Sunday, July 9, 2017

Thirst and hydration: Physiology and consequences of dysfunction

The constant supply of oxygen and nutriments to cells (especially neurons) is the role of the cardiovascular system. The constant supply of water (and sodium) for cardiovascular function is the role of thirst and sodium appetite and kidney function. This physiological regulation ensures that plasma volume and osmolality are maintained within set limits by initiating behaviour and release of hormones necessary to ingest and conserve water and sodium within the body. This regulation is separated into 2 parts; intracellular and extracellular (blood). An increased osmolality draws water from cells into the blood thus dehydrating specific brain osmoreceptors that stimulate drinking and release of anti diuretic hormone (ADH or vasopressin). ADH reduces water loss via lowered urine volume. Extracellular dehydration (hypovolaemia) stimulates specific vascular receptors that signal brain centres to initiate drinking and ADH release. Baro/volume receptors in the kidney participate in stimulating the release of the enzyme renin that starts a cascade of events to produce angiotensin II (AngII), which initiates also drinking and ADH release. This stimulates also aldosterone release which reduces kidney loss of urine sodium. Both AngII and ADH are vasoactive hormones that could work to reduce blood vessel diameter around the remaining blood. All these events work in concert so that the cardiovascular system can maintain a constant perfusion pressure, especially to the brain. Even if drinking does not take place ADH, AngII and aldosterone are still released. Furthermore, it has been observed that treatment of hypertension, obesity, diabetes and cancer can involve renin–AngII antagonists which could suggest that, in humans at least, there may be dysfunction of the thirst regulatory mechanism.

Angiotensin, thirst, and sodium appetite.


Angiotensin (ANG) II is a powerful and phylogenetically widespread stimulus to thirst and sodium appetite. When it is injected directly into sensitive areas of the brain, it causes an immediate increase in water intake followed by a slower increase in NaCl intake. Drinking is vigorous, highly motivated, and rapidly completed. The amounts of water taken within 15 min or so of injection can exceed what the animal would spontaneously drink in the course of its normal activities over 24 h. The increase in NaCl intake is slower in onset, more persistent, and affected by experience. Increases in circulating ANG II have similar effects on drinking, although these may be partly obscured by accompanying rises in blood pressure. The circumventricular organs, median preoptic nucleus, and tissue surrounding the anteroventral third ventricle in the lamina terminalis (AV3V region) provide the neuroanatomic focus for thirst, sodium appetite, and cardiovascular control, making extensive connections with the hypothalamus, limbic system, and brain stem. The AV3V region is well provided with angiotensinergic nerve endings and angiotensin AT1 receptors, the receptor type responsible for acute responses to ANG II, and it responds vigorously to the dipsogenic action of ANG II. The nucleus tractus solitarius and other structures in the brain stem form part of a negative-feedback system for blood volume control, responding to baroreceptor and volume receptor information from the circulation and sending ascending noradrenergic and other projections to the AV3V region. The subfornical organ, organum vasculosum of the lamina terminalis and area postrema contain ANG II-sensitive receptors that allow circulating ANG II to interact with central nervous structures involved in hypovolemic thirst and sodium appetite and blood pressure control. Angiotensin peptides generated inside the blood-brain barrier may act as conventional neurotransmitters or, in view of the many instances of anatomic separation between sites of production and receptors, they may act as paracrine agents at a distance from their point of release. An attractive speculation is that some are responsible for long-term changes in neuronal organization, especially of sodium appetite. Anatomic mismatches between sites of production and receptors are less evident in limbic and brain stem structures responsible for body fluid homeostasis and blood pressure control. Limbic structures are rich in other neuroactive peptides, some of which have powerful effects on drinking, and they and many of the classical nonpeptide neurotransmitters may interact with ANG II to augment or inhibit drinking behavior. Because ANG II immunoreactivity and binding are so widely distributed in the central nervous system, brain ANG II is unlikely to have a role as circumscribed as that of circulating ANG II. Angiotensin peptides generated from brain precursors may also be involved in functions that have little immediate effect on body fluid homeostasis and blood pressure control, such as cell differentiation, regeneration and remodeling, or learning and memory. Analysis of the mechanisms of increased drinking caused by drugs and experimental procedures that activate the renal renin-angiotensin system, and clinical conditions in which renal renin secretion is increased, have provided evidence that endogenously released renal renin can generate enough circulating ANG II to stimulate drinking. But it is also certain that other mechanisms of thirst and sodium appetite still operate when the effects of circulating ANG II are blocked or absent, although it is not known whether this is also true for angiotensin peptides formed in the brain. Whether ANG II should be regarded primarily as a hormone released in hypovolemia helping to defend the blood volume, a neurotransmitter or paracrine agent with a privileged role in the neural pathways for thirst and sodium appetite of all kinds, a neural organizer especially in sodium appetite.

