PHYSIOLOGICAL REVIEWS   Vol. 78 No. 3 July 1998, pp. 583-686
Copyright ©1998 by the American Physiological Society

Angiotensin, Thirst, and Sodium Appetite

J. T. FITZSIMONS

The Physiological Laboratory, Cambridge, United Kingdom

I. INTRODUCTION
    A. Angiotensin-Induced Drinking Behavior
    B. Renin-Angiotensin Systems
II. HYPOVOLEMIC THIRST AND SODIUM APPETITE
    A. Causes of Hypovolemic Thirst
    B. Detection of Hypovolemia and the Threshold of Response
    C. Arousal of Sodium Appetite
    D. Initial Evidence Suggesting Involvement of the Renal Renin-Angiotensin System in Drinking Caused by Hypovolemia
    E. The Question of Whether Angiotensins Originating in Brain and Other Tissues Are Involved in Drinking Behavior
    F. Comment
III. ANGIOTENSIN-INDUCED THIRST
    A. Angiotensin-Induced Water Intake in Rat
    B. Angiotensin-Induced Water Intake in Other Mammals
    C. Angiotensin-Induced Water Intake in Birds, Reptiles, and Fish
    D. Amphibians
    E. Importance of Sodium
    F. Comment
IV. ANGIOTENSIN-INDUCED SODIUM APPETITE
    A. Angiotensin-Induced Sodium Intake
    B. Angiotensin-Induced Sodium Appetite, a More Complex Response Than Angiotensin-Induced Thirst
    C. Comment
V. EFFECTS OF ANGIOTENSIN ANALOGS AND ANTAGONISTS ON DRINKING
    A. Angiotensin Structure-Activity and Drinking
    B. Angiotensin Antagonists
    C. Renin and Angiotensin II Precursors
    D. Angiotensin-(1--7) Heptapeptide
    E. Angiotensin-(2--8) Heptapeptide or Angiotensin III
    F. Angiotensin-(3--8) Hexapeptide or Angiotensin IV and Shorter Chain Angiotensin Peptides
    G. Comment
VI. CENTRAL NERVOUS SYSTEM AND ANGIOTENSIN-INDUCED DRINKING
    A. C-fos Expression After Angiotensin
    B. Circumventricular Organs
    C. Anteroventral Third Ventricular Region and Lamina Terminalis
    D. Organum Vasculosum of the Lamina Terminalis
    E. Subfornical Organ
    F. Amygdala
    G. Brain Stem and Area Postrema
    H. Comment
VII. ROLE OF ANGIOTENSIN PEPTIDES FORMED FROM PRECURSORS IN BRAIN IN DRINKING
    A. Components and Distribution
    B. Possible Functions
    C. Role in Drinking
    D. Comment
VIII. NEUROTRANSMITTERS AND ANGIOTENSIN-INDUCED DRINKING
    A. Acetylcholine
    B. Catecholamines
    C. Serotonin
    D. Excitatory and Inhibitory Amino Acids
    E. Tachykinins and Bombesin-Like Peptides
    F. Opioids
    G. Endothelins
    H. Natriuretic Peptides
    I. Vasopressin
    J. Oxytocin
    K. Prostaglandins
    L. Nitric Oxide
    M. Other Neuroactive Substances
    N. Comment
IX. DRUG-INDUCED HYPERRENINEMIA AND DRINKING
    A. -Adrenergics
    B. Furosemide
    C. Angiotensin-Converting Enzyme Inhibitors
    D. Histamine
    E. Serotonin
    F. 3,4-Methylenedioxymethamphetamine
    G. Insulin
    H. Comment
X. EXPERIMENTAL AND CLINICAL CAUSES OF RENIN-DEPENDENT DRINKING
    A. Obstruction of the Inferior Vena Cava
    B. Heart Failure
    C. Hyperoncotic Dialysis
    D. Sodium Appetite of Adrenal Insufficiency
    E. Circulatory Shock
    F. Experimental Renal Hypertension
    G. Diseases of the Kidney and Hyperreninemia
    H. Ureteric Ligation
    I. Diabetes Insipidus and the Brattleboro Rat
    J. Diabetes Mellitus
    K. Comment
XI. CONCLUSIONS
REFERENCES

	ABSTRACT

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Fitzsimons, J. T. Angiotensin, Thirst, and Sodium Appetite. Physiol. Rev. 78: 583-686, 1998.  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, or all of these, remains uncertain. ANG II-induced drinking behavior serves as a model of how other complex behaviors involving neural and peptide inputs might be organized.

