06-39b

7/21/2019 06-39b

http://slidepdf.com/reader/full/06-39b 1/8

CONTROL OF WATER CONTENT (EXTRACELLULAR OSMOLALITY)

Water accounts for half or more of body weight-approximately 60% in men and 50% in women-and isdistributed between the intracellular and extracellular fluid compartments (p. 50). Changes in whole-bodywater content lead to changes in osmolality, to which the CNS is extremely sensitive. Osmolality deviationsof ± 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 (p. 840), and (2) thirst mechanisms, which control the oral intake of water. These two effectormechanisms are part of negative feedback loops that begin within the hypothalamus. An increase inosmolality 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 Osmoreceptors in the Hypothalamus That Trigger the Release of

Arginine Vasopressin, Which Inhibits Water Excretion

An increase in the osmolality of the ECF is the primary signal for the secretion of AVP from the posteriorpituitary gland. An elegant series of animal studies by Verney in the 1940s established that infusing ahyperosmotic NaCl solution into the carotid artery abruptly terminates an established water diuresis (Fig.

39-7 A). Infusing hyperosmotic NaCl into the peripheral circulation has no effect because the hyperosmolarsolution becomes diluted by the time it reaches the cerebral vessels. Therefore, the osmosensitive site isintracranial. Surgically removing the posterior pituitary abolishes the effect of infusing hyperosmotic NaClinto the carotid artery (see Fig. 39-7B). However, injecting posterior-pituitary extracts into the animal inhibitsthe diuresis, regardless of whether the posterior pituitary is intact. Later work showed that Verney'sposterior-pituitary extract contained an "antidiuretic hormone"-now known to be AVP-that the posteriorpituitary secretes in response to increased plasma osmolality. When the plasma osmolality falls owing tothe intake of large volumes of water, AVP levels fall.

page 870

page 871

Figure 39-7 Sensing of blood osmolality in the dog brain. i.a., intraarterial injection; i.v., intravenous injection; p.o., oral intake. (Data fromVerney 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 approximately 290 mOsm. The threshold for AVP release issomewhat lower, approximately 280 mOsm (Fig. 39-8, red curve). Increasing the osmolality by only 1%above 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 completesthe feedback loop by instructing the kidneys to retain water (p. 840).

Figure 39-8 Dependence of arginine vasopressin (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 it is a change in plasma [NaCl] that is usually responsible for a change in plasma osmolality, othersolutes 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 has a low effective osmolality or tonicity (p. 77) and is thus ineffective in shrinkingcells.

Special Neurons in the Hypothalamus Synthesize Arginine Vasopressin and Transport it Along their Axons

7/21/2019 06-39b


to the Posterior Pituitary, Where They Store It in Nerve Terminals Prior to Release

The osmoreceptors of the CNS appear to be located in two areas that breech the blood-brain barrier: theorganum vasculosum of the lamina terminalis (OVLT) and the subfornical organ (SFO), two of the"circumventricular organs" (p. 409). Neurons in these regions (Fig. 39-9) are thus able to sense changes in plasma osmolality. They apparently behave as osmometers, responding to elevated osmolality byincreasing the activity of mechanosensitive cation channels located in their cell membranes, resulting insignificant membrane depolarization that increases the frequency of action potentials. Hypoosmolality

results in a striking depression of electrical activity. The osmosensitive neurons project to large-diameterneurons in the supraoptic and paraventricular nuclei of the anterior hypothalamus (see Fig. 39-9). Theseneurons synthesize AVP, package it into granules, and transport the granules along their axons to nerveterminals in the posterior lobe of the pituitary, which is part of the brain (p. 1012). When stimulated by theosmosensitive neurons, these magnocellular neurons release the stored AVP into the posterior pituitary-anarea that also lacks a blood-brain barrier-and AVP enters the general circulation.

