Hospital Practice

ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20

CNS Regulation of Salt and Water Intake David J. Ramsay & William F. Ganong To cite this article: David J. Ramsay & William F. Ganong (1977) CNS Regulation of Salt and Water Intake, Hospital Practice, 12:3, 63-69, DOI: 10.1080/21548331.1977.11707095 To link to this article: http://dx.doi.org/10.1080/21548331.1977.11707095

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CNS Regulation of Salt and Water Intake

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0 A V 1D

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RA MS AY

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W 1L L I A M F. G AN 0 N G

University of California, San Francisco

The brain has evolved a number of mechanisms to maintain body fluid balance. They include the sensation of thirst, which stimulates water intake, the secretion of vasopressin, which helps prevent water loss, and the secretion of aldosterone, which helps prevent sodium depletion. In the research described here, all three mechanisms are shown to be mediated by the actions of angiotensin on the brain.

In a normal intact animal, water drinking has a circadian rhythm, with greatest consumption coinciding with food intake. Such drinking is not a response to an immediate need for water, although presumably it enables an animal to anticipate its future needs and so maintain its day-to-day fluid balance. In contrast, primary, or regulatory, thirst is a response to an existing need for water and represents one of the mechanisms the brain has evolved to regulate body fluid balance. Another is secretion of vasopressin, the antidiuretic hormone of the posterior pituitary. Consider a man in a hot, arid desert who is becoming more and more dehydrated. Increasing vasopressin output helps reduce renal water loss. Thus the man produces a more and more concentrated urine; he also becomes thirsty. But although the rate at which water is excreted is reduced, it cannot stop altogether because a certain amount of solute must continue to be eliminated from the body. Thirst therefore drives him to seek out and drink water. Water accounts for 6o% of body weight, with intracellular fluid making up two thirds of that amount, or 40% of body weight, and extracellular fluid (interstitial fluid and plasma) constituting one third, or 20% of body weight. Osmotic equilibrium exists between these two compartments. The stimuli for drinking in conditions of water deprivation are increased osmolality of the extracellular fluid (cellular dehydration) and hypovolemia (extracellular dehydration). Both cellular dehydration and decreased extracellular fluid volume produce thirst and stimulate drinking, presumably by acting on a "thirst center" in the central nervous system. Experiments in dogs, goats, and rats and some experiences in clinical medicine indicate that there is an area in the anterior hypothalamus that, if stimulated, will give rise to increased drinking. Probably the most dramatic of the experiments were performed by Bengt Andersson of Stock-

holm who demonstrated that stimulating the anterior hypothalamus by means of implanted electrodes causes goats to drink quantities of water equal to so% of their body weight. In fact, under such stimulation, fully hydrated animals would go to any length to obtain more water, including climbing a stepladder. In contrast, lesions slightly lateral to the same area produced an adipsic animal. There have also been several reports of adipsia in humans with brain tumors involving the hypothalamus. The question that then arises is: What ordinarily activates the thirst or drinking center? The concept developed by Cannon and widely held for many years was that it was dryness of the mouth. According to this view, the thirst center influences the output of parasympathetic impulses to the salivary glands, which reduce salivary flow. When the sensation of dryness is picked up by sensory nerve endings in the mouth, the information is relayed to higher cortical centers in the brain that stimulate drinking. Certainly a dry mouth is usually associated with a primary water deficit, but although information may be going from the hypothalamic thirst center to higher cortical centers (probably by way of the limbic system and other motivational pathways), we now know that it is not necessary for an animal to have a dry mouth in order to seek water. Rather, disturbances in body fluid balance caused by cellular dehydration or extracellular fluid depletion produce an osmotic stimulus that involves osmoreceptors in the hypothalamus. Normally, the osmolality or osmotic pressure of the intracellular and extracellular fluid compartments is the

Dr. Ramsay is Vice Chairman and Associate Professor of Physi· ology and Dr. Ganong is Chairman and Professor of Physiology at the University of California School of Medicine, San Fran· ctsco, Calif Hospital Practice March 1977

63

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Chloride-

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Increase

Although the composition of intracellular and extracellular fluid (ICF and ECF) is different, the osmolalities are identical. Because ICF osmotic content is fixed, equilibrium is achieved by

same - approximately 285 milliosmoles per kilogram of water. The osmotic content of the intracellular fluid is fixed by the mixture of positively charged potassium ions and negatively charged indiffusible protein inside the cell. In the extracellular fluid, sodium

Sodium Depletion Extracellular Fluid

water movement between the two compartments. With water depletion, both compartments diminish equally; with sodium depletion,ICF compartment increases, ECF is reduced.

is the major positively charged ion, and the major negatively charged ions are chloride and bicarbonate. Because the osmotic content of the intracellular fiuid cannot be changed, osmotic equilibration between the two compartments can be achieved only by the

Control

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Changes in plasma osmolality of the cerebral circulation were shown to influence water intake biJ dogs in experiments graphed here. Decreasing cerebral plasma osmolality after Uhour water deprivation bv slow infusion of water into the bilateral carotid loops reduced water drinking in a dose-related manner (upper graph), as compared with controll in which iso-onnotfc saline was infused through the carotid. In contrast, increasing cerebral plasma osmolalit11 in fluid-repl(&te dogs b11 intracerebral infusions of hwertonfc saline provoked drinking in a dose-related manner (below). 0.15MNaCI 0.3MNaCI 0.45MNaCI 0.6MNaCI

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Hospital Practice March lfln

10 20 Water Intake (ml/kg)