	I. INTRODUCTION

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Angiotensin-induced drinking behavior is a remarkable phenomenon. I discuss it in detail and analyze the different circumstances in which angiotensin peptides may be involved in thirst and sodium appetite. There has been an enormous amount of work on these topics in the past 30 years, and it would be impracticable to survey all that has been published. What follows is therefore selective and very much what has interested me. I have tried to allow for personal bias by citing key review articles or chapters in books for certain aspects of the work described here. I have also given an extended list of monographs, multiauthor works, and conference proceedings devoted to thirst, sodium appetite, and renin-angiotensin systems.

Thirst is a sensation aroused by a need for water, and relief from it is sought by drinking water. We infer from our own experience in similar circumstances that the dehydrated animal eagerly seeking water is also experiencing thirst. But lecturing, singing, eating a spicy meal, seeking pleasure from a refreshing drink of water on a hot day, or just habit may lead to increased consumption of water, although there may be no immediate need for it and no thirst in the strict sense of the word. Perhaps the appropriate term to use here is appetite for water. There are also circumstances in which animals continue to drink water or can be made to do so even though their needs for water have been met many times over. For example, rats infused with more water than they needed in the 24 h, by routes that bypassed the mouth and pharynx, continued to drink spontaneously about one-third or more of their preinfusion intake of water (184). It is important to be aware of circumstances such as these when assessing the results of experiments on drinking behavior. We reasonably assume that animals experience the same sensations as ourselves when they suffer the same deficits, but we should also recognize that animals, like ourselves, drink water for reasons other than to repair a water deficit; they have urges and preferences as well as needs that they seek to gratify. And although it is desirable that we restrict the word thirst to the sensation aroused by a lack of water, in general usage it incorporates both an idea of appetite for water as well as a drive toward relief of a need. We are often tempted by water as well as driven to assuage our thirst.

Increased sodium appetite indicates a need for sodium, and relief will be sought by consuming salt or salty foods. But much more so than with thirst, experience of a previous occasion of sodium deficit and the satisfaction afforded by the taste of salt and consequent intake may so condition behavior that an appetite for repetition of this experience is quickly established. In other words, sodium intake is commonly driven by preference as well as need, and the subject gains satisfaction from it as well as relief. Cannon (89) wrote, "It is not to be supposed that the two motivating agencies  the pang and the pleasure  are as separate as we have been regarding them for the purposes of analysis in the present discussion. They may be closely mingled; when relief from hunger or thirst is found, the appetite may simultaneously be satiated." Cannon was discussing hunger (the pang) and appetite (the pleasure) for food, but his remarks apply with equal force to hunger or appetite for sodium. In most circumstances of sodium need, sodium intake is undoubtedly driven by need, but there is also an element of preference: both the pang and the pleasure operate. These are the reasons why, like most workers in the field from Richter (479) onward, I have preferred to use the word sodium or salt appetite rather than sodium hunger, since appetite implies preference as well as need and it takes account of the powerful effects of learning on the response to a need. I have also preferred to use sodium instead of salt because salt can mean a nonsodium salt.

View larger version (23K): [in this window] [in a new window]   FIG. 1.   Formation of angiotensin peptides. Nonrenin angiotensinogenases include tonin and cathepsins D and G.

	II. HYPOVOLEMIC THIRST AND SODIUM APPETITE

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Cellular dehydration and hypovolemia are the two principal causes of deficit-induced drinking. Loss of cell water is detected by osmoreceptors (and possibly sodium-sensitive receptors) located in the hypothalamus and elsewhere that share in the cellular dehydration and give rise to thirst. There is long-standing evidence on monitoring of extracellular fluid volume by stretch receptors in the walls of the heart and vasculature (232, 547). Hypovolemia is detected by these receptors which cause a delayed increase in sodium appetite as well as thirst. It is in drinking behavior induced by hypovolemia that renin-angiotensin systems seem to be most involved. Circulating ANG II derived from renal renin contributes to hypovolemic thirst. It also plays a role in increased sodium appetite, acting with the mineralocorticoids and other hormones. The part played by ANG II formed locally in the brain in these behaviors is uncertain, but in the rat, it may be more important in sodium appetite than in thirst. Other angiotensin peptides formed in the periphery or brain may contribute, but information is lacking. The circumstance in which hypovolemia leads to increased intakes of water and NaCl, some of the methods used to elicit these behaviors, and early evidence implicating renal renin are considered here.

