Brain Research Bulletin, Vol. 27, pp. 495-499. 0 Pergamon Press plc, 1991. Printed in the U.S.A
0361-9230/91
$3.00 + .OO
Regulation of Fluid Intake in Dogs Following Water Deprivation DAVID J. RAMSAY
AND TERRY N. THRASHER
Department of Physiology, University of California, San Francisco, San Francisco, CA 94143-0400
RAMSAY, D. J. AND T. N. THRASHER. Regulation of fluid intake in dogs following water deprivation. BRAIN RES BULL 27(3/4) 495-499, 1991 .-Whereas water loss in land living animals occurs continuously, water intake takes place discontinuously. At the normal operating set point of plasma osmolality, urine is more concentrated than plasma due to secretion of vasopressin. Thus animals operate around a state of mild dehydration. As water loss occurs, the severity of dehydration and thirst increase in intensity and at some point water intake occurs. Sufficient water is consumed to return plasma osmolality to the normal operating set point. Food intake and water balance are interdependent as food provides the osmoles which determine obligatory renal solute excretion. When dry food with the same osmotic content was substituted for canned food (water content 74%). dogs increased water intake from 24.224.3 to 62.2k8.8 mlikg. Urine output and urine osmolality were unchanged, as under conditions of normal hydration, near maximal urine concentration is achieved. Changing water intake is the only available variable to maintain water balance. During water deprivation, the major renal mechanism appears to be natriuresis. In rehydration, satiety mechanisms ensure appropriate water intake and renal sodium conservation restores sodium balance. Dehydration Thirst Food intake and thirst Free water clearance
Water balance Urine osmolality Osmolal clearance
Plasma osmolality Satiety Vasopressin Urine concentration Dehydration natriuresis Organum vasculosum laminae terminalis (OVLT)
The fallacy in this view is that if an animal were driven to water-seeking behavior in proportion to its capacity to concentrate urine, the search for water would dominate and suppress the expression of other behaviors important to the survival of the animal. Specifically, exhibited behaviors are discontinuous because selection between drives has to occur according to a hierarchy for survival of the individual, and tbis hierarchy will change according to nume~us factors in the external and internal environments. An animal which is not drinking may be thirsty. The inputs which signal negative water balance may be present, but not be powerful enough to push water drinking to the top of the behavioral hierarchy. Figure 1 demonstrates these relationships from data obtained in a group of normally hydrated dogs. The abscissa depicts the plasma osmolality of blood perfusing the cerebral osmoreceptors, and ‘0’ tbe value when blood samples are taken from dogs with free access to food and water in their home kennels (absolute value 295 mosm/kg H,O). These animals do not show spontaneous drinking, but are secreting sufficient vasopressin to produce urine 2 to 3 times more concentrated than plasma. It could be argued, therefore, that a ‘normal’ state of hydration is that of mild dehydmtion if an equality of urine and plasma osmolality is taken as the condition when there is neither overhydration nor dehydration. In terms of renal physiology, this would be the point when urine flow equals osmolal clearance and free water clearance is zero, and thus the urine is isosmotic with plasma. Thus fluid intake would be providing precisely the appropriate amount of water to allow excess osmotically active solutes in the body to be excreted in the urine without activation of urinary concentration or dilution mechanisms. In contrast, random
THE intake of fluid is an integral part of the complex matrix of control systems which maintain the constancy of extracellular fluid composition and volume (6, 9, 18). In terrestrial animals, oral intake of water, either as fluid or contained in or derived from food, is the only input to the system (2). Evaporative loss of water from cutaneous surfaces always occurs, and may be increased dramatically as a consequence of temperature regulation. ~lrnon~ loss always occurs, as partially saturated air is inspired and expired gases are fully saturated with water vapor dependent simply on body temperature. The difference between water content of inspired and expired air, always a negative value, represents water loss. Salivary loss may also be significant, for example in animals that use it for grooming or thermolysis, Urine is elaborated continuously, the volume of water lost largely dependent on osmotic~ly active solutes, both present in the diet and as a result of metabolism, which have to be excreted. The continuous loss of water from these four routes puts a relentless negative drain on the water content of the body. Water intake is the only route which allows repair of these continually occurring losses.
THENORMAL STATE OF HYD~~ON A major difficulty in unravelling the role of thirst in body fluid control mechanisms is that drinking is a discontinuous behavior. A normal animal is often viewed by the physiologist as caring for its water balance by producing concentrated urinewhich it does. In contrast, the same animal is described as not being thirsty because it is not always drinking. Thus drinking is viewed as the final act of desperation when the normal process of fluid regulation by fine renal tuning has failed!
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few minutes (4,26). The intake of water ceases before gastrointestinal absorption of the ingestate has occurred and, thus. consequent restoration of body fluid volume and composition. Indeed, dehydrated dogs with gastric fistulae drink equal volumes to intact dogs, again showing the importance of oropharyngeal factors in short-term satiety mechanisms (26). Similarly, inhibition of vasopressin secretion occurs during and shortly after drinking, a phase where oropharyngeal factors. and not body fluid inputs, prevail. The amount of water ingested is sufficient to restore plasma osmolality to its set point. There is no overcompensation. Although the balance between short-term and long-term mechanisms which stop drinking varies between species, the general point holds; that is, the appropriate volume of fluid to restore the volume and composition of the extracellular fluid to normal is consumed. The set point of plasma osmolality is one in which concentrated urine is being produced, and although thirst may be present. spontaneous drinking does not normally occur. Change
in Cerebral Plasma Osmolahty (mosmol’kg)
I The relationship between plasma vasopressin (solid line) and water intake (broken line) in dogs and change in plasma osmolality.
