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Thirst has evolved for vertebrate terrestrial adaptation. We previously showed that buccal drying induced a series of drinking behaviours (migration to water-taking water into the mouth-swallowing) in the amphibious mudskipper goby, thereby discovering thirst in ray-finned fish. However, roles of dipsogenic/antidipsogenic hormones, which act on the thirst center in terrestrial tetrapods, have remained unclear in the mudskipper thirst. Here we examined the hormonal effects on the mudskipper drinking behaviours, particularly the antagonistic interaction between angiotensin II (AngII) and atrial natriuretic peptide (ANP) which is important for thirst regulation in mammalian 'forebrain'. Expectedly, intracerebroventricular injection of ANP in mudskippers reduced AngII-increased drinking rate. ANP also suppressed the neural activity at the 'hindbrain' region for the swallowing reflex, and the maintenance of buccopharyngeal water due to the swallowing inhibition may attenuate the motivation to move to water. Thus, the hormonal molecules involved in drinking regulation, as well as the influence of buccopharyngeal water, appear to be conserved in distantly related species to solve osmoregulatory problems, whereas hormonal control of thirst at the forebrain might have been acquired only in tetrapod lineage during evolution.

Estradiol (E2) plays an important role in controlling the homeostasis of body fluids. Several studies have reported the involvement of the hypothalamic pituitary adrenal axis (HPA) in the homeostatic control of hydromineral balance and the influence of estrogens on the modulation of this system. Nevertheless, until now, the physiological relevance of HPA axis activity on the hydromineral balance in females has not yet been fully elucidated. Therefore, the objective of the present study was to evaluate the effects of E2 (20 μg/animal) pretreatment on neuroendocrine and hydroelectrolyte changes induced by adrenalectomy (ADX) with or without glucocorticoid hormone replacement (corticosterone, CORT; 10 mg/kg) in ovariectomized rats (OVX). The results show that sodium appetite, natriuresis and the elevated plasma angiotensin II (ANG II) concentration induced by ADX were attenuated by E2 pretreatment. Additionally, a reduction of AT1 mRNA expression in the subfornical organ (SFO) and an increase in plasma atrial natriuretic peptide (ANP) concentrations by E2 pretreatment were observed. E2 pretreatment reversed the reduction in water intake induced by ADX in ADX CORT-replaced rats. Moreover, E2 pretreatment attenuated corticotropin releasing factor (CRF) mRNA expression in the paraventricular nucleus (PVN) induced by ADX. In contrast, E2 pretreatment increased CRF mRNA expression in the PVN in ADX CORT-replaced rats. Taken together, these results suggest that E2 has an important role in the modulation of behavioral and neuroendocrine responses involved in the maintenance of body fluid homeostasis in ADX rats with or without glucocorticoid replacement therapy.

Studies on how the body senses the need to correct extracellular and intracellular volumes and ionic concentration changes is relatively scanty. The present studies were designed to determine the effect of oral distilled water (DW) and saline loads, gargling with DW and DW preload on thirst perception (TP) and drinking in euhydrate and dehydrated subjects. The subjects were healthy male volunteers between the ages of 17 and 35 years. Group A subjects were given DW or various concentrations of sodium chloride [NaCl] orally. Subjects in groups B, C and D were dehydrated for 18 hours before the experiment. Group B gargled 500 ml of DW in divided volume of 50 ml at five minutes interval over a period of 50 minutes. Group C gargled with DW and different concentrations of NaCl. Group D were preloaded with four volumes of DW before ad libitum DW intake. TP was rated using the Visual Analogue Scale. Results showed that in Group A, drinking DW reduced TP, suggesting that baseline TP in normal euhydrate subjects is slightly elevated. Drinking DW reduced TP more than drinking NaCl solutions. Gargling resulted in a gradual fall in TP. The decrease in TP was statistically significant after 30 minutes of gargling. Gargling with different concentrations of NaCl solutions resulted in significant reductions in TP in all the groups. There was a significant decrease in TP in the group preloaded with 1000 ml of distilled water at 5 minutes of rehydration. At 20 minutes TP was abolished suggesting that approximately 1000 ml of water was needed for the rehydration. These results show that baseline TP in euhydrates is elevated and that TP increases in dehydrated subjects. Gargling reduces TP, but did not abolish thirst. It is suggested that a fall in plasma osmolality due to drinking may be responsible for abolishing thirst.