Experimental procedures that have been used to arouse hypovolemic thirst include bleeding, inducing sodium deficiency (371), causing sequestration of extracellular fluid by intraperitoneal (175) or subcutaneous injection (560, 567) of hyperoncotic colloid, and interfering with venous return to the heart by obstructing the inferior vena cava (176, 178, 197, 614). Among clinical causes are severe diarrhea and vomiting, some forms of renal disease, congestive heart failure, and circulatory shock. Many of the experimental and clinical causes are considered in section X. Hypovolemia leads to an increase in circulating ANG II, and this contributes to drinking, although it is not exclusively responsible for the overall drinking response. On the other hand, even in the absence of any other stimulus, thirst can be aroused by injecting ANG II or causing it to be formed by drugs or surgical procedures. Because there is no additional renal renin release in cellular dehydration, circulating ANG II does not contribute to the thirst aroused, although angiotensin of cerebral origin may (see sect. VII). In mixed cellular and extracellular dehydration, ANG II like any other thirst stimulus adds its effect to the overall drinking response. As for spontaneous day-to-day drinking, here water intake is usually in excess of need, and much of the evidence suggests that drinking is determined by habit, showing the characteristics of a nyctohemeral rhythm entrained with feeding, with no fluid deficit or hormonal signal involved (184). However, it has also been suggested that release of histamine and transient hypovolemia associated with feeding may cause release of enough renal renin to stimulate drinking.

Hypovolemia is detected by vascular stretch receptors in various parts of the circulation and possibly by other types of receptor as well (197, 232, 252, 292, 522). Unloading of cardiopulmonary and arterial stretch receptors as venous return and cardiac output drop, pulse pressure narrows, and mean arterial pressure falls, causes a number of compensatory responses, including increased sympathetic activation; decreased vagal tone; increased secretion of renin, aldosterone, ACTH, and vasopressin; and increased drinking. Reflex circulatory adjustments to loss of volume are rapid; renal conservation of water and electrolytes and replacement of the deficits of water and sodium by intake mechanisms are slower responses that depend on both neural and hormonal mechanisms. A deficit in plasma volume of ~8-10% (or this degree of underfilling in critical receptor regions in the heart and blood vessels) causes significant drinking, a threshold that is considerably higher than the deficit of 1 or 2% of cellular water needed to arouse osmotic thirst.

It seems possible that the hypovolemic threshold is higher than the osmotic because the range of blood flow rates required in different activities is so extended and the scope for changes in the distribution of cardiac output and the partitioning of fluid across the capillary wall so great that it is necessary to avoid the controls of extracellular volume being constantly triggered by smaller changes in plasma volume. The ample reserve of fluid in the interstitial fluid compartment acts as a buffer for plasma volume and can be mobilized through operation of the Starling capillary filtration/reabsorption system should the need to correct hypovolemia arise. It would be inappropriate if the circulatory adjustments accompanying different levels of bodily activity were to arouse thirst because of what turned out to be temporary understimulation of vascular stretch receptors, which ended as soon as the activity diminished and circulatory function returned to the resting state. It would make little sense were hypovolemic thirst mechanisms to keep switching on and off in this way because of transient shifts of blood between vascular beds. But once the loss of circulating volume becomes significant and persistent, drinking under the control of hypovolemic thirst is as vigorous as that caused by equivalent cell dehydration, and the amounts of water drunk may be greater than after cellular dehydration of similar magnitude. The requirements of the cellular fluid compartment are different; in contrast to the variable volume demands of the circulation, stability of cellular water content is a necessary condition for normal cell function.