FIG.
urine samples taken from terrestrial mammals show urine to be more concentrated than plasma. Kidneys seem to operate normally in the concentrating mode. The normal operating set point of extracellular fluid osmolality/volume is one where renal conservation of water normally occurs but drinking is intermittent. There is an abundance of literature [see (6) for review] which describes drinking before dehydration occurs. Indeed, a recent paper (10) describes drinking in pigs which seems to be unrelated to changes in plasma osmolality or volume, and cannot be explained by thresholds established by acute testing of cellular or extracellular dehydration thresholds in this species (3). Such drinking is often termed anticipatory. There is no doubt that a myriad of factors influence water intake, and a more detailed discussion follows. However, mammalian organisms seem to operate around set points in the dehydrated, rather than the overhydrated. range. THIRST THRESHOLD In humans, it is possible to assess thirst by asking individuals how thirsty they are, using a visual analogue scale (16, 19, 20). Although this subject is somewhat controversial, with appropriate experimental design, it can be shown that there is residual thirst in normally hydrated individuals although water intake is absent. This thirst can be depressed by water loading. There is ample evidence that raising plasma osmolality in humans by techniques such as hypertonic saline infusion or water deprivation causes increases in thirst ratings and in water consumption (16, 20, 21, 23). The results in Fig. 1 show the equivalence of drinking and vasopressin responses to raised plasma osmolality in dogs. It is of great interest that in these relationships increases in both water intake and plasma vasopressin occur only when the normal plasma osmolality in dogs has been exceeded. When this threshold has been reached, water intake and vasopressin secretion are stimulated in parallel. The importance of regulation of drinking and vasopressin secretion around the normal ‘set point’ of plasma osmolality has also been demonstrated by investigations of mechanisms which stop a bout of drinking, rather than those which initiate it. Following a period of water deprivation, dogs drink rapidly and imbibe a volume of water appropriate to their deficits within a
THE INITIATION OF DRINKING AS A RESPONSE TO DEHYDRATION
During water deprivation, the continual obligatory loss of water is not replaced by water ingestion, and will result in a raised extracellular fluid osmolality and reduced extracellular fluid volume. Although exchange of solute and water between body fluid compartments will ameliorate the severity of these changes. both cellular and extracellular dehydration will develop. If factors which encourage further water loss are present. such as a hot arid environment, dehydration can occur quite rapidly (1). There is ample evidence to show that both cellular and extracellular dehydration can act alone to stimulate drinking and vasopressin secretion in a wide variety of species (6,lS). Thus it is not surprising that both factors are operative in stimulating the initiation of drinking during dehydration. The interaction between cellular and extracellular factors in dehydration drinking has been studied in dogs surgically prepared with their common carotid arteries exteriorized in skin loops (17). This technique allows effects of raised plasma osmolality (cellular dehydration) acting on cerebral osmoreceptors to be separated from reduced volume (extracellular dehydration) acting on vascular receptors. In these experiments, the raised osmolality stimulus to forebrain cerebral osmoreceptors in dehydrated dogs was eliminated by intracarotid infusions of small amounts of water. Drinking was reduced by 70%, whereas similar intravenous infusions of water were without effect. In another series of experiments, the reduced volume stimulus was removed by infusing the dehydrated dogs with intravenous artificial extracellular fluid before water was offered. In this case, water intake was reduced by 30%. When the intracarotid water and intravenous artificial extracellular fluid infusion techniques were combined, dehydrated dogs no longer consumed any water. It is therefore reasonable to conclude that 70% of the stimulus to drinking in water deprived dogs is due to cellular dehydration and 30% to extracellular dehydration. Similar results have been obtained in the case of vasopressin secretion (29). Although the balance between cellular and extracellular dehydration differs between species-for example, in primates 85% of the stimulus appears to be cellular-both mechanisms are implicated in dehydration drinking (13). IS ALL WATER INTAKE DEFICIT RELATED?
The mechanisms discussed thus far allow a simple model of the control of water intake to be developed. From the normal
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set points of plasma osmolality and volume, dehydration occurs as water is lost from cutaneous, pulmonary and renal routes. Additionally, osmotically active osmoles are added to the system by eating. According to this model, thirst would be stimulated and drinking of sufficient water to return plasma osmolality and volume to their set points would occur. In animals, this model may well account for most, if not all, of the fluid intake. However, the system is obviously more complex than this simple model. In animals, water intake may occur as a result of intake of a variety of fluids, and is subject to social and behavioral factors. Much fluid intake is associated with food intake, and it has been shown that many of the factors which influence the ingestion of food affect thirst (7,ll). In humans, the situation is even more complex, as fluid is often ingested as a result of additives, e.g., caffeine, alcohol, sugar, rather than for its water content. Moreover, social and a complex of other factors are even more influential than in other species. However, an underlying fact should not be overlooked. The normal animal is continually producing a concentrated urine. With all the influences that can modify fluid intake, the deficit model still applies in that fluid is not ingested in excess of need. Even in humans, urine osmolality averages 600-800 mosm/kg H,O, a value double that of plasma. Of course, excessive fluid intake-for example, beer drinking-can cause urinary dilution to occur, but the normal situation is for urine to be concentrated. Thus it could be argued that in spite of the myriad of influences which can impact thirst, the simple deficit model of water intake provides the physiological foundation which underpins the system. FOODINTAKEANDWATERCONSUMF’TION The relationship between food and water intake in dogs has been shown to be periprandial (22). Most of the drinking takes place during and after feeding, but many dogs show anticipatory drinking in the hour or two before feeding when fed once each 24 hours. If the time of feeding is shifted within the 24-hour period, then time of drinking, including the anticipatory phase, changes within a few days. In the series of experiments depicted in Fig. 2, the feeding time was kept constant, but the water content of the food was altered. The dogs were first fed a diet of canned food for a period of at least two weeks. The canned food had a water content of 74%. The results in Fig. 2 represent 24-hour water balance data for water intake and urine output averaged over 5 days, when a steady state had been achieved. During this period, daily water intake averaged 24.2 r4.3 ml/kg and represented 44% of the total. The dogs were then changed to dry food, which