Neurons of the organum vasculosum of the lamina terminalis (OVLT) are necessary for thirst and vasopressin secretion during hypersmolality in rodents. Recent evidence suggests the osmosensitivity of these neurons is mediated by a gene product encoding the transient receptor potential vanilloid-1 (TRPV1) channel. The purpose of the present study was to determine whether mice lacking the TRPV1 channel had blunted thirst responses and central Fos activation to acute and chronic hyperosmotic stimuli. Surprisingly, TRPV1-/- vs. wild-type mice ingested similar amounts of water after injection (0.5 ml sc) of 0.5 M NaCl and 1.0 M NaCl. Chronic increases in plasma osmolality produced by overnight water deprivation or sole access to a 2% NaCl solution for 48 h produced similar increases in water intake between wild-type and TRPV1-/- mice. There were no differences in cumulative water intakes in response to hypovolemia or isoproterenol. In addition, the number of Fos-positive cells along the lamina terminalis, including the OVLT, as well as the supraoptic nucleus and hypothalamic paraventricular nucleus, was similar between wild-type and TRPV1-/- mice after both acute and chronic osmotic stimulation. These findings indicate that TRPV1 channels are not necessary for osmotically driven thirst or central Fos activation, and thereby suggest that TRPV1 channels are not the primary ion channels that permit the brain to detect changes in plasma sodium concentration or osmolality.

It has been suggested that while the sialogogue pilocarpine elicits salivary secretion by acting directly on acinar cells of the salivary glands, it induces drinking behavior by acting on muscarinic receptors in the central nervous system. To study which brain regions are affected by the peripherally injected pilocarpine, we investigated changes in the numbers of c-Fos immunoreactive cells. The injections increased the numbers of c-Fos immunoreactive cells in the subfornical organ, median nucleus of preoptic area, organum vasculosum of lamina terminalis, paraventricular nucleus and supraoptic nucleus. Intracerebroventricular injection of pilocarpine produced similar changes in the expression of c-Fos immunoreactivity. The increases in immunoreactive expression induced by both the intraperitoneally and intracerebroventricularly injected pilocarpine were suppressed by previous intracerebroventricular injection of the muscarinic receptor antagonist atropine. Electrophysiological experiments using slice preparations and whole cell recordings showed that pilocarpine depolarized the membrane of neurons in the subfornical organ and suppressed the inhibitory GABAergic synaptic currents by a presynaptic action. The results suggest that peripherally applied pilocarpine does not act only on the salivary glands as a sialogogue, but also evokes thirst sensation by acting on the center controlling body fluid balance in the central nervous system.

Obestatin, a product of post-translational processing of the ghrelin prohormone, has been reported to act in the brain to inhibit thirst. We extended our initial studies on water drinking by examining the effects of obestatin on hypovolemia-induced water and saline drinking and vasopressin release in male rats. Intracerebroventricular administration of obestatin significantly inhibited water, but not saline (0.3 M NaCl) drinking in response to a hypovolemic challenge. Obestatin also inhibited, in a dose-related fashion, dehydration-induced vasopressin secretion without affecting plasma oxytocin levels. Vasopressin release induced by central angiotensin II administration was attenuated significantly by prior administration of obestatin. Finally, central administration of an antiserum specific to obestatin resulted in an exaggerated basal vasopressin release and an increased vasopressin response to overnight water deprivation. Antiserum treatment also resulted in significantly increased ad libitum water drinking and drinking in response to dehydration. We conclude that this product of post-translational processing of the ghrelin prohormone may be an important contributor to the physiologic regulation of fluid and electrolyte homeostasis.

Microdialysis was employed to investigate whether N-methyl-d-asparatate (NMDA) glutamate receptor mechanisms are involved in the modulation of serotonin (5-hydoxytryptamine, 5-HT) release in the region of the lateral parabrachial nucleus (LPBN) in freely moving rats. Perfusion of NMDA (10 and 50 microM) through the microdialysis probe significantly enhanced extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the LPBN area. Local perfusion of the NMDA antagonist dizocilpine (MK801, 10 and 50 microM) did not change the basal 5-HT and 5-HIAA levels in the LPBN area. MK801 (10 microM) administered together with NMDA antagonized the stimulant effect of NMDA (10 microM). The intake of 0.3M NaCl and water induced by subcutaneous injections of the diuretic furosemide (FURO, 10 mg/kg) and the angiotensin converting enzyme inhibitor captopril (CAP, 5 mg/kg) produced significant increases in the 5-HT and 5-HIAA concentrations in the LPBN area. The increased levels of 5-HT and 5-HIAA caused by the combined treatment with FURO and CAP were attenuated by perfusion of MK801 (10 microM). These results indicate the participation of NMDA receptors in the control of 5-HT release in the LPBN area.

