the rate of water intake can rise to levels sufficient to replace all but the most extraordinary rates of loss (as in many patients with severe pituitary or nephrogenic diabetes insipidus). In this situation, the osmotic threshold for thirst effectively determines the highest levels to which plasma osmolality is allowed to rise. However, if the thirst mechanism fails, the antidiuretic mechanism cannot compensate because it cannot generate water to offset even minimal obligatory losses caused by urination and evaporation.
In humans, blood pressure and volume vary appreciably throughout the day (see Fig. 25-11). However, because the stimulus response curve is curvilinear (see Fig. 25-7), these hemodynamic changes are usually too small to affect thirst or vasopressin secretion. Even if the hemodynamic changes reach levels sufficient to affect thirst or vasopressin secretion, the fundamental nature of the osmoregulatory system is not compromised because they merely raise or lower the setpoint a few percent, depending on whether blood pressure, effective blood volume, or both are rising or falling. This constant resetting has the effect of slightly widening the range over which plasma osmolality is allowed to fluctuate, but it does not jeopardize the essential osmoregulatory system. Consequently, plasma vasopressin as well as plasma osmolality remain relatively constant throughout the day except for the small, transient increases that occur after meals (see Fig. 25-11). Urine osmolality and flow, on the other hand, show considerable circadian variation owing largely to changes in the rate of solute excretion throughout the day.
The contributions of vasopressin and thirst to the regulation of blood volume and pressure are trivial and occur largely as an indirect consequence of efforts to preserve osmolality. Indeed, in situations in which total body sodium is increased abnormally, thirst and vasopressin act in such a way as to aggravate, instead of ameliorate, the underlying hypervolemia. The responsibility for coping with disturbances in volume rests primarily with those elements of the renal and endocrine systems that regulate sodium excretion. This distinction is useful to bear in mind when considering the pathogenesis of clinical disorders of salt and water balance.

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  13. […] production and letdown during nursing: oxytocin and prolactin. Oxytocin is also involved in the physiological mechanism that causes thirst. So if you feel very thirsty, this is […]

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