provided a similar calorific and osmolar intake, but had less than 5% content of water. The water intake increased and within a few days had reached a steady state value of 62.2k8.8 ml/kg, which represented 96% of the water intake. Total daily water intake remained the same. A striking feature of these results is that the adjustments which occurred to maintain water balance were in water intake, not urine output. Twenty-four hour urine output was remarkably constant being 22.1? 2.2 ml/kg when the dogs were fed canned food, and 20.1 k3.5 ml/kg when changed to dry. Moreover, urine osmolality remained constant. The effectiveness of thirst mechanisms in ensuring that body fluid homeostasis was maintained is shown by the constancy of plasma osmolality being 299 t 2 mosm/kg H,O when canned food was fed, and 297 ? 2 mosmkg H,O during dry food feeding. These simple observations give some insight into the importance of thirst mechanisms in the control of fluid homeostasis. Urine osmolality throughout was 1500-1600 mosm/kg H,O; that is, approximately 5 x plasma osmolality. The maximum urine osmolality that can be achieved in dogs is 67 x plasma. Thus, although when the food was changed from canned to dry it would have been theoretically possible for the urine to become somewhat more concentrated and to conserve renal water loss, this did not occur. In fact, plasma vasopressin did not change between canned and dry food regimes, which perhaps is not too surprising as plasma osmolality remained constant. Presumably, as might be predicted from the results in Fig. 1, when dry food is substituted for canned, plasma osmolality would tend to rise and should stimulate both thirst and vasopressin secretion and, thus, urinary concentration. However, the burden of maintenance of plasma osmolality seems to be placed on water intake, not further urinary concentration. These results call into question the view that thirst only is brought into play under emergency situations of body fluid depletion, and renal mechanisms usually provide the major regulatory input (5). Changing diet can hardly be termed an emergency situation. It seems as if renal water conservation mechanisms in dogs usually operate close to maximum, and that thirst mechanisms provide the major control when plasma osmolality is threatened. The physiological underpinning of the control of thirst provided by the deficit drinking model seems apparent. DEHYDRATION NATRIURESIS During the past few years, the importance of the control of sodium excretion in the defense of plasma osmolality has been realized. When water is withheld or restricted, a natriuresis develops, and this loss of solute provides a further protective mechanism to buffer plasma osmolality from undue increases (12, 14, 25, 26). In dogs, 24-hour water, but not food, deprivation results in a steady rise in plasma osmolality with the expected increase in plasma vasopressin. However, urinary volume does not fall (27). This is because of an increased urinary sodium loss which obligates continued excretion of water. Thus, similar to the results of changing the water content of the diet, urinary conservation of water during dehydration is not evident. Conditions which initiate a dehydration natriuresis involve a fall in extracellular fluid volume together with an increase in its osmolality or sodium concentration. During the 24-hour period of water deprivation in dogs, a negative sodium balance of 1.9 * 0.2 mEq/kg was accumulated. Following water drinking, profound renal sodium retention allowed sodium balance to be returned to normal. The physiological importance of dehydration natriuresis to the control of plasma osmolality can be seen in the responses of OVLT lesioned dogs and sheep to water depriva-
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3. The effect of offering a variety of fluids on consumption in 24water deprived dogs. The volume of the various fluids consumed minutes was measured (open bars). One hour later, water was ofto test satiety (closed bars).
mechanism is an accurate one (2). Dogs drink rapidly following a period of water deprivation and usually replace the deficit in less than 5 minutes. Oroph~ngeal metering of fluid intake is involved, and the same signals are used to inhibit vasopressin secretion (25,26). The satiety due to oropharyngeal metering is temporary, however, and is only permanent when body fluid restoration follows the ingestion of the fluid. In previous experiments, we have shown that this short-term satiety and inhibition of vasopressin also occurs if artificial extracellular fluid is substituted for water. With Bjijm Applegren, we decided to investigate whether water-deprived dogs would show similar short-term satiety and inhibition of vasopressin secretion if other fluids were offered in place of water. We had already shown that soft canned food did not have satiating effects on thirst following water deprivation. In the present series of experiments, seven 24hour water deprived dogs were offered a variety of fluids on separate occasions including water, differing concentrations of saline and mannitol, bouillon made isosmotic with plasma and milk. These fluids were offered for 5 minutes, and access to water allowed one hour later to assess satiety. The results are shown in Fig. 3. The volumes of the various fluids ingested were remarkably similar, showing that the dehydrated dogs poorly disc~minated the nature of the fluid drunk. Differences did occur, however, as the molality of the saline solution was increased, and as its concentration approached the aversive level, the volume consumed was reduced. It is of interest that the aversive saline concentration is similar to the maximal range of urinary concentration of sodium. There were differences, however, in the degree of permanent satiety as judged by water intake when offered one hour later. In general, only when water was offered originally was the satiety complete. In this second phase, dogs consumed quantities of water necessary to achieve correction of fluid deficits that were not provided by the fluid originally offered and drunk. Thus, for example, when 2.7 NaCl was consumed, increased amounts of water were drunk at the end of one hour, presumably to compensate for the effects of the hy~~smotic NaCl on plasma com~sition. The results in Fig. 4 show the effects of the fluid ingested on plasma vasopressin levels in the first 3 minutes of drinking. Ingestion of water or isosmotic solutions caused rapid inhibition of vasopressin secretion. With increased osmolality of ingested fluid, the inhibition of vasopressin secretion became less marked. ety
tion (1524). This lesion prevents dehydration natriuresis, and during water deprivation plasma osmolality rises 2-3 times the amount in intact animals. However, although dehydration natriuresis has been demonstrated in a large number of species, its existence has been questioned in humans. The point has been made that when humans are deprived of water they respond by reducing urine volume and increasing concentration and usually there is an antinatriuresis. The explanation for this may lie in the normal operating or set point of plasma osmolality in humans compared with other mammals that have been studied. Results presented in this chapter have shown that normal dogs function with a urine osmolality which approaches maximal concentration. This is also true of the most studied species, the laboratory rat. As has been shown by many individuals, including Vemey, a well hydrated dog responds to water deprivation by decreasing urine volume and increasing its osmolality, as does the human (28). However, it appears that dogs and rats usually operate with near maximal urinary osmolalities. Perhaps when challenged with water dep~vation, the only viable mechanism that is left to prevent large increases in plasma osmolality is thirst and urinary loss of solute if water is not available. In contrast, humans, at least those in temperate climates, have urinary osmolality which is only twice that of plasma, although maximal concentration of four-fold can be achieved. Presumably this is due to the various factors which contribute to high intake of fluid in humans discussed previously. Thus humans start in a similar situation to well hydrated dogs (or rats) and show antidiuresis when water deprivation occurs. Whether more prolonged periods of water deprivation will cause natriuresis in humans, as it does in other mammals that have been studied. remains to be elucidated. SATIETY
As has been described earlier, many species repair water deficits so rapidly that mechanisms other than signals from correction of body fluid deficits must be involved in satiety. The volume of fluid ingested is appropriate to the deficit so the sati-
THIRST FOLLOWING
499
DEPRIVATION
An interesting finding was that the isosmotic bouillon (soup) did not inhibit vasopressin secretion, whereas milk did. In a separate experiment, canned food mixed with water also failed to inThe mechanism which allows hibit vasopressin secretion. discrimination between “food” and “fluid” in the inhibition of vasopressin secretion during ingestion is not clear. In summary, it appears that the thirst drive is so strong in dehydrated dogs that they do not reject fluids unless body fluid homeostasis would be severely compromised, for example, strongly hypertonic saline. Such a mechanism would allow animals to ingest a wide variety of fluids to correct, even if only partially, body fluid deficits, and would have obvious survival value.