Water balance depends essentially on fluid intake and urine excretion. Mild dehydration and the consequent hypertonicity of the extracellular fluid induce an increase in vasopressin secretion, thus stimulating urine concentrating processes and the feeling of thirst. The osmotic threshold for the release of vasopressin is lower than that for thirst and also shows appreciable individual variation. Sustained high levels of vasopressin and low hydration induce morphological and functional changes in the kidney. However, they could also be risk factors in several renal disorders, such as chronic renal failure, diabetic nephropathy and salt-sensitive hypertension.

Both osmoreception and baroreception are thought to involve ion channels that are sensitive to changes in membrane stretch. We investigated the effect of a blocker of stretch-activated ion channels, the Gd3+ ion, on osmoregulatory and cardiovascular responses in the intact rat. Intracerebroventricular injection of 50-100 nmol Gd3+ reduced thirst induced by various treatments. Similar doses also reduced intake of saline induced by various treatments. Intracerebroventricular injection of 100 nmol Gd3+ transiently increased arterial pressure and reduced the pressor response to intracerebroventricular angiotensin II (Ang II). Systemic administration of Gd3+ failed to alter thirst, except for a high dose (270 micromol/kg) that induced illness. This high dose failed to prevent urinary hypertonicity and excretion of a load of hypertonic NaCl. Intravenous infusion of 270 micromol/kg of Gd3+ reduced blood pressure and pressure responses to intravenous phenylephrine, but did not reduce the baroreceptor reflex control of heart rate. We conclude that the effects of Gd3+ on thirst and on the cardiovascular system are probably not due to a direct effect of the drug on stretch-sensitive ion channels. Instead, many of the effects of Gd3+ were compatible with blockade of voltage-gated Ca2+ channels.

Serotonin antagonism in the lateral parabrachial nucleus (LPBN) enhances sodium appetite induced by hypovolaemia and angiotensin-mineralocorticoid activation, but produces no sodium intake in euhydrated animals. In the present work, male adult rats (n=21) that received bilateral injections of the serotonergic antagonist methysergide (4 microg/0.2 microl) into the LPBN combined to intragastric load of 2 M NaCl (2 ml/rat), ingested hypertonic NaCl (ingestion of 4.3 +/- 1.6 ml/2 h of 0.3 M NaCl versus vehicle into LPBN: 0.2 +/- 0.2 ml/2 h, P<0.05). Methysergide- and vehicle-treated animals also ingested water (9.5 +/- 0.7 and 7.2+/-0.5 ml/2 h, respectively, P>0.05) as expected from the state of cell dehydration produced by the load. Ingestion of water (11.0 +/- 1.2 ml/2 h), and of 0.3 M NaCl (1.1 +/- 0.7 ml/2 h) were not altered by methysergide in NaCl loaded rats with misplaced LPBN injections (n=15).The ingestion of hypertonic NaCl by rats with serotonergic blockade in the LPBN suggests that the circuits subserving sodium appetite are activated, but at the same time strongly inhibited through the LPBN, during cell dehydration.

Volume overload is a chronic, troublesome problem in many patients on hemodialysis. These patients suffer from hyperdipsia with inability to excrete water. Angiotensin-converting enzyme inhibitor (ACEI) has been shown to decrease thirst and interdialytic weight gain in 2-4 weeks of usage. We investigated the effect of long-term use of ACEI, as levels of angiotensin II tends to go back to normal level after 6 months of use. We compared hemodialysis patients on ACEI for more than 6 months to patients not on ACEI. Seven patients were taking ACEI compared to 51 controls in the other group. Almost one third of patients in each group had an interdialytic weight gain > 5% of dry weight. No significant difference was found between the two groups with regard to interdialytic weight gain, thirst and mouth dryness scores, and interdialytic mean blood pressure change. There was no demonstrable effect of angiotensin receptor blocking drugs on weight gain or thirst. We conclude that long-term ACEI may not continue to suppress inappropriate thirst and fluid intake after 6 months in hemodialysis patients.