Role of brain angiotensin II in thirst and sodium appetite of sheep.

The contribution of brain angiotensin II (ANG II) to thirst and Na+ appetite of sheep was evaluated. Thirst was stimulated by water deprivation, intracarotid or intracerebroventricular infusion of ANG II, or intracarotid or intracerebroventricular infusion of hypertonic solution. Intracerebroventricular infusion, over 1-3 h, of the ANG II type 1 (AT1) receptor antagonist, losartan, decreased or abolished water intake caused by all of the stimuli tested. Intracerebroventricular infusion of ZD-7155, another AT1-receptor antagonist, blocked ANG II-induced water intake. Neither losartan nor ZD-7155 infused intracerebroventricularly altered the Na+ appetite of Na(+)-depleted sheep. Intracerebroventricular infusion of losartan over 3 h, however, did block the increase in water intake and the decrease in Na+ intake caused by intracerebroventricular infusion of hypertonic NaCl in Na(+)-depleted sheep. Intracerebroventricular infusion of the ANG II type 2 (AT2) receptor antagonist, PD-123319, over 1-3 h, did not alter ANG II-induced water intake or Na+ depletion-induced Na+ intake. These results are consistent with the proposition that brain ANG II, working via AT1 receptors, is involved in the neural system controlling some aspects of physiological thirst and Na+ appetite. A role for AT2 receptors in physiological thirst or Na+ appetite is not supported by the present results.

Conditions for secretion of vasopressin in pressor amounts in water-replete rats. By Iriuchijima J.

Conditions for secretion of pressor amounts of vasopressin were sought in conscious, water-replete rats. The characteristic lowering of arterial pressure on injection of a vasopressin antagonist was used to detect vasopressin secretion in pressor amounts. The absence or marked abatement of both baroreceptor impulses and adrenomedullary secretion were found necessary for secretion of vasopressin in pressor amounts: the vasopressin antagonist lowered arterial pressure in rats with sinoaortic denervation and ganglion blockade or adrenalectomy. Besides baroreceptor activity and adrenomedullary secretion, anesthetics were also found inhibitory on vasopressin release in pressor amounts. The adrenomedullary hormone signaling the presence of adrenomedullary activity to the vasopressin releasing mechanism was identified as noradrenaline and not adrenaline. It is suggested that the vasopressin pressor mechanism is recruited to sustain arterial pressure when the sympathoadrenal system fails.

[Role of vasopressin in arterial hypertension].
[Article in French]
Thibonnier M, Sassano P, Daufresne S, Menard J.

On isolated arteriole preparations vasopressin behaves as an extremely potent vasoconstrictor. In healthy animals and man its pressor effect is counteracted by several compensatory mechanisms, including stimulation of the baroreceptor reflex with reduction of sympathetic activity, decrease in renin secretion, sodium loss and reduction of vascular response to vasopressor agents. Alterations of these mechanisms unmask the hypertensive effect of vasopressin as shown by several experimental hypertension models in animals. In human pathology vasopressin has been shown to be a good indicator of the severity pf arterial hypertension, but its role in that disease will only be determined when vascular antagonists of vasopressin devoid of paryial agonistic activity become available.

[Cardiovascular effect of the antidiuretic hormone arginine vasopressin].
[Article in German]
Rascher W.

The two major biological actions of vasopressin are antidiuresis and vasoconstriction. The antidiuretic action of low concentrations of vasopressin is well established and concentrations 10 to 100 times above those required for antidiuresis elevate arterial blood pressure. Antidiuresis is mediated by V2-receptors at the kidney, whereas vasopressin constricts arterioles by binding at V1-receptors. Pharmacological effects of specific antagonists of the vasoconstrictor activity of vasopressin (vascular or V1-receptor antagonists) are presented. Low concentrations of vasopressin do have significant hemodynamic effects. Physiological concentrations of vasopressin cause vasoconstriction and elevate systemic vascular resistance. In subjects with intact cardiovascular reflex activity, however, cardiac output falls concomitantly and blood pressure therefore does not change. In animals with baroreceptor deafferentation or in patients with blunted baroreceptor reflexes (autonomic insufficiency) a rise in plasma vasopressin causes vasoconstriction and an increase in blood pressure, because cardiac output does not fall under these conditions. Vasopressin contributes substantially via increase in systemic vascular resistance to maintain blood pressure during water deprivation. During hemorrhage and hypotension vasopressin has a major role to restore blood pressure. In experimental hypertension vasopressin contributes to the development and maintenance of high blood pressure in DOCA, but not in genetic hypertensive rats. The role of vasopressin in human hypertension is not yet clear. Vasopressin in extrahypothalamic areas of the brain affects circulatory regulation by interaction with central cardiovascular control centers. The exact mechanism of how vasopressin is involved in central regulation of blood pressure remains to be established. In contrast to our previous opinion vasopressin is a vasoactive hormone also at low plasma concentrations. Its cardiovascular action is more complex than previously assumed.