SUMMARY
The results presented and discussed in this chapter have stressed that the normal operating water balance set point of animals studied in the laboratory that have free access to food and water includes quite marked renal water conservation. It can be argued, therefore, that normal body fluid regulation occurs around a set point of mild dehydration, and that studies of water deprivation allow normal deficit driven regulatory processes to be studied. During dehydration, renal water conservation responses are limited, and thirst mechanisms dominate in the maintenance of normal plasma osmolality.
REFERENCES 1. Adolph, E. F. Physiology of man in the desert. New York: Inter-
science; 1947. 2. Adolph, E. F. Regulation of water intake in relation to body water
3
4 5
9. 10.
11. 12. 13.
14.
15.
16.
content. In: Handbook of physiology, alimentary canal, food and water intake. sect. 6, vol. 1. Washington, DC: American Physiological Society; 1967:163-171. Anderson, C. R.; Houpt, T. R. Hypertonic and hypovolemic stimulation of thirst in pigs. Am. .I. Physiol. 258(Regul. Integr. Comp. Physiol. 27):Rl49-R154. Bellows, R. T. Time factors in water drinking in dogs. Am. J. Physiol. 125:87-97; 1939. Cowley, A. W.; Skelton, M. M.; Merrill, D. C. Osmoregulation during high salt intake: Relative importance of drinking and vasopressin secretion. Am. J. Physiol. 25l(Regul. Integr. Comp. Physiol. 20):R878-R886; 1986. Fitzsimons, J. T. The physiology of thirst and sodium appetite. Cambridge: Cambridge University Press; 1979. Fitzsimons, J. T.; LeMagnen, J. Eating as a regulatory control of drinking. J. Comp. Physiol. Psychol. 67:273-283; 1969. Gilman, A. The relation between blood osmotic pressure, fluid distribution and voluntary water intake. Am. J. Physiol. 120:323-328; 1937. Holmes, J. H.; Gregersen, M. I. Observations on drinking induced by hypertonic solutions. Am. J. Physiol. 162:326-337;1950. Houpt, T. R.; Anderson, C. R. Spontaneous drinking: Is it stimulated by hypertonicity or hypovolemia? Am. J. Physiol. 258(Regul. lntegr. Comp. Physiol. 27):Rl43-R148; 1990. Kraly, F. S. The physiology of drinking elicited by eating. Psychol. Rev. 91:478490; 1984. Luke, R. G. Natriuresis and chloruresis during hydropenia in the rat. Am. J. Physiol. 224:13-20; 1973. Maddison, S.; Wood, R. J.; Rolls, E. T.; Rolls B. J.; Gibbs, J. Drinking in the rhesus monkey: Peripheral factors. J. Comp. Physiol. Psychol. 94:365-374; 1980. McKinley, M. J.; Denton, D. A.; Nelson, J. F.; Weisinger, R. S. Dehydration induces sodium depletion in rats, rabbits and sheep. Am. J. Physiol. 245(Regul. Integr. Comp. Physiol. 14):R287-R292; 1983. McKinley, M. J.; Denton, D. A.; Park, R. C.; Weisinger, R. S. Cerebral involvement in dehydration induced natriuresis. Brain Res. 263:340-343; 1983. Phillips, P. A.; Rolls, B. J.; Ledingham, J. G. G.; Forling, M. L.; Morton, J. J. Osmotic thirst and vasopressin release in humans: A double blind crossover study. Am. J. Physiol. 248(Regul. Integr.
Comp. Physiol. 12):R6454650; 1985. 17. Ramsay, D. J.; Rolls, B. J.; Wood, R. J. Thirst following water deprivation in dogs. Am. J. Physiol 232(Regul. Integr. Comp. Physiol. l):R93-RlOO; 1977. 18. Ramsay, D. J.; Thrasher, T. N.; Bie, P. Endocrine components of body fluid homeostasis. Comp. Biochem. Physiol. 9OA:777-780; 1988. 19. Robertson, G. L. Abnormalities of thirst regulation. Kidney Int. 25: 4-69; 1984. 20. Robertson, G. L. Osmoregulation of thirst and vasopressin secretion: Functional properties and their relationship to water balance. In: Schrier, R., ed. Vasopressin. New York: Raven Press; 1985: 202-213. 21. Robertson, G. L.; Athar, S.; Shelton, R. L. Osmotic control of vasopressin function. In: Andocoli, T. E.; Grantham, J. J.; Rector, F. C., Jr., eds. Disturbances in body fluid osmolality. Bethesda: American Physiological Society; 1977: 1125-148. 22. Rolls, B. J.; Ramsay, D. J. The elevation of endogenous angiotensin and thirst in the dog. In: Peters, G.; Fitzsimons, J. T.; PetersHoepeli, L., eds. Control mechanisms of drinking. Berlin: Springer Verlag; 1975:74-78. 23. Rolls, B. J.; Wood, R. J.; Rools, E. J.; Lind, H.; Lind, R. W.; Ledingham, J. C. G. Thirst following water deprivation in humans. Am. J. Physiol. 239(Regul. Integr. Comp. Physiol. 8):R476-R482; 1980. 24. Thrasher, T. N.; Keil, L. C.; Ramsay, D. J. Altered responses to dehydration in dogs with lesions of the organum vasculosum laminae terminalis. Proceedings of the 29th International Congress of Physiological Sciences; 1983:49. 25. Thrasher, T. N.; Keil, L. C.; Ramsay, D. J. Drinking, oropharyngeal signals and inhibition of vasopressin secretion in dogs. Am. J. Physiol. 253(Regul. Integr. Comp. Physiol. 22):R5094515; 1987. 26. Thrasher, T. N.; Nistal-Herrera, J. F.; Keil, L. C.; Ramsay. D. J. Satiety and inhibition of vasopressin secretion after drinking ;n dogs. Am. J. Physiol. 240(Endocrinol. Metab. 3):E394-E401: 1981. 27. Thrasher, T. N.; Wade, C. E.; Keil, L. C.; Ramsay, d. J. Sodium balance and aldosterone during dehydration and rehydration in the dog. Am. J. Physiol. 247(Regul. Integr. Comp. Physiol. 16):R76R83; 1984. 28. Vemey, E. B. The antidiuretic hormone and the factors which determine its release. Proc. R. Sot. Lond. [Biol.] 135:25-106; 1947. 29. Wade, C. E.; Keil, L. C.; Ramsay, D. J. Role of volume and osmolality in the control of plasma vasopressin in dehydrated dogs. Neuroendocrinology 37:349-353; 1983.