To test the hypothesis that progesterone, independent of estrogen, decreases the plasma osmotic threshold for arginine vasopressin (AVP) release and thirst onset, we compared AVP and thirst responses to hypertonic saline infusion (HSI) during administration of oral contraceptives (OCs) containing progesterone (OCP) with responses to infusion of OCs containing progesterone and estrogen (OCEP). Eight women (29 +/- 2 yr) were infused with 3% NaCl (120 min, 0.1 ml. kg body wt(-1). min(-1)) and consumed fluid (90 min, 15 ml/kg body wt) in the early follicular and midluteal phases of a 28-day menstrual cycle and also after 4 wk of OCP and after 4 wk of OCEP in a randomized crossover design. Baseline plasma osmolality (P(osm)) was lower in the luteal phase (280 +/- 1 mosmol/kgH(2)O) and during OCEP (283 +/- 1 mosmol/kgH(2)O) than in the follicular phase (286 +/- 1 mosmol/kgH(2)O, P < 0.05) but was unaffected by OCP (284 +/- 1 mosmol/kgH(2)O). P(osm) remained lower in the follicular phase than in the luteal phase and with OCEP throughout the first 50 min of HSI. The mean abscissal plasma AVP concentration-P(osm) intercept was unaffected by OCP (267 +/- 1 mosmol/kgH(2)O) but was greater in the follicular phase (273 +/- 2 mosmol/kgH(2)O) than in the luteal phase (266 +/- 4 mosmol/kgH(2)O) and with OCEP (268 +/- 2 mosmol/kgH(2)O, P < 0.05). There were no differences in osmotic thresholds for thirst onset across experimental days. Despite the lower osmotic threshold for AVP release during the luteal phase and with OCEP, fluid balance, renal free water clearance, and Na(+) regulation during HSI were unaffected by menstrual phase or OC treatment, indicating a lower osmotic operating point for body water balance. OCP did not affect osmotic AVP regulation, suggesting that progesterone does not affect osmotic fluid regulation through a mechanism independent of estrogen.

To assess the fluid regulatory responses in aging adults, we measured thirst perception and osmoregulation during and after infusion of hypertonic NaCl) saline in older (72 +/- 2 yr, n = 6) and younger (26 +/- n = 6) subjects. Hypertonic saline was infused at 0.1 min-1.kg-1 for 120 min. On a separate day, the same subjects were infused identically with isotonic saline as a control. After infusion and a 30-min equilibration period, the drank water ad libitum for 180 min. Hypertonic infusion led to graded increases in plasma osmolality (Posm; 18 +/- 2 and 20 +/- 2 mosmol/kgH2O) and percent changes plasma volume (16.2 +/- 1.9 and 18.0 +/- 1.2%) that were in older and younger subjects. Osmotically stimulated increases in thirst (94.8 +/- 18.9 and 88.3 +/- 25.6 mm), assessed on a line rating scale, and plasma arginine vasopressin concentration (6.08 +/- 1.50 and 4.51 +/- 1.37 pg/ml, for older younger, respectively) were also unaffected by age. subsequent hypervolemia, both groups of subjects sufficient water to restore preinfusion levels of Posm. Renal handling of free water and sodium was also unaffected by age during recovery from hypertonic saline infusion, but was significantly lower in older subjects during recovery from saline infusion, resulting in net fluid retention and a significant fall in Posm (6 mosmol/kgH2O). In contrast to earlier reports of a blunted thirst response to dehydration hypertonicity, we found that osmotically stimulated thirst and renal osmoregulation were intact in older adults after hypertonic saline infusion.

To investigate whether angiotensin-converting enzyme inhibitor (ACE-I) potentially alleviates hyperdipsia, the effect of cilazapril on dialysis-associated excessive thirst was studied by evaluating various dipsogenic parameters in patients undergoing chronic hemodialysis (HD) who manifest an excessive interdialysis body weight gain of more than 5%, and show simultaneous severe-to-moderate hyperdipsia. An initial single dose of 1 mg of cilazapril given at the end of the HD session produced a marked improvement in the interdialysis thirst scores and a simultaneous reduction in plasma angiotensin II (AII) concentration due to the inhibition of ACE activity. The interdialysis body weight gain in the cilazapril treatment period was significantly smaller than that in the nontreatment period. None of the other parameters including blood pressure, plasma osmolarity, and serum Na and K concentration were different in the treatment vs. the nontreatment period. The present data help to explain the potential pharmacological action of AII in the physiology of thirst and suggest that cilazapril may effectively alleviate dialysis-associated hyperdipsia at least on some occasions. The mechanism by which ACE-I exerts an antidipsogenic action may, in part, be accounted for by the reduction in plasma concentration of AII, as a result of the ACE inhibition.