We can only speculate on the mechanisms that are responsible for the long-term precision of blood volume control. This control, which allows for large short-term variations in the distribution of blood and the partitioning of fluid between the plasma and interstitial compartments depending on circulatory needs, implies the accurate monitoring of volume in certain strategic regions of the circulation, at least for part of the time, perhaps integrated over the long-term during periods of rest.

Neural and hormonal effector mechanisms vary the intake, distribution, and excretion of fluid and electrolytes in accordance with long-term needs. The immediate increase in water intake is caused by altered neural inputs from the vasculature reinforced by increases in circulating ANG II. Circulating ANG II contributes directly to the overall drinking response by stimulating structures in the central nervous system and, if the hypovolemia is severe, it is also important in maintaining the blood pressure and therefore the behavioral competence of the animal. However, it is not essential in hypovolemic thirst that can occur in the absence of circulating ANG II.

An increase in sodium appetite is the second behavioral response to hypovolemia. Many mammals in sodium deficit seek and ingest salt, driven to do so by increased sodium appetite (122, 498, 523), an innate behavior that serves sodium homeostasis (148). Sodium appetite is also expressed in many birds, including the pigeon. Animals seek and ingest what they like as well as what they need, and much sodium intake is preference driven; for ourselves, table salt is a common condiment, and sodium-replete rats readily accept and drink large quantities of isotonic NaCl, the saline concentration they prefer. Sodium is normally a major urinary constituent and represents the excess of intake over the amounts needed by the body. It is important in the investigation of need-driven sodium appetite to offer concentrations of sodium solutions that the sodium-replete animals normally avoid. Under these conditions, we can be reasonably sure that any NaCl intake is need driven. Sodium appetite is well developed in inland-dwelling herbivores including some primates, particularly during pregnancy and lactation when calls on fluid and electrolyte reserves of the body are greatest, or when sodium deficiency develops as a result of, for example, intestinal infection. Herbivores in the wild may travel long distances to places where salt is to be found, and this is presumably why their predators also tend to congregate at these places. But omnivores, including humans, and carnivores when they are unable to satisfy their sodium needs from their prey, show increased sodium appetite when sodium deficient.

Inducing sodium deficiency by placing the subject on a low-sodium regime is the simplest way to generate an appetite, and of course, here ANG II levels increase. The combination of dietary restriction and enforced sweating was used by McCance (371) in his classical experiments on himself and colleagues, published in 1936, on the effects of inducing sodium chloride deficiency and, although the study of sodium appetite was not the primary purpose of this experiment, the subjects made some interesting observations on alterations in their sense of flavor and taste. In a more recent study, experimental sodium deficiency in 10 human subjects caused increased preference for salty foods (32). More active procedures to make animals sodium deficient, which may be combined with dietary sodium restriction, are treatment with furosemide or other natriuretic drugs (see sect. IXB); peritoneal dialysis with isosmotic glucose; unilateral fistulation of the parotid salivary gland in sheep, calf, and goat (122); and adrenalectomy (see sect. XD). The methods used to arouse hypovolemic thirst also cause increased sodium appetite, and to these may be added subcutaneous injection of buffered Formalin, which is an effective natriorexigenic stimulus (669).

Sodium appetite can also be induced in the absence of need for sodium by administration of the hormones of sodium deficiency, the mineralocorticoids and ANG II, which are normally secreted in extra amounts in the circumstances just mentioned. But to these should be added the hormones of pregnancy and lactation and the stress hormones of the hypothalamo-pituitary-adrenocortical axis, corticotrophin releasing hormone (CRH), ACTH, and glucocorticoids (122, 597), although these are of varying effectiveness and there are species differences in the effects produced. Angiotensin II-induced sodium appetite is considered in detail in section IV, and the reproductive hormones are considered in sections IIIA4 and IVA3.