0361-9230/91
$3.00 + .OO
Regulation of Fluid Intake in Dogs Following Water Deprivation DAVID J. RAMSAY
AND TERRY N. THRASHER
Department of Physiology, University of California, San Francisco, San Francisco, CA 94143-0400
RAMSAY, D. J. AND T. N. THRASHER. Regulation of fluid intake in dogs following water deprivation. BRAIN RES BULL 27(3/4) 495-499, 1991 .-Whereas water loss in land living animals occurs continuously, water intake takes place discontinuously. At the normal operating set point of plasma osmolality, urine is more concentrated than plasma due to secretion of vasopressin. Thus animals operate around a state of mild dehydration. As water loss occurs, the severity of dehydration and thirst increase in intensity and at some point water intake occurs. Sufficient water is consumed to return plasma osmolality to the normal operating set point. Food intake and water balance are interdependent as food provides the osmoles which determine obligatory renal solute excretion. When dry food with the same osmotic content was substituted for canned food (water content 74%). dogs increased water intake from 24.224.3 to 62.2k8.8 mlikg. Urine output and urine osmolality were unchanged, as under conditions of normal hydration, near maximal urine concentration is achieved. Changing water intake is the only available variable to maintain water balance. During water deprivation, the major renal mechanism appears to be natriuresis. In rehydration, satiety mechanisms ensure appropriate water intake and renal sodium conservation restores sodium balance. Dehydration Thirst Food intake and thirst Free water clearance
Water balance Urine osmolality Osmolal clearance
Plasma osmolality Satiety Vasopressin Urine concentration Dehydration natriuresis Organum vasculosum laminae terminalis (OVLT)
The fallacy in this view is that if an animal were driven to water-seeking behavior in proportion to its capacity to concentrate urine, the search for water would dominate and suppress the expression of other behaviors important to the survival of the animal. Specifically, exhibited behaviors are discontinuous because selection between drives has to occur according to a hierarchy for survival of the individual, and tbis hierarchy will change according to nume~us factors in the external and internal environments. An animal which is not drinking may be thirsty. The inputs which signal negative water balance may be present, but not be powerful enough to push water drinking to the top of the behavioral hierarchy. Figure 1 demonstrates these relationships from data obtained in a group of normally hydrated dogs. The abscissa depicts the plasma osmolality of blood perfusing the cerebral osmoreceptors, and ‘0’ tbe value when blood samples are taken from dogs with free access to food and water in their home kennels (absolute value 295 mosm/kg H,O). These animals do not show spontaneous drinking, but are secreting sufficient vasopressin to produce urine 2 to 3 times more concentrated than plasma. It could be argued, therefore, that a ‘normal’ state of hydration is that of mild dehydmtion if an equality of urine and plasma osmolality is taken as the condition when there is neither overhydration nor dehydration. In terms of renal physiology, this would be the point when urine flow equals osmolal clearance and free water clearance is zero, and thus the urine is isosmotic with plasma. Thus fluid intake would be providing precisely the appropriate amount of water to allow excess osmotically active solutes in the body to be excreted in the urine without activation of urinary concentration or dilution mechanisms. In contrast, random
THE intake of fluid is an integral part of the complex matrix of control systems which maintain the constancy of extracellular fluid composition and volume (6, 9, 18). In terrestrial animals, oral intake of water, either as fluid or contained in or derived from food, is the only input to the system (2). Evaporative loss of water from cutaneous surfaces always occurs, and may be increased dramatically as a consequence of temperature regulation. ~lrnon~ loss always occurs, as partially saturated air is inspired and expired gases are fully saturated with water vapor dependent simply on body temperature. The difference between water content of inspired and expired air, always a negative value, represents water loss. Salivary loss may also be significant, for example in animals that use it for grooming or thermolysis, Urine is elaborated continuously, the volume of water lost largely dependent on osmotic~ly active solutes, both present in the diet and as a result of metabolism, which have to be excreted. The continuous loss of water from these four routes puts a relentless negative drain on the water content of the body. Water intake is the only route which allows repair of these continually occurring losses.
THENORMAL STATE OF HYD~~ON A major difficulty in unravelling the role of thirst in body fluid control mechanisms is that drinking is a discontinuous behavior. A normal animal is often viewed by the physiologist as caring for its water balance by producing concentrated urinewhich it does. In contrast, the same animal is described as not being thirsty because it is not always drinking. Thus drinking is viewed as the final act of desperation when the normal process of fluid regulation by fine renal tuning has failed!
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496
RAMSAY AND THRASHER
few minutes (4,26). The intake of water ceases before gastrointestinal absorption of the ingestate has occurred and, thus. consequent restoration of body fluid volume and composition. Indeed, dehydrated dogs with gastric fistulae drink equal volumes to intact dogs, again showing the importance of oropharyngeal factors in short-term satiety mechanisms (26). Similarly, inhibition of vasopressin secretion occurs during and shortly after drinking, a phase where oropharyngeal factors. and not body fluid inputs, prevail. The amount of water ingested is sufficient to restore plasma osmolality to its set point. There is no overcompensation. Although the balance between short-term and long-term mechanisms which stop drinking varies between species, the general point holds; that is, the appropriate volume of fluid to restore the volume and composition of the extracellular fluid to normal is consumed. The set point of plasma osmolality is one in which concentrated urine is being produced, and although thirst may be present. spontaneous drinking does not normally occur. Change
in Cerebral Plasma Osmolahty (mosmol’kg)
I The relationship between plasma vasopressin (solid line) and water intake (broken line) in dogs and change in plasma osmolality.
