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.

Abstract

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.
Abstract

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.
Abstract

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.
Abstract

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.


PHYSIOLOGY & BEHAVIOR
EDITORS-IN-CHIEF
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

elderly still do not recognize they are thirsty

The tragedy of waiting to get thirsty hits home when it is realized that the sharpness of thirst perception is gradually lost, as we get older. Phillips and associates have shown that after 24 hours of water deprivation, the elderly still do not recognize they are thirsty: “The important finding is that despite their obvious physiologic need, the elderly subjects were not markedly thirsty.” Bruce and associates have shown that, between the ages of 20 to 70, the ratio of water inside the cells to the amount of water outside the cells drastically changes from 1.1 to 0.84. Undoubtedly this marked change in the intracellular water balance would not take place if the osmotic push and pull of life could favor water diffusion through the cell membranes everywhere in the body—at the rate of 0.001 centimeters per second. Only by relying on the reverse osmotic process of expanding the extracellular water content of the body, so as to filter and inject “load-free” water into vital cells by the actions of vasopressin and the renin-angiotensin-aldosterone systems—when the body physiology is constantly forced to rely on its drought- management programs—could such a drastic change in the water balance of the body result.

Waiting To Get Thirsty Is To Die Prematurely And Very Painfully.

Heinz Valtin, M.D. an emeritus professor at Dartmouth Medical School, has ventured the opinion that there is no scientific merit in drinking 8 x 8-ounce glasses of water a day and not waiting to get thirsty before correcting dehydration. This view, published in the American Journal of Physiology, August 2002, is the very foundation of all that is wrong with modern medicine, which is costing this nation $1.7 trillion a year, rising at the rate of 12 percent every year. Dr. Valtin’s view is as absurd as waiting for the final stages of a killer infection before giving the patient the appropriate antibiotics. His views are based on the erroneous assumption that dry mouth is an accurate sign of dehydration.

Like the colleagues he says he has consulted, Dr. Valtin does not seem to be aware of an important paradigm shift in medicine. All past views in medicine were based on the wrong assumption that it is the solutes in the body that regulate all functions and that the solvent has no direct role in any of the body’s physiological functions. In medical schools it is taught that water is only a solvent, a packing material and a means of transport, that water has no metabolic function of its own. I have come across this level of ignorance about the primary physiological role of water at another Ivy League medical school from another eminent professor of physiology who, like Dr. Valtin, researched and taught the water-regulatory mechanisms of the kidney to medical students and doctors. Only when I asked him what “hydrolysis” is, did the penny drop and he admitted the scientific fact that water is a nutrient and does indeed possess a dominant metabolic role in all physiological functions of the body.

Dr. Valtin’s emphasis on the water-regulatory role of the kidneys limits his knowledge to the body’s mechanisms of “deficit management” of the water needs of the body. He seems to base his views of thirst management of the body on the vital roles of vasopressin, the antidiuretic hormone, and the renin-angiotensin system, the elements that get engaged in the drought-management programs of the body, when the body has already become dehydrated. Indeed, he thinks dehydration is a state of the body when it loses 5 percent of its water content; and that one should wait until at some level of such water loss the urge to drink some kind of “fluid” will correct the water deficit in the body. This view might have seemed plausible 25 years ago. Today, it exposes the tragic limitations of knowledge of the human physiology that is available to a prestigious medical school in America.

In his recently published and widely reported assertions, Dr. Valtin does not take into consideration the fact that water is a nutrient. Its vital “hydrolytic” role would be lost to all the physiological functions that would be affected by its shortage in its osmotically “free state.” Another oversight is the fact that it is the interior of the cells of the body that would become drastically dehydrated. In dehydration, 66 percent of the water loss is from the interior of the cells, 26 percent of the loss is from extracellular fluid volume and only 8 percent of the loss is borne by the blood tissue in the vascular system, which constricts within its network of capillaries and maintains the integrity of the circulation system.

Philippa M, Wiggin has shown that the mechanism that controls or brings about the effective function of the cation pumps utilizes the energy transforming property of water, the solvent; “The source of energy for cation transport or ATP synthesis lies in increases in chemical potentials with increasing hydration of small cations and polyphosphate anions in the highly structured interfacial aqueous phase of the two phosphorylated intermediates.” Waiting to get thirsty, when the body fluids become concentrated before thirst is induced, one loses the energy-generating properties of water in the dehydrated cells of the body. This is a major reason why we should prevent dehydration, rather than wait to correct it. This new understanding of the role of water in cation exchange is enough justification to let the body engage in prudent surplus water management rather than forcing it into drought and deficit water management, which is what Dr. Valtin is recommending people to do.

In his research on the “conformational change in biological macromolecules,” Ephraim Katchalski-Katzir of the Weizmann Institute of Science has shown that the “proteins and enzymes of the body function more efficiently in solutions of lower viscosity.” Thus, water loss from the interior of the cells would adversely affect their efficiency of function. This finding alone negates Dr. Valtin’s view that we should let dehydration get established before drinking water. Since it is desirable that all cells of the body should function efficiently within their physiological roles, it would be more prudent to optimally hydrate the body rather than wait for the drought management programs of the body to induce thirst. Furthermore, it is much easier for the body to deal with a slight surplus of water than to suffer from its shortfall and have to ration and allocate water to vital organs at the expense of less vital functions of the body. The outcome of constantly circulating concentrated blood in the vascular system is truly an invitation to catastrophe.