Increased sodium appetite caused by mineralocorticoids has been abundantly studied and verified since Richter's discovery of the phenomenon more than 50 years ago (122). A U-shaped function describes the effects of systemic administration of mineralocorticoid on sodium appetite; replacement doses of deoxycorticosterone acetate (DOCA) reverse the increased NaCl intake that follows adrenalectomy, whereas larger than replacement doses of DOCA or aldosterone stimulate NaCl intake in intact and adrenalectomized rats despite the accompanying sodium retention and suppression of renal renin secretion (56, 221, 475, 478, 479, 668). Arousal of sodium appetite depends on central actions of mineralocorticoids. Receptor binding studies have shown that there are two receptor subtypes for corticosteroids, mineralocorticoid (type I or MR), and glucocorticoid (type II or GR). Both are present in rat brain, and their regional distribution is similar. The highest uptakes of aldosterone and corticosterone are in the hippocampus, septum, and amygdala (402), and there is a brief report that bilateral adrenal steroid implants in the amygdala caused an increase in intake of NaCl but not water (472). Central nervous structures involved in increased sodium appetite are discussed in section VI.

Sodium appetite can be aroused in rats by inducing the syndrome of apparent mineralocorticoid excess (AME) using the active component of licorice, glycyrrhizic acid, or its hydrolytic product, 18-glycyrrhetinic acid (105, 106). The pattern of increased drinking produced resembles that which occurs after administration of excessive amounts of mineralocorticoid, but plasma corticosteroid levels are not increased. Apparent mineralocorticoid excess has been identified as a cause of human hypertension (529). The clinical picture is similar to that produced by excess mineralocorticoids, with sodium retention, hypertension, potassium loss, and inhibition of the renin-angiotensin system. In type I AME, inactivation of glucocorticoids is impaired because the enzyme 11-hydroxysteroid dehydrogenase (11-OHSD), which oxidises cortisol to cortisone, is congenitally deficient or has been blocked by licorice (557). Type II AME is secondary to a deficiency in the A-ring reduction metabolic pathway. In rats, licorice prevents oxidation of corticosterone, the glucocorticoid in rodents, to 11-dehydrocorticosterone. Failure to inactivate glucocorticoids allows the mineralocorticoid receptors, whose affinities for glucocorticoids and mineralocorticoids in vitro are the same (402), to be powerfully stimulated by the large amounts, relative to aldosterone, of glucocorticoid present. Mineralocorticoid receptors, including those in brain (323), are normally protected from stimulation by glucocorticoids by this enzyme. Licorice inhibits 11-OHSD activity in kidney and other tissues, exposing the mineralocorticoid receptors to glucocorticoid stimulation, but the 11-oxoreductase activity of liver is mainly unaffected, ensuring reconversion of inactive 11-ketosteroid to active glucocorticoid (401). Glycyrrhizic acid-induced increases in sodium appetite were abolished by adrenalectomy but could be restored by administration of cortisol or corticosterone but not by replacement dosage of DOCA (107). Increased sodium appetite in AME suggests that 11-OHSD inactivation of glucocorticoid also operates in those parts of the brain responsible for mineralocorticoid-induced appetite.

The stimulating effect of DOCA is much smaller in rabbit and sheep, and aldosterone seems ineffective in these species (122). Dogs, hamsters, and gerbils also fail to show significant natriorexigenic responses to mineralocorticoids (498). On the other hand, it has been shown that several adrenal steroids in slow-release pellet form, of which deoxycorticosterone (DOC) was the most potent, evoked sodium appetite in BALB/c mice (45), although it was stated earlier that mice do not show a natriorexigenic response to mineralocorticoids (498, 499). The pigeon develops an increase in sodium appetite in response to subcutaneous DOCA (151). Glucocorticoids can generate sodium appetite in rabbit and sheep but in rat only when accompanied by mineralocorticoid (668). Adrenocorticotrophic hormone (Synacthen) stimulates sodium appetite in rabbit, rat (659), and sheep. In rabbit, the effect is mediated partly by the adrenal cortex, but there is also an extra-adrenal effect, since ACTH has some action in adrenalectomized animals, presumably by acting directly on the brain (122). Mineralocorticoid-induced sodium appetite is a primary natriorexigenic effect on brain; it is independent of and unaffected by the developing "escape" from mineralocorticoid action on the kidney. Corticosteroid therapy, or excessive mineralocorticoid secretion whether accompanied by increases or decreases in circulating ANG II, could contribute to inappropriate or excessive sodium intake in human. Continuing sodium intake in the face of sodium retention indicates that the intake is not homeostatically determined.