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movement of water. If the extracellular fiuid osmolality falls, for example, as a result of drinking water, water must enter the cells in order to maintain osmotic equilibrium. Similarly, if extracellular fluid osmolality increases, as in dehydration, water must be drawn from the cells in order to maintain osmotic equilibrium. Thus it is impossible for extracellular fiuid osmolality to change without a concomitant change in both extracellular and intracellular fiuid volume. The cells are behaving, in other words, as perfect osmometers, and because they do, the osmolality of the extracellular fluid is the major control over intracellular fluid volume. If extracellular fiuid osmolality decreases too much, intracellular fiuid volume must expand. The commonest type of body fiuid imbalance seen clinically is cellular dehydration due to water deprivation. During a :z4-hour period of water deprivation, loss of water by respiration, sweating, and excretion by the kidneys will lead to an increase in extracellular fluid osmolality of 10 to 1:z milliosmoles per kilogram of water. The less water taken in, the greater becomes the concentration of the extracellular fluid. Any increase in the osmolality of the extracellular fluid due to an increase in sodium concentration causes withdrawal of water from the cells. A 1% to :z% decrease in intracellular water will cause drinking. At the same time, extracellular fluid

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volume will also decrease, and thus the body fluid deficit will be shared equally by both body fluid compartments. In this condition, animals will make up the fluid deficit by drinking precisely the right amount of fluid to replace the loss, although species vary in terms of how rapidly they make up the deficit. Dogs will make it up very quickly; humans do so more slowly. Cellular dehydration has been produced experimentally in dogs and humans by infusing hypertonic sodium chloride.· It causes shrinkage of cells all over the body, including the groups of cells in the lateral preoptic area of the hypothalamus that have been identified as osmoreceptors. It is now generally accepted that shrinkage of these cells as the result of cellular dehydration is the stimulus for water intake in conditions of increasing extracellular fluid osmolality. Water output in the same circumstances is regulated by a similar mechanism. E. B. Vemey proposed, in 1947, that another group of osmoreceptors, in or near the supraoptic nucleus, control vasopressin secretion by reacting to changes in their own volume as osmolality of extracellular fluid increases and decreases. The precise nature of the cellular mechanism involved is still not known. Infusing hypertonic sucrose also will stimulate drinking and vasopressin secretion, whereas infusing hypertonic urea has relatively little effect. Similarly, injection of hypertonic sodium chloride or sucrose directly into the hypothalamus also stimulates drinking and vasopressin secretion, but again hypertonic urea has little or no effect. This is consistent with the finding that any osmotically reactive substance that causes a net withdrawal of water from cells gives rise to drinking. Urea, on the other hand, enters cells more easily than sodium and sucrose and causes little cellular dehydration; hence raising extracellular osmolality with urea will not stimulate drinking. To put it another way, in order for extracellula"r fluid osmolality increases to stimulate drinking and vasopressin secretion, the hypothalamic osmoreceptors must shrink, just as do all other cells in the body. Experiments on dogs in our laboratory indicate that 70% of the drive that

change in its osmotic composition. There are two ways in which a decrease in extracellular fluid volume can bring about drinking. The first mechanism involves the distention receptors on the low-pressure side of the circulation. Located in the left and right atria, vena cava, and pulmonary

leads to drinking after 24-hour water deprivation is accounted for by an osmotic stimulus resulting from cellular dehydration. The remaining 30% of the drive is caused by a hypovolemic stimulus resulting from a reduction in extracellular fluid volume or blood volume that is not complicated by a Control

Renal Hypertension

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Days Thoracic Caval Constriction

Abdominal Caval Constriction

Exctssive thirst is often associated with renal hypertension and congestive cardiac failure. After renal artery constriction in dog (top), water intake increased. and drinking occurred around the clock rather than primarily after feeding. Congestive failure induced by thoracic caval, but not by abdominal caval, constriction also increased drinking. Hospital Practice Ma~h 1977

65

500

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400

0

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Saline

2

Time(hr) Saralasin Acetate

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Each gray bar above represents cumulative amount of water drunk by a dog in cardiac failure during each hour of a three-hour infusion of normal saline (control period). Adding the angiotensin antagonist saralasin acetate to the saline infusion in the experimental period (color bars) significantly reduced water intake, indicating that angiotensin is involved in the excessive thirst associated with congestive cardiac failure.

veins, these receptors fire at the end of diastole in response to the phase of maximum distention. A reduction in blood volume - and consequently a reduction in the rate of venous returncauses a reduction in the rate of firing of these receptors, and this information is relayed to the CNS via visceral afferents. This reflex mechanism induces water drinking and vasopressin secretion when the reduction in blood volume is 10% or possibly even less. If the decrease in venous return becomes greater, the consequent reduction in arterial blood pressure causes an increase in firing of the sympathetic nerves that innervate the juxtaglomerular cells of the kidneys, thereby activating the renin-angiotensin system. This system is familiar to the reader in the context of hypertension, but that it should also play a major role in CNS regulation of thirst and water balance is probably less well known. Very recent experiments (that confirm some earlier ones) indicate that the renin-angiotensin system affects water metabolism by regulating vasopressin secretion. That the·mechanisms gov-

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Hospital Practice March 1977

erning input as weJI as output of water should be so linked is not only elegantly symmetrical but entirely consistent with the concept of homeostasis. We will return to this point later on, but let us first recall the salient aspects of the renin-angiotensin system itself. Renin is a proteolytic enzyme secreted into the bloodstream by the juxtaglomerular cells in the afferent arterioles of the kidneys. In the blood it acts on an a 2 globulin produced in the liver and called angiotensinogen, or renin substrate. Angiotensinogen is converted to a decapeptide, angiotensin I, which is relatively inactive, but it is converted in turn to the active oc~

CNS regulation of salt and water intake.

Hospital Practice ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20 CNS Regulation of Salt and Wate...
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