Angiotensin II (A-II), a potent inducer of thirst-related behavior in many vertebrate species, was injected into the third ventricle of the brain of the spadefoot toad, Scaphiopus couchii. Following injection of 10 ng A-II the animals demonstrated a significant increase in water absorption response (WR) behavior, in which toads press their ventral skin to a moist surface and absorb water by osmosis. This increase in the frequency of WR behavior was positively correlated with an increase in water gain during a 2-hr period indicating that centrally injected A-II stimulates water intake by this amphibian species. We have previously demonstrated that WR behavior is also induced by intraperitoneal (i.p.) injections of A-II in several anuran species, including S. couchii. Thus, amphibians, like other vertebrates, demonstrate an increase in water intake in response to either centrally administered or circulating A-II. A second series of experiments was conducted to determine whether the above response to A-II might be secondary to increases in the circulating levels of aldosterone (ALDO) or antidiuretic hormone because the release of both of these hormones has been shown by others to be stimulated by A-II. Scaphiopus couchii injected i.p. with either ALDO or arginine vasotocin in dosages of 1, 10, and 100 micrograms/100 g body weight showed no increase in WR behavior relative to toads injected with saline alone. These results suggest that A-II acts directly on the brain of S. couchii to induce WR behavior.

Changes in water intake after intraperitoneal injection of a nitric oxide synthase (NOS) inhibitor was studied in the rat. Administration of NW-nitro-L arginine methyl ester (L-NAME) at a dose of 50 mg/kg attenuated osmotic thirst induced by intraperitoneal injection of hypertonic saline, but did not affect spontaneous intake of water and thirst induced by subcutaneous injection of angiotension II. Pretreatment with L-arginine significantly attenuated the inhibition of osmotic thirst evoked with subsequent L-NAME. Administration of NW-nitro-D-arginine methyl ester (D-NAME) altered neither the spontaneous nor the osmotic drinking behavior. These findings suggest that NO may affect the osmotically induced drinking.

Desalivate rats consumed significantly less water than sham-operated rats in response to acute challenges with a variety of dipsogens, including polyethylene glycol (PEG), isoproterenol, serotonin, and an angiotensin I converting enzyme inhibitor (CEI). Nonsignificant reductions were recorded after treatments with either angiotensin II or hypertonic NaCl. Meal-related hyperdipsia, and resultant possible hyperhydration, of desalivate rats does not account fully for these reductions in experimental thirsts. The mean 24-h intake of three concentrations of NaCl, in choice with water, showed no difference in the preferences for NaCl of desalivate and sham-operated animals. During chronic administration of CEIs, both desalivate and sham-operated rats showed comparable induction of NaCl appetite.

Objective: Osmoregulation is normally studied using a 5% saline infusion. This may be deleterious in fluid overloaded patients. Twenty per cent mannitol is another osmotic stimulant. This study aimed to compare 20% mannitol infusion with 5% saline as an osmotic stimulant to thirst and vasopressin secretion in normal volunteers., Design and Patients: Eight healthy volunteers studied on 2 occasions in random order. Each study involved a 2-hour infusion period of either hypertonic (5%) saline (0.06 ml/kg/h) or hypertonic (20%) mannitol (0.07 ml/kg/h)., Measurements: Plasma vasopressin (pVp), plasma sodium, plasma osmolality (pOsm), haematocrit (HCT), blood pressure, thirst, blood glucose and volume drunk at end of infusion., Results: Five per cent saline infusion stimulated significantly higher levels of pOsm, pVp and thirst than 20% mannitol. Plasma sodium rose significantly during 5% saline infusion and fell during 20% mannitol infusion. HCT fell and mean arterial pressure rose in both infusions but the changes were not clinically significant. Piecewise linear regression analysis defined the overall threshold for pVp release for the two solutions as 5% saline, 292 mosm/kg and 20% mannitol, 291 mosm/kg, and the post threshold slope as 5% saline, 0.46 pmol/l pVp per mosm and 20% mannitol, 0.30 pmol/l pVp per mosm. The threshold for thirst onset was 5% saline, 291 mosm/kg and 20% mannitol, 290 mosm/kg, and the post threshold slope, 5% saline, 0.58 cm thirst per mosm and 20% mannitol, 0.28 cm thirst per mosm. The differences between the calculated osmotic thresholds and slopes post threshold for the two infusions were not significant for the pVp versus pOsm relationship. The difference between the cumulative volume drunk following the two infusions did not reach statistical significance. Mannitol caused a significant diuresis., Conclusions: Twenty per cent mannitol infusion is an effective osmotic stimulant to thirst and vasopressin release in normal individuals, but is less potent than 5% saline infusion.