FIG.
urine samples taken from terrestrial mammals show urine to be more concentrated than plasma. Kidneys seem to operate normally in the concentrating mode. The normal operating set point of extracellular fluid osmolality/volume is one where renal conservation of water normally occurs but drinking is intermittent. There is an abundance of literature [see (6) for review] which describes drinking before dehydration occurs. Indeed, a recent paper (10) describes drinking in pigs which seems to be unrelated to changes in plasma osmolality or volume, and cannot be explained by thresholds established by acute testing of cellular or extracellular dehydration thresholds in this species (3). Such drinking is often termed anticipatory. There is no doubt that a myriad of factors influence water intake, and a more detailed discussion follows. However, mammalian organisms seem to operate around set points in the dehydrated, rather than the overhydrated. range. THIRST THRESHOLD In humans, it is possible to assess thirst by asking individuals how thirsty they are, using a visual analogue scale (16, 19, 20). Although this subject is somewhat controversial, with appropriate experimental design, it can be shown that there is residual thirst in normally hydrated individuals although water intake is absent. This thirst can be depressed by water loading. There is ample evidence that raising plasma osmolality in humans by techniques such as hypertonic saline infusion or water deprivation causes increases in thirst ratings and in water consumption (16, 20, 21, 23). The results in Fig. 1 show the equivalence of drinking and vasopressin responses to raised plasma osmolality in dogs. It is of great interest that in these relationships increases in both water intake and plasma vasopressin occur only when the normal plasma osmolality in dogs has been exceeded. When this threshold has been reached, water intake and vasopressin secretion are stimulated in parallel. The importance of regulation of drinking and vasopressin secretion around the normal ‘set point’ of plasma osmolality has also been demonstrated by investigations of mechanisms which stop a bout of drinking, rather than those which initiate it. Following a period of water deprivation, dogs drink rapidly and imbibe a volume of water appropriate to their deficits within a
THE INITIATION OF DRINKING AS A RESPONSE TO DEHYDRATION
During water deprivation, the continual obligatory loss of water is not replaced by water ingestion, and will result in a raised extracellular fluid osmolality and reduced extracellular fluid volume. Although exchange of solute and water between body fluid compartments will ameliorate the severity of these changes. both cellular and extracellular dehydration will develop. If factors which encourage further water loss are present. such as a hot arid environment, dehydration can occur quite rapidly (1). There is ample evidence to show that both cellular and extracellular dehydration can act alone to stimulate drinking and vasopressin secretion in a wide variety of species (6,lS). Thus it is not surprising that both factors are operative in stimulating the initiation of drinking during dehydration. The interaction between cellular and extracellular factors in dehydration drinking has been studied in dogs surgically prepared with their common carotid arteries exteriorized in skin loops (17). This technique allows effects of raised plasma osmolality (cellular dehydration) acting on cerebral osmoreceptors to be separated from reduced volume (extracellular dehydration) acting on vascular receptors. In these experiments, the raised osmolality stimulus to forebrain cerebral osmoreceptors in dehydrated dogs was eliminated by intracarotid infusions of small amounts of water. Drinking was reduced by 70%, whereas similar intravenous infusions of water were without effect. In another series of experiments, the reduced volume stimulus was removed by infusing the dehydrated dogs with intravenous artificial extracellular fluid before water was offered. In this case, water intake was reduced by 30%. When the intracarotid water and intravenous artificial extracellular fluid infusion techniques were combined, dehydrated dogs no longer consumed any water. It is therefore reasonable to conclude that 70% of the stimulus to drinking in water deprived dogs is due to cellular dehydration and 30% to extracellular dehydration. Similar results have been obtained in the case of vasopressin secretion (29). Although the balance between cellular and extracellular dehydration differs between species-for example, in primates 85% of the stimulus appears to be cellular-both mechanisms are implicated in dehydration drinking (13). IS ALL WATER INTAKE DEFICIT RELATED?
The mechanisms discussed thus far allow a simple model of the control of water intake to be developed. From the normal
THIRST FOLLOWING
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497
DEPRIVATION
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set points of plasma osmolality and volume, dehydration occurs as water is lost from cutaneous, pulmonary and renal routes. Additionally, osmotically active osmoles are added to the system by eating. According to this model, thirst would be stimulated and drinking of sufficient water to return plasma osmolality and volume to their set points would occur. In animals, this model may well account for most, if not all, of the fluid intake. However, the system is obviously more complex than this simple model. In animals, water intake may occur as a result of intake of a variety of fluids, and is subject to social and behavioral factors. Much fluid intake is associated with food intake, and it has been shown that many of the factors which influence the ingestion of food affect thirst (7,ll). In humans, the situation is even more complex, as fluid is often ingested as a result of additives, e.g., caffeine, alcohol, sugar, rather than for its water content. Moreover, social and a complex of other factors are even more influential than in other species. However, an underlying fact should not be overlooked. The normal animal is continually producing a concentrated urine. With all the influences that can modify fluid intake, the deficit model still applies in that fluid is not ingested in excess of need. Even in humans, urine osmolality averages 600-800 mosm/kg H,O, a value double that of plasma. Of course, excessive fluid intake-for example, beer drinking-can cause urinary dilution to occur, but the normal situation is for urine to be concentrated. Thus it could be argued that in spite of the myriad of influences which can impact thirst, the simple deficit model of water intake provides the physiological foundation which underpins the system. FOODINTAKEANDWATERCONSUMF’TION The relationship between food and water intake in dogs has been shown to be periprandial (22). Most of the drinking takes place during and after feeding, but many dogs show anticipatory drinking in the hour or two before feeding when fed once each 24 hours. If the time of feeding is shifted within the 24-hour period, then time of drinking, including the anticipatory phase, changes within a few days. In the series of experiments depicted in Fig. 2, the feeding time was kept constant, but the water content of the food was altered. The dogs were first fed a diet of canned food for a period of at least two weeks. The canned food had a water content of 74%. The results in Fig. 2 represent 24-hour water balance data for water intake and urine output averaged over 5 days, when a steady state had been achieved. During this period, daily water intake averaged 24.2 r4.3 ml/kg and represented 44% of the total. The dogs were then changed to dry food, which