In humans and most mammals, the antidiuretic hormone is AVP, which is encoded by the messenger RNAfor preproneurophysin II. After cleavage of the signal peptide, the resulting prohormone contains AVP,neurophysin II (NpII), and a glycopeptide. Cleavage of the prohormone within the secretory granule yieldsthese three components. AVP has nine amino acids, with a disulfide bridge connecting two cysteineresidues. Mutations of NpII impair AVP secretion, suggesting 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 discussedlater, 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 AVPlevels when secretion has ceased. The half-life of AVP in the circulation is 18 minutes. Diseases of the liverand kidney may impair AVP degradation and thus contribute to fluid retention. For example, the congestionof the liver and impairment of renal function that accompany heart failure can compromise AVP breakdownand lead to inappropriately high circulating levels of AVP.

Increased Osmolality Stimulates a Second Group of Osmoreceptors That Trigger Thirst, Which Promotes

Water Intakepage 871

page 872

Figure 39-9 Control of arginine vasopressin (AVP) synthesis and release by osmoreceptors. Osmoreceptors are located in the organumvasculosum laminae terminalis (OVLT) and subfornical organ (SFO), two areas that breech the blood-brain barrier.

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 intwo 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 theOVLT and SFO.

Hyperosmolality triggers two parallel feedback-control mechanisms that have a common end point (Fig.39-10): an increase in whole-body free water. In response to hyperosmolality, the AVP osmoreceptors inthe 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 anappetite for water, which 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.

Several Nonosmotic Stimuli Also Enhance Arginine Vasopressin Secretion

Although an increase in plasma osmolality is the primary trigger for AVP release, several other stimuli

7/21/2019 06-39b


increase AVP release, including a decrease in effective circulating volume or arterial pressure andpregnancy. Conversely, volume expansion diminishes AVP release.

REDUCED EFFECTIVE CIRCULATING VOLUME.

As noted earlier, a mere 1% rise in plasma osmolality stimulates AVP release by a detectable amount.However, fairly large reductions in effective circulating volume (5%-10%) are required to stimulate AVPrelease of similar amounts. However, once the rather high threshold for nonosmotic release of AVP is

exceeded, AVP release rises steeply with further volume depletion. The interaction between osmotic andvolume stimuli on AVP release is illustrated in Figure 39-8, which shows that the effective circulatingvolume modifies the slope of the relationship between plasma AVP levels and osmolality, as well as theosmotic threshold for AVP release. At a fixed osmolality, volume contraction (Fig. 39-8, green curve)increases the rate of AVP release. Therefore, during volume depletion, a low plasma osmolality that wouldnormally inhibit the release of AVP allows AVP secretion to continue. This leftward shift of the osmolalitythreshold for AVP release is accompanied by an increased slope, reflecting an increased sensitivity of theosmoreceptors to changes in osmolality.

The left side of Figure 39-10 summarizes the pathways by which decreased effective circulating volumeand low arterial pressure enhance AVP release. A reduction in left atrial pressure-produced by volumedepletion-via low-pressure receptors in the left atrium decreases the firing rate of vagal afferents (p. 548).

These afferents signal brainstem neurons, causing neurons in the hypothalamus to release AVP. Indeed, atconstant osmolality, AVP secretion varies inversely with left-atrial pressure. In addition, low effectivecirculating volume triggers granular cells in the JGA to release renin, which leads to the formation of ANGII, which acts on receptors in the OVLT and the SFO to stimulate AVP release. Even more important, a fallin the arterial pressure causes high-pressure carotid-sinus baroreceptors to similarly stimulate AVP release(p. 535).

page 872

page 873

Figure 39-10 Feedback systems involved in the control of osmolality. OVLT, organum vasculosum laminae terminalis; PVN, paraventricularnucleus; SFO, subfornical organ; SON, supraoptic nucleus of the hypothalamus.