In the present paper, the acute effect of third ventricle injections of lead acetate (5, 10, 100, 1000 ng/rat) on the drinking behavior of adult, male, Wistar rats was investigated. Lead generates a prompt and significant reduction in water intake induced by three different circumstances: dehydration (14 h of water deprivation) and after carbachol (2 micrograms/rat, ICV) or angiotensin II (10 ng/rat, ICV) administration. These results show that lead may produce very fast actions in the central nervous system and suggest that inhibition of water intake by lead may depend on impairment of central cholinergic and/or angiotensinergic functions.

Previous research on the ontogeny of sodium appetite in the rat has shown that sodium deficit first engenders sodium intake at 12 days of age, whereas direct stimulation of the brain renin--angiotensin system by intracranial injection of renin increases intake of NaCl solution as early as 3 days postnatally. Similar activation of brain angiotensin also increases thirst, so that the specificity of the precocious sodium intake remains undetermined. In this article we report experiments that dissociate neonatal renin-evoked sodium appetite and thirst, and establish the specificity of the appetite. Our findings confirm that sodium appetite can first be discerned at 3 days of age, and show that it rapidly develops until 12 days of age. During this developmental window, renin-evoked sodium appetite is dissociated from thirst because (a) NaCl is preferred to water, (b) the appetite develops faster than thirst, and (c) 3-day-old renin-stimulated pups will avidly lick dry NaCl. These results show that activation of brain angiotensin in the 3-day-old rat pup evokes a precocious and specific sodium appetite.

The octapeptide, angiotensin II (A-II), induces drinking behavior in several vertebrate species; however, relatively little is understood about A-II-induced thirst in amphibians. Scaphiopus couchii and Bufo cognatus were dehydrated to 90% of their ad libitum weight. This level of dehydration was sufficient to induce water absorption response (WR) behavior in both species. Fully hydrated toads injected intraperitoneally with A-II exhibited a significant amount of WR behavior. The minimum effective dose for inducing WR behavior was 10 micrograms/100 g-animal for S. couchii and 100 micrograms/100 g-animal for B. cognatus. When dehydrated toads were treated with the A-II receptor antagonist, Thr8-saralasin, S. couchii, exhibited a significant increase in WR behavior, while B. cognatus did not respond behaviorally. Finally, treatment of dehydrated toads with captopril, a compound that inhibits conversion of angiotensin I to A-II, did not significantly affect WR behavior in either species. These results support other findings that A-II may be involved in WR behavior in amphibians. However, the failure of Thr2-saralasin or captopril to inhibit WR behavior in dehydrated toads suggests that the receptor mechanisms involved in thirst regulation in toads may be different from those in mammals, and the renin-angiotensin system may not be the only potential mediator of WR behavior in these species.

Earlier studies in rabbits revealed that in this species, in contrast to most other species studied, water intake was not influenced by injection or infusion of angiotensin II (ANG II). In order to establish whether ANG II has any role in the regulation of water intake of rabbits, a comprehensive study of the effect of converting enzyme inhibition was undertaken. Enalaprilat was given systemically in various doses to sodium- and water-replete, sodium-deplete, and water-deprived rabbits, and the intake and excretion of water and sodium was measured. In replete rabbits systemic injection of enalaprilat, 8 mg/kg and 8 micrograms/kg, but not 0.8 mg/kg, was followed by increased daily water intake. In sodium-deplete rabbits injection of enalaprilat, 80 mg/kg, was followed by water drinking within 1 h, and daily sodium intake was reduced. Systemic administration of ANG II increased, but did not restore to control level the sodium appetite of sodium-deplete rabbits attenuated by 80 mg/kg enalaprilat. Rabbits deprived of water for 24 h, however, drank the same amount of water after injection of vehicle or enalaprilat, 80 and 8 mg/kg. The efficacy of converting enzyme inhibition was also tested by measuring the blood pressure response to ANG I. Blood pressure responses revealed that in replete animals converting enzyme activity was depressed below control levels for 30 h after injection of 80 mg/kg enalaprilat. In sodium-deplete rabbits blood pressure fell following injection of 80 mg/kg enalaprilat and did not return to control level until 48 h after the injection.(ABSTRACT TRUNCATED AT 250 WORDS)