provided a similar calorific and osmolar intake, but had less than 5% content of water. The water intake increased and within a few days had reached a steady state value of 62.2k8.8 ml/kg, which represented 96% of the water intake. Total daily water intake remained the same. A striking feature of these results is that the adjustments which occurred to maintain water balance were in water intake, not urine output. Twenty-four hour urine output was remarkably constant being 22.1? 2.2 ml/kg when the dogs were fed canned food, and 20.1 k3.5 ml/kg when changed to dry. Moreover, urine osmolality remained constant. The effectiveness of thirst mechanisms in ensuring that body fluid homeostasis was maintained is shown by the constancy of plasma osmolality being 299 t 2 mosm/kg H,O when canned food was fed, and 297 ? 2 mosmkg H,O during dry food feeding. These simple observations give some insight into the importance of thirst mechanisms in the control of fluid homeostasis. Urine osmolality throughout was 1500-1600 mosm/kg H,O; that is, approximately 5 x plasma osmolality. The maximum urine osmolality that can be achieved in dogs is 67 x plasma. Thus, although when the food was changed from canned to dry it would have been theoretically possible for the urine to become somewhat more concentrated and to conserve renal water loss, this did not occur. In fact, plasma vasopressin did not change between canned and dry food regimes, which perhaps is not too surprising as plasma osmolality remained constant. Presumably, as might be predicted from the results in Fig. 1, when dry food is substituted for canned, plasma osmolality would tend to rise and should stimulate both thirst and vasopressin secretion and, thus, urinary concentration. However, the burden of maintenance of plasma osmolality seems to be placed on water intake, not further urinary concentration. These results call into question the view that thirst only is brought into play under emergency situations of body fluid depletion, and renal mechanisms usually provide the major regulatory input (5). Changing diet can hardly be termed an emergency situation. It seems as if renal water conservation mechanisms in dogs usually operate close to maximum, and that thirst mechanisms provide the major control when plasma osmolality is threatened. The physiological underpinning of the control of thirst provided by the deficit drinking model seems apparent. DEHYDRATION NATRIURESIS During the past few years, the importance of the control of sodium excretion in the defense of plasma osmolality has been realized. When water is withheld or restricted, a natriuresis develops, and this loss of solute provides a further protective mechanism to buffer plasma osmolality from undue increases (12, 14, 25, 26). In dogs, 24-hour water, but not food, deprivation results in a steady rise in plasma osmolality with the expected increase in plasma vasopressin. However, urinary volume does not fall (27). This is because of an increased urinary sodium loss which obligates continued excretion of water. Thus, similar to the results of changing the water content of the diet, urinary conservation of water during dehydration is not evident. Conditions which initiate a dehydration natriuresis involve a fall in extracellular fluid volume together with an increase in its osmolality or sodium concentration. During the 24-hour period of water deprivation in dogs, a negative sodium balance of 1.9 * 0.2 mEq/kg was accumulated. Following water drinking, profound renal sodium retention allowed sodium balance to be returned to normal. The physiological importance of dehydration natriuresis to the control of plasma osmolality can be seen in the responses of OVLT lesioned dogs and sheep to water depriva-
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3. The effect of offering a variety of fluids on consumption in 24water deprived dogs. The volume of the various fluids consumed minutes was measured (open bars). One hour later, water was ofto test satiety (closed bars).
mechanism is an accurate one (2). Dogs drink rapidly following a period of water deprivation and usually replace the deficit in less than 5 minutes. Oroph~ngeal metering of fluid intake is involved, and the same signals are used to inhibit vasopressin secretion (25,26). The satiety due to oropharyngeal metering is temporary, however, and is only permanent when body fluid restoration follows the ingestion of the fluid. In previous experiments, we have shown that this short-term satiety and inhibition of vasopressin also occurs if artificial extracellular fluid is substituted for water. With Bjijm Applegren, we decided to investigate whether water-deprived dogs would show similar short-term satiety and inhibition of vasopressin secretion if other fluids were offered in place of water. We had already shown that soft canned food did not have satiating effects on thirst following water deprivation. In the present series of experiments, seven 24hour water deprived dogs were offered a variety of fluids on separate occasions including water, differing concentrations of saline and mannitol, bouillon made isosmotic with plasma and milk. These fluids were offered for 5 minutes, and access to water allowed one hour later to assess satiety. The results are shown in Fig. 3. The volumes of the various fluids ingested were remarkably similar, showing that the dehydrated dogs poorly disc~minated the nature of the fluid drunk. Differences did occur, however, as the molality of the saline solution was increased, and as its concentration approached the aversive level, the volume consumed was reduced. It is of interest that the aversive saline concentration is similar to the maximal range of urinary concentration of sodium. There were differences, however, in the degree of permanent satiety as judged by water intake when offered one hour later. In general, only when water was offered originally was the satiety complete. In this second phase, dogs consumed quantities of water necessary to achieve correction of fluid deficits that were not provided by the fluid originally offered and drunk. Thus, for example, when 2.7 NaCl was consumed, increased amounts of water were drunk at the end of one hour, presumably to compensate for the effects of the hy~~smotic NaCl on plasma com~sition. The results in Fig. 4 show the effects of the fluid ingested on plasma vasopressin levels in the first 3 minutes of drinking. Ingestion of water or isosmotic solutions caused rapid inhibition of vasopressin secretion. With increased osmolality of ingested fluid, the inhibition of vasopressin secretion became less marked. ety
tion (1524). This lesion prevents dehydration natriuresis, and during water deprivation plasma osmolality rises 2-3 times the amount in intact animals. However, although dehydration natriuresis has been demonstrated in a large number of species, its existence has been questioned in humans. The point has been made that when humans are deprived of water they respond by reducing urine volume and increasing concentration and usually there is an antinatriuresis. The explanation for this may lie in the normal operating or set point of plasma osmolality in humans compared with other mammals that have been studied. Results presented in this chapter have shown that normal dogs function with a urine osmolality which approaches maximal concentration. This is also true of the most studied species, the laboratory rat. As has been shown by many individuals, including Vemey, a well hydrated dog responds to water deprivation by decreasing urine volume and increasing its osmolality, as does the human (28). However, it appears that dogs and rats usually operate with near maximal urinary osmolalities. Perhaps when challenged with water dep~vation, the only viable mechanism that is left to prevent large increases in plasma osmolality is thirst and urinary loss of solute if water is not available. In contrast, humans, at least those in temperate climates, have urinary osmolality which is only twice that of plasma, although maximal concentration of four-fold can be achieved. Presumably this is due to the various factors which contribute to high intake of fluid in humans discussed previously. Thus humans start in a similar situation to well hydrated dogs (or rats) and show antidiuresis when water deprivation occurs. Whether more prolonged periods of water deprivation will cause natriuresis in humans, as it does in other mammals that have been studied. remains to be elucidated. SATIETY
As has been described earlier, many species repair water deficits so rapidly that mechanisms other than signals from correction of body fluid deficits must be involved in satiety. The volume of fluid ingested is appropriate to the deficit so the sati-
THIRST FOLLOWING
499
DEPRIVATION
An interesting finding was that the isosmotic bouillon (soup) did not inhibit vasopressin secretion, whereas milk did. In a separate experiment, canned food mixed with water also failed to inThe mechanism which allows hibit vasopressin secretion. discrimination between “food” and “fluid” in the inhibition of vasopressin secretion during ingestion is not clear. In summary, it appears that the thirst drive is so strong in dehydrated dogs that they do not reject fluids unless body fluid homeostasis would be severely compromised, for example, strongly hypertonic saline. Such a mechanism would allow animals to ingest a wide variety of fluids to correct, even if only partially, body fluid deficits, and would have obvious survival value.