Two clinical examples in which reduced effective circulating volume leads to increases in AVP are severehemorrhagic shock and hypovolemic shock (e.g., shock due to excessive loss of ECF, as in cholera). Inboth cases, the water retention caused by AVP release accounts for the accompanying hyponatremia. Inthe 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 (p.79). 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 hypoosmolality of the bodyfluids 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 (p. 864). In this situation, the water retention may be so severe that

the patient develops hyponatremia (i.e., hypoosmolality).

VOLUME EXPANSION.

In contrast to volume contraction, chronic volume expansion reduces AVP secretion, as a consequence ofthe rightward shift of the threshold to higher osmolalities and of a decline in the slope (Fig. 39-8, bluecurve). 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,

leaving plasma [Na+] unchanged. However, because chronic volume expansion downregulates AVP

release, the kidneys do not retain adequate water, resulting in hypernatremia (i.e., elevated plasma [Na+])

7/21/2019 06-39b


and hyperosmolality.

PREGNANCY.

A leftward shift in the threshold for AVP release and thirst often occurs during pregnancy. These changesprobably reflect the action of chorionic gonadotrophin 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 smallerchange may also occur in the late phase of the menstrual cycle.

OTHER FACTORS.page 873

page 874

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+ balanceand thereby reducing the volume of extracellular fluid (ECF). Clinicians use diureticsto treat edema (see box on p. 473) in patients with heart failure, cirrhosis of theliver, or nephrotic syndrome. Common to these edematous diseases is an abnormalshift of ECF away from the effective circulating volume, thereby activating the

feedback pathways. The result is Na+ retention and expansion of total extracellular

volume. However, this expansion, which results in edema formation, falls short ofcorrecting the underlying decrease in the effective circulating volume. Why most ofthis "added" extracellular volume remains "ineffective"-and does not restore theeffective circulating volume-is not intuitive but reflects the underlying pathology thatinitiated the edema in the first place. Thus, treating these diseases requires

generating a negative Na+ balance, which can often be achieved by rigid dietary

Na+ restriction and/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 OF DIURETICS

The site and mechanism of a diuretic's action determines the magnitude and natureof the response (Table 39-3). Both chemically and functionally, diuretics are veryheterogeneous. For example, acetazolamide produces diuresis by inhibiting

carbonic anhydrase and thus the component of proximal-tubule Na+ reabsorption

that is coupled to

reabsorption. The diuretic effect of hydrochlorothiazide is largely due to itsability to inhibit Na/Cl cotransport in the distal convoluted tubule. Spironolactone(which resembles aldosterone) competitively inhibits mineralocorticoid receptors inprincipal cells of the initial and cortical collecting tubule. Mannitol (reduced fructose)

is a powerful osmotic diuretic that reduces net Na+ transport along water-permeable

nephron segments by retaining water in the lumen.

An "ideal" diuretic should promote the excretion of urine whose compositionresembles 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 Ca

++, as well as with urinary

concentrating ability. Thus, many diuretics disturb the normal plasma electrolytepattern. Table 39-4 summarizes the most frequent side effects of diuretic use on theelectrolyte composition of the ECF. These electrolyte derangements are thepredictable consequences of the mechanism of action of individual diuretics at

specific tubule sites. Secondary Effects of Diuretic Drugs

DELIVERY OF DIURETICS

Diuretics generally inhibit transporters or channels at the apical membrane of tubulecells. How do the diuretics get there? Plasma proteins bind many diuretics so that

7/21/2019 06-39b


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 proximaltubule can secrete diuretics and thereby produce high luminal concentrations. Forexample, the basolateral organic-anion transporter system that carries PAH (p. 799)also secretes the diuretics furosemide, ethacrynic acid, and spironolactone. Theorganic cation transporter (p. 802) secretes amiloride. The subsequent reabsorptionof fluid in the loop of Henle and downstream nephron segments further

concentrates diuretics in the tubule lumen. Not surprisingly, renal disease maycompromise the delivery of diuretics. Reduced Delivery of Diuretics in Renal

Disease

RESPONSE OF NEPHRON SEGMENTS DOWNSTREAM FROM A DIURETIC'S SITE

OF ACTION

The proximal tubule reabsorbs the largest fraction of filtered Na+, with the loop of

Henle, the distal convoluted tubule, and the collecting ducts retrieving smallerfractions. Thus, intuition might suggest that the proximal tubule would be the besttarget 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 (p. 786). 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 thick ascending limb of

Henle's loop (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 presently 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 the loopdiuretics. Nevertheless, distally acting diuretics are important because their effects

are long lasting and because they are "K+ -sparing" (i.e., they tend to conserve body

K+).