The tragedy of waiting to get thirsty hits home when it is realized that the sharpness of thirst perception is gradually lost, as we get older. Phillips and associates have shown that after 24 hours of water deprivation, the elderly still do not recognize they are thirsty: “The important finding is that despite their obvious physiologic need, the elderly subjects were not markedly thirsty.” Bruce and associates have shown that, between the ages of 20 to 70, the ratio of water inside the cells to the amount of water outside the cells drastically changes from 1.1 to 0.84. Undoubtedly this marked change in the intracellular water balance would not take place if the osmotic push and pull of life could favor water diffusion through the cell membranes everywhere in the body—at the rate of 0.001 centimeters per second. Only by relying on the reverse osmotic process of expanding the extracellular water content of the body, so as to filter and inject “load-free” water into vital cells by the actions of vasopressin and the renin-angiotensin-aldosterone systems—when the body physiology is constantly forced to rely on its drought- management programs—could such a drastic change in the water balance of the body result.

Two other scientific discoveries are disregarded when Dr. Valtin recommends people should wait until they get thirsty before they drink water. One, the initiation of the thirst mechanisms is not triggered by vasopressin and the renin-angiotensin systems—these systems are only involved in water conservation and forced hydration of the cells. Thirst is initiated when the Na+-K+-ATPase pump is inadequately hydrated. It is water that generates voltage gradient by adequately hydrating the pump proteins in the neurotransmission systems of the body. This is the reason the brain tissue is 85 percent water and cannot endure the level of “thirst-inducing” dehydration that is considered safe in the article published by Dr. Valtin.

Two, the missing piece of the scientific puzzle in the water- regulatory mechanisms of the body, which has been exposed since 1987, and Dr. Valtin and his colleagues need to know about it, is the coupled activity of the neurotransmitter histamine to the efficiency of the cation exchange; its role in the initiation of the drought- management programs; and its role in the catabolic processes when the body is becoming more and more dehydrated. Based on the primary water-regulatory functions of histamine, and the active role of water in all physiologic and metabolic functions of the body—as the hydrolytic initiator of all solute functions—the symptoms of thirst are those produced by excess histamine activity and its subordinate mechanisms which get engaged in the drought- management programs of the body. They include asthma, allergies and the major pains of the body, such as heartburn, colitis pain, rheumatoid joint pain, back pain, migraine headaches, fibromyalgic pains, and even anginal pain. And, since vasopressin and the rennin-angiotensin-aldosterone activity in the body are subordinates to the activation of histamine, their role in raising the blood pressure is a part of the drought-management programs of the body. Their purpose of forced delivery of water into vital cells demands a greater injection pressure to counteract the direction of osmotic pull of water from inside the cells of the body, when it is dehydrated.

From the new perspective of my 22 years of clinical and scientific research into molecular physiology of dehydration, and the peer-reviewed introduction of a paradigm shift in medical science, recognizing histamine as a neurotransmitter in charge of the water regulation of the body, I can safely say the 60 million Americans with hypertension, the 110 million with chronic pains, the 15 million with diabetes, the 17 million with asthma, the 50 millions with allergies, and more, all did exactly as Dr. Valtin recommends. They all waited to get thirsty. Had they realized water is a natural antihistamine and a more effective diuretic, these people would have been saved the agony of their health problems.

References:

1. Wiggins PM; A Mechanism of ATP-Driven Cation Pumps; PP-266-269, Biophysics of Water, Eds. Felix Franks and Sheila F. Mathis, John Wiley and Sons, Ltd.1982
2. Ephraim Katchalski-Katzir: Conformational Changes In Biological Macromolecules; Biorheology, 21, PP. 57-74, 1984.
3. Phillips PA; Rolls BJ; Ledingham JGG; Forsling ML; Morton JJ; Crowe MJ and Wollner L; Reduced Thirst After Water Deprivation In Healthy Elderly Men; The New England Journal of Medicine, PP.753-759, Vol. 311, No. 12, Sept. 20 1985.
4. Bruce A; Anderson M; Arvidsson B and Isacksson B; Body Composition, Predictions of Normal body Potassium, Body Water and Body Fat in Adults on the Basis of Body Height, Body Weight and Age; Scand. J. Clin. Lab. Invest, 40, 461-473, 1980.
5. Batmanghelidj F. M.D. Pain: A Need For Paradigm Change; Anticancer Research, Vol. 7, No. 5 B, PP. 971-990, Sept.- Oct. 1987; full article posted on www.watercure.com
6. Batmanghelidj F. M.D. Your Body’s Many Cries for Water; Global Health Solutions, Inc.
7. Batmanghelidj F. M.D. Neurotransmitter Histamine: An Alternative View; Page 37 of the Book of Abstracts; The 3rd Interscience World Conference on Inflammation, Analgesics and Immunomodulators, 1989 Monte-Carlo. The Abstract and the full article are posted on the Website www.watercure.com
8. Batmanghelidj F. M.D; ABC of Asthma, Allergies and Lupus; Global Health Solutions, Inc.

For more information on the role of histamine, see the articles on this topic in the science section, www.watercure.com/Topics10.htm or read my book ABC of Asthma, Allergies and Lupus.

F. Batmanghelidj, M.D.