This study simultaneously evaluated multiple circulating neurohormones, osmolality, thirst, and fluid balance in eight actively drinking, alcoholic males and seven controls before and 12 hr after an ethanol challenge. Basal levels of serum osmolality and thirst were significantly higher in alcoholics compared with controls, yet actively drinking alcoholics at the start of the study had normal vasopressin (AVP) levels, plasma angiotensin II (Ang II), plasma renin activity, plasma aldosterone (Aldo), and plasma catecholamines. In response to ethanol, serum osmolalities rose significantly higher while plasma AVP levels became significantly suppressed in alcoholics. After the ethanol stimulus, plasma Ang II levels of alcoholics were significantly higher than those of controls at 11 AM (12.15 +/- 4.49 vs. 1.83 +/- 0.6 pg/ml, p less than 0.02) and 12 noon (14.93 +/- 6.81 vs. 1.37 +/- 0.17 pg/ml, p less than 0.04). Neither plasma renin activity nor Aldo changed in accordance with the elevated plasma Ang II in alcoholics. Diuresis in the alcoholics, assessed by the sum of urine output following the challenge dose, was significantly less than that of controls. Thirst scores and fluid intakes after the ethanol challenge did not differ between alcoholics and controls. The lack of an Ang II-mediated increase in plasma Aldo or thirst response suggests that ethanol may have a specific blunting effect on Ang II receptors. This study demonstrates that ethanol can be used as a provocative test in chronic alcoholics to uncover aberrant hormonal responses for two systems, namely, Ang II and AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

We report the case of a young man who became adipsic following a subarachnoid hemorrhage and subsequently had two episodes of life-threatening hypernatremia. Investigations demonstrated that he had defective osmoregulated thirst and AVP release, but normal AVP responses to hypotension and nausea. There is also evidence that he had intact baroregulated thirst. We discuss the results of our investigations in the context of current models of hypothalamic-neurohypophysial function.

It is known that intraperitoneally (IP) injected adrenaline (A) inhibits food intake in otherwise hungry animals. In a recent work, Hinton et al. (6) showed that IP A also inhibits water intake in thirsty rats, concluding that A's effect is unspecific. We administered A IP or intramuscularly (IM) in different doses in rats made thirsty either by 18-h water deprivation or by subcutaneous injection of hypertonic saline or polyethylene glycol. IP A reduced water intake in all experimental conditions. A dose-related inhibition was observed in water-deprived animals. On the other hand, IM A showed a small effect only at the highest dose (50 micrograms/100 g body weight). When some of these experiments were repeated using noradrenaline (NA) and isoproterenol (IS), IM administration of either substance showed no effect. IP administration reduced water intake significantly only at the highest dose of NA (50 micrograms/100 g). It is concluded that water intake inhibition by catecholamines in rats made thirsty either by osmotic or by volumetric challenges is of porto-hepatic origin and, in contrast with food intake inhibition, has no beta-adrenergic component.

The emergence of the rat's ability to respond behaviorally to a bodily sodium deficit was examined. Sucklings were depleted of bodily sodium by furosemide injections and their ability to replenish sodium by imbibing 3% NaCl solution was measured at different ages. The results suggest that the appetite for salt, as a response to sodium deficit, matures at weaning age.

Three experiments tested whether the subfornical organ (SFO) could be a site of action for the antidipsogenic effects of atrial natriuretic peptide (ANP) in rats. Pretreatment with 100, 230, or 500 pmol ANP in the SFO reduced drinking induced by 10 pmol angiotensin II in the SFO. Drinking in response to water deprivation was reduced by ANP in rats having cannulas in or near the SFO, but not in rats having cannulas distant from the SFO or in the ventricles. Finally, ANP had no effect on eating or drinking after food deprivation, suggesting that the rats in the other experiments were not acutely incapacitated. The SFO may mediate the central effects of ANP on drinking induced by angiotensin or in response to water deprivation and could play a similar role in the central effects of ANP on salt appetite, diuresis, vasopressin secretion, and blood pressure.