It is sometimes advantageous to use two diuretics that act at different sites alongthe nephron, generating a synergistic effect. Thus, if a loop diuretic alone isproviding an inadequate diuresis, one could complement its action with

acetazolamide, which can deliver a larger Na+ load to the inhibited loop.

BLUNTING OF DIURETIC ACTION WITH CHRONIC USE

The prolonged administration of a diuretic may lead to a sustained loss of body

weight, but only a transient natriuresis. 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 aldosterone and AVP, and decreased secretion of ANP.Hypertrophy and/or increased activity of tubule segments downstream of the mainsite of action of the diuretic can also contribute to the diminished efficacy of the drugduring chronic administration. Blunting of Diuretic Action

page 874

page 875

Table 39-3. ACTION OF DIURETICS

PHYSIOLOGICAL

REGULATION OF

"TARGET"

7/21/2019 06-39b


SITE TARGET DRUG Stimulator Inhibitor

TEXT

REFERENCE

TO TARGET

PCT Carbonicanhydrase

Acetazolamide p. 853

PCT Na-Hexchanger

Dopamine ANG II,Sympathetic

nerve activity,α-adrenergicagonists

Dopamine p. 852

TAL Na/K/Clcotrans-porter

"Loop Diuretics":FurosemideBumetanideEthacrynic acid

Aldosterone PGE2 p. 778

DCT Na/Clcotransporter

ThiazidesMetolazone

Aldosterone p. 779

CCT Na+ channel Amiloride

Triamterene

Spironolactone

Aldosterone p. 779

IMCD cGMP-gatedcationchannel

Amiloride Aldosterone ANP p. 788

Water-permeablesegments

Waterchannels

Osmotic diuretics(mannitol)

Physicalfactors, AVP

Box on p. 782

ANG II, angiotensin II; ANP, atrial natriuretic peptide; AVP, arginine vasopressin; cGMP, cyclic guanosine collecting tubule; DCTmonophosphate; CCT, cortical distal convoluted tubule IMCD, inner meduallary collecting duct; PCT, proximal convolutedtubule; PGE2, proastagladin E2; TAL, thick ascending limb of the loop of Henle

Table 39-4. COMPLICATIONS OF DIURETIC THERAPY

COMPLICATION

CAUSATIVE

DIURETIC SYMPTOMS CAUSATIVE FACTORS

Extracellularvolume Depletion

Loop diuretics andthiazides

Lassitude, thirst, musclecramps, hypotension

Rapid reduction of plasmaVolume

K+ depletion Acetazolamide,

loop diuretics,thiazides

Muscle weakness,paralysis, cardiacarrhythmias

Flow and Na+-related

stimulation of distal K+

secretion

K+ retention Amiloride,

triamterene,spironolactone

Cardiac arrhythmias,muscle cramps, andparalysis

Blocking ENaC in thecollecting duct

Hyponatremia Thiazides,furosemide

CNS symptoms, coma Block of Na+ transport in

water-impermeable nephronsegment

Metabolic alkalosis Loop diuretics,thiazides

Cardiac arrhythmias,CNS symptoms

Excessive Cl- excretion,

secondary volumecontraction

Metabolic acidosis Acetazolamide,amiloride,triamterene

Hyperventilation,muscular and neurologicdisturbances

Interference with H+

secretion

Hypercalcemia Thiazides Abnormal tissue

calcification,disturbances of nerveand muscle function

Increased Ca2+

reabsorption

in distal convo Luted tubule

7/21/2019 06-39b


Hyperuricemia Thiazides, loopdiuretics

Gout Consequence of decreasedECV that activates proximalfluid and uric acidreabsorption