SUMMARY
The results presented and discussed in this chapter have stressed that the normal operating water balance set point of animals studied in the laboratory that have free access to food and water includes quite marked renal water conservation. It can be argued, therefore, that normal body fluid regulation occurs around a set point of mild dehydration, and that studies of water deprivation allow normal deficit driven regulatory processes to be studied. During dehydration, renal water conservation responses are limited, and thirst mechanisms dominate in the maintenance of normal plasma osmolality.
REFERENCES 1. Adolph, E. F. Physiology of man in the desert. New York: Inter-
science; 1947. 2. Adolph, E. F. Regulation of water intake in relation to body water
3
4 5
9. 10.
11. 12. 13.
14.
15.
16.
content. In: Handbook of physiology, alimentary canal, food and water intake. sect. 6, vol. 1. Washington, DC: American Physiological Society; 1967:163-171. Anderson, C. R.; Houpt, T. R. Hypertonic and hypovolemic stimulation of thirst in pigs. Am. .I. Physiol. 258(Regul. Integr. Comp. Physiol. 27):Rl49-R154. Bellows, R. T. Time factors in water drinking in dogs. Am. J. Physiol. 125:87-97; 1939. Cowley, A. W.; Skelton, M. M.; Merrill, D. C. Osmoregulation during high salt intake: Relative importance of drinking and vasopressin secretion. Am. J. Physiol. 25l(Regul. Integr. Comp. Physiol. 20):R878-R886; 1986. Fitzsimons, J. T. The physiology of thirst and sodium appetite. Cambridge: Cambridge University Press; 1979. Fitzsimons, J. T.; LeMagnen, J. Eating as a regulatory control of drinking. J. Comp. Physiol. Psychol. 67:273-283; 1969. Gilman, A. The relation between blood osmotic pressure, fluid distribution and voluntary water intake. Am. J. Physiol. 120:323-328; 1937. Holmes, J. H.; Gregersen, M. I. Observations on drinking induced by hypertonic solutions. Am. J. Physiol. 162:326-337;1950. Houpt, T. R.; Anderson, C. R. Spontaneous drinking: Is it stimulated by hypertonicity or hypovolemia? Am. J. Physiol. 258(Regul. lntegr. Comp. Physiol. 27):Rl43-R148; 1990. Kraly, F. S. The physiology of drinking elicited by eating. Psychol. Rev. 91:478490; 1984. Luke, R. G. Natriuresis and chloruresis during hydropenia in the rat. Am. J. Physiol. 224:13-20; 1973. Maddison, S.; Wood, R. J.; Rolls, E. T.; Rolls B. J.; Gibbs, J. Drinking in the rhesus monkey: Peripheral factors. J. Comp. Physiol. Psychol. 94:365-374; 1980. McKinley, M. J.; Denton, D. A.; Nelson, J. F.; Weisinger, R. S. Dehydration induces sodium depletion in rats, rabbits and sheep. Am. J. Physiol. 245(Regul. Integr. Comp. Physiol. 14):R287-R292; 1983. McKinley, M. J.; Denton, D. A.; Park, R. C.; Weisinger, R. S. Cerebral involvement in dehydration induced natriuresis. Brain Res. 263:340-343; 1983. Phillips, P. A.; Rolls, B. J.; Ledingham, J. G. G.; Forling, M. L.; Morton, J. J. Osmotic thirst and vasopressin release in humans: A double blind crossover study. Am. J. Physiol. 248(Regul. Integr.
Comp. Physiol. 12):R6454650; 1985. 17. Ramsay, D. J.; Rolls, B. J.; Wood, R. J. Thirst following water deprivation in dogs. Am. J. Physiol 232(Regul. Integr. Comp. Physiol. l):R93-RlOO; 1977. 18. Ramsay, D. J.; Thrasher, T. N.; Bie, P. Endocrine components of body fluid homeostasis. Comp. Biochem. Physiol. 9OA:777-780; 1988. 19. Robertson, G. L. Abnormalities of thirst regulation. Kidney Int. 25: 4-69; 1984. 20. Robertson, G. L. Osmoregulation of thirst and vasopressin secretion: Functional properties and their relationship to water balance. In: Schrier, R., ed. Vasopressin. New York: Raven Press; 1985: 202-213. 21. Robertson, G. L.; Athar, S.; Shelton, R. L. Osmotic control of vasopressin function. In: Andocoli, T. E.; Grantham, J. J.; Rector, F. C., Jr., eds. Disturbances in body fluid osmolality. Bethesda: American Physiological Society; 1977: 1125-148. 22. Rolls, B. J.; Ramsay, D. J. The elevation of endogenous angiotensin and thirst in the dog. In: Peters, G.; Fitzsimons, J. T.; PetersHoepeli, L., eds. Control mechanisms of drinking. Berlin: Springer Verlag; 1975:74-78. 23. Rolls, B. J.; Wood, R. J.; Rools, E. J.; Lind, H.; Lind, R. W.; Ledingham, J. C. G. Thirst following water deprivation in humans. Am. J. Physiol. 239(Regul. Integr. Comp. Physiol. 8):R476-R482; 1980. 24. Thrasher, T. N.; Keil, L. C.; Ramsay, D. J. Altered responses to dehydration in dogs with lesions of the organum vasculosum laminae terminalis. Proceedings of the 29th International Congress of Physiological Sciences; 1983:49. 25. Thrasher, T. N.; Keil, L. C.; Ramsay, D. J. Drinking, oropharyngeal signals and inhibition of vasopressin secretion in dogs. Am. J. Physiol. 253(Regul. Integr. Comp. Physiol. 22):R5094515; 1987. 26. Thrasher, T. N.; Nistal-Herrera, J. F.; Keil, L. C.; Ramsay. D. J. Satiety and inhibition of vasopressin secretion after drinking ;n dogs. Am. J. Physiol. 240(Endocrinol. Metab. 3):E394-E401: 1981. 27. Thrasher, T. N.; Wade, C. E.; Keil, L. C.; Ramsay, d. J. Sodium balance and aldosterone during dehydration and rehydration in the dog. Am. J. Physiol. 247(Regul. Integr. Comp. Physiol. 16):R76R83; 1984. 28. Vemey, E. B. The antidiuretic hormone and the factors which determine its release. Proc. R. Sot. Lond. [Biol.] 135:25-106; 1947. 29. Wade, C. E.; Keil, L. C.; Ramsay, D. J. Role of volume and osmolality in the control of plasma vasopressin in dehydrated dogs. Neuroendocrinology 37:349-353; 1983.