Mineralocorticoid treatment, or induction of AME, also causes increased water intake, which is usually regarded as being exclusively secondary to NaCl intake, but some increased intake also occurs when water only is available to drink in dog (164, 461) and rat on a high salt (475, 479) or normal (unpublished data) diet. Furthermore, the relation between water intake and NaCl intake is not always close; in mouse, DOC stimulated NaCl intake but had no effect on water intake, whereas the combination of DOC with other corticosteroids, and especially with ACTH, caused increased water intake as well as NaCl (45). Apart from the osmotic effect of the NaCl intake, increased water intake may be the result of mineralocorticoid-induced potassium depletion giving rise to cellular dehydration and failure of renal concentrating ability. Potassium deficiency has long been recognized as a cause of a diabetes insipidus-like syndrome with polydipsia and vasopressin-resistant polyuria both in animals and in humans. The stimulating effect of potassium depletion on water intake may be primary; the polyuria of hypokalemic subjects is often in excess of the urine volume required by their concentrating defect (39).

Increased sodium appetite is an essential and appropriate defense mechanism against sodium deficiency, but other mineral deficiencies may also cause increased NaCl intake. These are circumstances where the relation between sodium appetite and sodium need and/or its hormonal accompaniments appear to be completely absent. In addition to the polydipsia/polyuria syndrome already mentioned, potassium depletion in rat caused increased intake of NaCl as well as KCl (122). Rats also show increased sodium appetite in response to calcium depletion even in the absence of sodium loss or increases in the hormones of sodium homeostasis. The appetite is not related to plasma calcium levels, the hormones controlling calcium, or the renin-angiotensin-aldosterone system, and at present it is unexplained (627, 628).

Because ANG II and mineralocorticoids are central in the body's defenses against sodium loss and consequent hypovolemia, much of the experimental effort to try and elucidate the physiological basis of sodium appetite has been devoted to these hormones. One approach to investigate possible participation of renal renin in sodium appetite has been to lower plasma levels of renin and ANG II by bilateral nephrectomy, or to prevent the effects of renin secretion with appropriate renin-angiotensin system antagonists (see sect. V). Another approach has been to try to stimulate or restore sodium appetite by elevating plasma ANG II levels directly or by administering renin, or by stimulating renal renin secretion pharmacologically or surgically. These approaches complement studies on the possible role of cerebral renin in sodium appetite and its relation, if any, to renal renin; they are essentially those used to assess the renin contribution to thirst.

I proposed that the renal renin-angiotensin system has a direct and physiological role in certain types of drinking behavior as a result of certain findings on caval obstruction as a stimulus to drinking in the rat (176, 178). The procedure of caval obstruction was devised as a method of mimicking the circulatory effects of severe hypovolemia. Within 30 min to 1 h after constriction of the abdominal inferior vena cava just above the renal veins, there was an increase in water intake followed much later by an increase in sodium intake; there was also a marked fall in urine flow and electrolyte excretion so that for a time the animal gained weight as it retained fluid. Because this stimulus to thirst was found to be less effective in the nephrectomized rat than in the intact rat, it seemed that renin or some other renal factor released as a result of the reduced venous return to the heart could have been partly responsible for the increased drinking. Making the rat anuric by bilateral ureteric ligation, a procedure which preserves the endocrine function of the kidney, did not prevent caval obstruction-induced drinking. Experimental support for the theory of renal renin involvement in this behavior came with the finding that saline extracts of the renal cortex of rat caused increased drinking especially in nephrectomized rats. The properties of the rat renal extract were found to be similar to those of renin and purified commercial pig renin caused a dose-dependent increase in drinking (178).

The idea that the kidney might contribute to thirst, although not through renin secretion, was proposed by Linazasoro et al. (341). They suggested that when the supply of water to the body is lacking, the kidney liberates a thirst factor that helps the body to resist dehydration. They found that in bilaterally nephrectomized rats that were allowed free access to water, the loss of body weight and fall in water intake that usually occur could be prevented by injecting an extract of pig kidney. Because renin apparently did not have these effects, Jiménez-Díaz et al. (288) concluded that the renal thirst factor is not renin. However, there were already clues that the renal thirst factor might indeed be renin. In a series of experiments on accelerated hypertensive disease in nephrectomized dogs (368) and rats (367), Masson and co-workers found that the syndrome was intensified by renin, which stimulated water intake. But they considered that increased drinking was secondary to hypovolemia consequent on increased capillary transudation and they stated that ". . . thirst induced by renin in nephrectomized rats is not the result of primary stimulation of thirst centers . . ." (367). Asscher and Anson (17) came to a similar conclusion, finding that renal extracts stimulated water intake in nephrectomized rats, but attributing this to hypovolemia caused by leakage of fluid into the tissues.