CNS, central nervous system; ECV, extracellular volume; ENaC, epithelial Na+ channel

page 875

page 876

Pain, nausea, and several drugs (e.g., morphine, nicotine, and high doses of barbiturates) stimulate AVPsecretion. In contrast, alcohol and drugs that block the effect of morphine (opiate-antagonists) inhibit AVPsecretion, promoting diuresis. Of great clinical importance is the hypersecretion of AVP that may occur after surgery. Also, ectopic metastases of some malignant tumors secrete large amounts of AVP. Such secretionof inappropriate amounts of "antidiuretic hormone" leads to pathologic 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 the box on p. 844).

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 bloodpressure-lead to the sensation of thirst. Low effective circulating volume and low blood pressure stimulatethirst centers in the hypothalamus via the same pathways by which they stimulate AVP release (see Fig.39-10).

In addition to thirst, some of these hypothalamic areas are also involved in stimulating the desire to ingest

salt (i.e., Na+ appetite). In Chapter 57, we discuss the role of the hypothalamus in the control of appetite (p.

1227).

Defense of the Effective Circulating Volume Has Priority over the Osmolality

Under physiologic conditions, the body regulates plasma volume and plasma osmolality independently.

However, as discussed, this clear separation of defense mechanisms against volume and osmoticchallenges 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 absoluteblood volume (e.g., hemorrhage) and decreases in effective circulating volume even when absolute ECFvolume 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.

An exception to the rule of defending volume over osmolality occurs during severe water loss (i.e.,dehydration). In this case, the hyperosmolality that accompanies the dehydration maximally stimulates AVPsecretion and thirst (see Fig. 39-10). 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 acuteloss of an equivalent volume of blood. Because dehydration reduces effective circulating volume, you 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 theadrenal medulla less sensitive to ANG II, thus reducing 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, insevere dehydration, the body violates the principle of defending volume over osmolality.

References

REFERENCES

Books and Reviews

Bourque CW, Oliet SHR: Osmoreceptors in the central nervous system. Annu Rev Physiol 59:601-619, 1997.

7/21/2019 06-39b


DiBona GF, Kopp UC: Neural control of renal function. Physiol Rev 77: 75-197, 1997.

Fitzsimons JT: Angiotensin, thirst and sodium appetite. Physiol Rev 78: 583-686, 1998.

Gutkowska J, Antunes-Rodrigues J, McCann SM: Atrial natriuretic peptide in brain and pituitary gland. Physiol Rev 77:465-515, 1997.

Nader PC, Thompson JR, Alpern RJ: Complications of diuretic use. Semin Nephrol 8:365-387, 1988.

Navar LG, Zou L, Von Thun A, et al: Unraveling the mystery of Gold-blatt hypertension. News Physiol Sci 13:170-176, 1998.

Rolls BJ, Rolls ET: Thirst. Cambridge, England, Cambridge University Press, 1982.

Journal Articles

Chou CL, Marsh DJ: Role of proximal convoluted tubule in pressure diuresis in the rat. Am J Physiol 251:F283-F289, 1986.

Mason WT: Supraoptic neurones of rat hypothalamus are osmosensitive. Nature 287:154-157, 1980.

Oliet SHR, Bourque CW: Mechanosensitive channels transduce osmosensitivity in supraoptic neurons. Nature 364:341-343, 1993.

Rabkin R, Share L, Payne PA, et al: The handling of immunoreactive vasopressin by the isolated perfused rat kidney. J Clin Invest63:6-13, 1979.

Verney EG: The antidiuretic hormone and the factors which determine its release. Proc R Soc London B Biol Sci 135:25-106, 1947.

Printed from STUDENT CONSULT: Medical Physiology (on 24 August 2006)© 2006 Elsevier

06-39b

Documents