Founding Editor, MATTHEW J. WAYNER

Editorial Advisory Board
MICHAEL BAUM, Boston University, Boston, MA
TIMOTHY J. BARTNESS, Georgia State University, Atlanta, GA
GARY K. BEAUCHAMP, Monell Chemical Senses Center, Philadelphia, PA
LARRY L. BELLINGER, Baylor College of Dentistry, Dallas, TX
D. CAROLINE BLANCHARD, University of Hawaii, Manoa, Honolulu, HI
RICHARD J. BODNAR, Queens College of the City University of New York,
Flushing, NY
THOMAS W. CASTONGUAY, University of Maryland, College Park, MD
LIQUE M. COOLEN, University of Cincinnati, Cincinnati, OH
WIM E. CRUSIO, Laboratoire de Neurosciences Cognitives, Talence, France
SIETSE F. DE BOER, University of Illinois at Urbana-Champaign, Urbana, IL
JUAN M. DOMINGUEZ, The University of Texas at Austin, Austin, Texas
DAVID A. EDWARDS, Emory University, Atlanta, GA
D.P. FIGLEWICZ LATTEMANN, VA Puget Sound Health Care System,
Seattle, WA
CHERYL A. FRYE, SUNY at Albany, Albany, NY
RONALD J. JANDACEK, University of Cincinnati, Cincinnati, OH
ROBIN B. KANAREK, Tufts University, Medford, MA
KEITH KENDRICK, AFRC Babraham Institute, Cambridge, England
SARAH F. LEIBOWITZ, The Rockefeller University, New York, NY
BRUCE S. McEWEN, The Rockefeller University, New York, NY
MARILYN Y. McGINNIS, University of Texas at San Antonio, San Antonio, TX
KLAUS A. MICZEK, Tufts University, Medford, MA
GUY MITTLEMAN, University of Memphis, Memphis, TN
PIERRE MORMEDE, University de Bordeaux, Bordeaux, France
RANDY J. NELSON, The Ohio State University, Columbus, OH
MELLY S. OITZL, Leiden/Amsterdam Center for Drug Research and Leiden
University Medical Center, Leiden, The Netherlands
JAMES G. PFAUS, Concordia University, Montréal, Québec, Canada
SUSAN RITTER, Washington State University, Pullman, WA
ROBERT J. RODGERS, University of Leeds, Leeds, UK
NEIL E. ROWLAND, University of Florida, Gainesville, FL
PAUL A. RUSHING, National Institute of Health, Bethesda, MD, USA
NORBERT SACHSER, Westfalische Wilhelms Universität,
Münster, Germany
GARY J. SCHWARTZ, The New York Hospital–Cornell Medical Center, White
Plains, NY
ANTHONY SCLAFANI, Brooklyn College, Brooklyn, NY
ANDREA SGOIFO, University of Parma Via Usberti, Parma, Italy
GERARD P. SMITH, The New York Hospital–Cornell Medical Center,
White Plains, NY
WILLIAM P. SMOTHERMAN, State University of New York, Binghamton, NY
VOLKER STEFANSKI, Dept. of Animal Physiology, Universitätsstr. 30, 95440
Bayreuth, Germany
URSULA STOCKHORST, Institute of Psychology, Osnabrueck, Germany
JOHN G. VANDENBERGH, North Carolina State University, Raleigh, NC
ZOE S. WARWICK, University of Maryland, Baltimore, MD
RICHARD S. WEISINGER, La Trobe University, Victoria, Australia
MARGRIET S. WESTERTERP-PLANTENGA, Maastricht University, Maastricht,
The Netherlands

STEPHEN WOODS, University of Cincinnati, Cincinnati, OH

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