Because the caval obstruction experiments described above suggested that there are occasions when endogenously released renin as opposed to injected renin or renal extracts contributes to thirst, it seemed likely that renin acted by more physiological mechanisms than by causing or exacerbating hypovolemia. The question now arose whether, as for other effects of renin, increased drinking in response to caval obstruction was mediated by ANG II (178). This proved to be the case. It was found that ANG II caused increased drinking when infused intravenously into water-replete rats at doses below those which produced marked changes in hematocrit value and that it restored the nephrectomized rat's reduced water intake in response to caval obstruction near to that of a normal rat's response (200). In an investigation of norepinephrine-induced eating in rat, it had been observed that intrahypothalamic injection of ANG II caused drinking (51). It was now shown that injection of small amounts of ANG II into the anterior hypothalamus and preoptic region caused dose-dependent increases in water intake in the water-replete rat (149), suggesting that increased circulating ANG II caused drinking by acting on accessible structures in the central nervous system. Shortly after these early experiments on ANG II-induced water intake, intracranial ANG II was also shown to cause increased NaCl intake (72, 96).

	III. ANGIOTENSIN-INDUCED THIRST

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One of the most striking stimulatory effects of any substance on any motivated behavior is the vigorous, short-latency burst of drinking that follows injection of ANG II into sensitive structures in the brain. The initial increase in water intake is followed by a developing increase in NaCl intake (see sect. IV). Systemic injection of ANG II also causes water-replete animals to start drinking, although the response is less predictable than after intracranial administration. Responsiveness to the dipsogenic effect of ANG II is present in all vertebrate groups examined (Table 1), including certain euryhaline bony fish, but excluding amphibians and elasmobranch fish. Renin and some other components of the renin-angiotensin cascade given by intracranial or systemic injection also cause increased drinking.

View larger version (17K): [in this window] [in a new window]   FIG. 2.   Water intake in 15 min after injection of angiotensin (ANG) II in subfornical organ (SFO) or in adjacent lateral ventricle (LV) or third ventricle (3V). Numerator in each fraction is number of rats responding, and denominator is number of animals injected at particular dose and injection site. [From Simpson et al. (537).]

2. Systemic administration

An increase in drinking can also be produced by systemic administration of ANG II or its precursors, or by causing release of renin from the kidney by pharmacological or surgical means (see sects. IX and X). Although it is difficult to make direct comparisons because the techniques of administration are so different, the conditions required for eliciting drinking in response to systemic ANG II are more exacting than those for intracranial administration. With the use of appropriate doses to obtain maximal responses by the two routes, drinking responses caused by intravenous infusion are generally smaller than those following intracranial administration. In contrast to the robust drinking response that is almost invariably obtained with intracranial ANG II, there are well-documented cases in the literature where systemic ANG II has failed to cause drinking.

Angiotension II is usually given by continuous intravenous infusion to unrestrained animals using an external infusion system (0.05-3.0 µg·kg¹·min¹; Ref.

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View larger version (35K): [in this window] [in a new window]   FIG. 3.   Regression of plasma ANG II concentrations after intravenous infusion of ANG II at 1, 25, 50, or 100 pmol·kg1·min1 for 60 min in nephrectomized rats. Plasma ANG II levels produced by various thirst stimuli in other rats are indicated by arrows on regression line. Top shaded area represents plasma ANG II level at dipsogenic threshold for intravenous ANG II, and bottom shaded area is range of controls. Intact 25 and 100 pmol·kg1· min1 indicates level of circulating ANG II after a 60-min infusion into unanesthetized rats with intact kidneys. DI, diabetes insipidus; RH, renal hypertension; PEG, polyethylene glycol; Isop, isoproterenol. [From Mann et al. (355).]