Various hypertonic solutions were infused in healthy human volunteers to determine their effect on thirst and vasopressin secretion. Hypertonic saline and mannitol produced prompt and parallel increases in plasma osmolality and vasopressin concentration. For both of these solutes, there was a high degree of correlation between these measurements. The slope describing this relationship varied considerably between individuals, but the same subjects showed similar slopes with either saline or mannitol. Both solutions stimulated thirst. Hypertonic urea infusions produced a comparable rise in osmolality but produced a smaller increase in plasma vasopressin and stimulated thirst in only one of the subjects. With urea, the correlation between plasma osmolality and vasopressin was significantly lower. Within individuals, the slope describing this relationship was significantly correlated with that seen during hypertonic saline. Hypertonic glucose significantly increased plasma osmolality but decreased plasma vasopressin and had no detectable effect on thirst. We conclude that osmoregulation of vasopressin in humans is mediated by a selective osmoreceptor that is located primarily outside of the blood-brain barrier and that individual differences in osmoregulatory sensitivity are not solute specific.

1. Osmotically stimulated thirst and vasopressin release were studied during infusions of hypertonic sodium chloride and hypertonic D-glucose in euglycaemic clamped diabetic patients and healthy controls. 2. Infusion of hypertonic sodium chloride caused similar elevations of plasma osmolality in diabetic patients (288.0 +/- 1.0 to 304.1 +/- 1.6 mosmol/kg, mean +/- SEM, P less than 0.001) and controls (288.6 +/- 0.9 to 305.7 +/- 0.6 mosmol/kg, P less than 0.001), accompanied by progressive increases in plasma vasopressin (diabetic patients, 0.9 +/- 0.3 to 7.7 +/- 1.5 pmol/l, P less than 0.001; controls 0.5 +/- 0.1 to 6.5 +/- 1.0 pmol/l, P less than 0.001) and thirst ratings (diabetic patients 1.0 +/- 0.2 to 7.1 +/- 0.5 cm, P less than 0.001; controls 1.8 +/- 0.4 to 8.0 +/- 0.5 cm, P less than 0.001) in both groups. 3. Drinking rapidly abolished thirst and vasopressin secretion before major changes in plasma osmolality occurred in both diabetic patients and healthy controls. 4. There were close and significant correlations between plasma vasopressin and plasma osmolality (diabetic patients, r = +0.89, controls r = +0.93) and between thirst and plasma osmolality (diabetic patients r = +0.95, controls r = +0.97) in both diabetic patients and healthy controls during hypertonic saline infusion. 5. Hypertonic D-glucose infusion caused similar elevations in blood glucose in diabetic patients (4.0 +/- 0.2 to 20.1 +/- 1.2 mmol/l, P less than 0.001) and healthy controls (4.3 +/- 0.1 to 19.3 +/- 1.2 mmol/l, P less than 0.001) but did not change plasma vasopressin or thirst ratings.(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction between lithium+ and water balance was studied in nine patients suffering manic-depressive trouble. Nephrogenic diabetes insipidus with polyuria and polydipsia was induced by Li+ in one case only. No trouble was apparent in eight cases. However, the applied method of investigation by lacking, and next, excess of water, vasopressin and ADH tests, measurements of urinary osmolarity and clearances, showed up a trouble of concentration in four cases, improved by ADH. The Li+ frequently (50%) induces a trouble of urinary concentration, without polyuria; it is brought to light only by biological investigations. Its origin is double, nephrogenic, which is the most important, and central by a pituitary component. In the other hand, the change in water metabolism, studied by the same tests, showed us a decrease of the clearance Li+ after lacking of water (deshydratation), and an increase after water surcharge. That result is not concordant, chiefly in regards to the water surcharge, with former experiments. It appears that our method (division by horary periods for measurement of clearance, study of circadian cycle of urinary Li+) permits some observations more precise than global gathering and measurement of clearances. That method also allows to make evident a circadian cycle of renal clearance of Li+, according to, for some part, with the renal movement of water. That remark would also have some consequence on lithium-therapy practice.

Serial studies were designed to characterized changes in osmoregulation throughout gestation. Eight women underwent a 2-h infusion of hypertonic saline before conception, during gestational weeks 5-8, 10-12, and 28-33, and then 10-12 wk postpartum. Basal plasma osmolality (Posmol) was already significantly decreased by 5-8 wk (P less than 0.001) and remained 10 mosmol.kg-1 below nonpregnant values throughout pregnancy. The apparent threshold for AVP release (defined as the abscissal intercept of the regression line relating plasma AVP [PAVP] to Posmol) was also decreased significantly throughout gestation, as was the osmotic threshold for thirst (derived from analogue scales relating desire to drink to Posmol). The decrement in osmotic thirst threshold appeared to precede that for AVP release, and consistent with this 24-h urine volumes were significantly greater at 5-8 wk gestation (P less than 0.05). The slopes of each regression equation defining PAVP vs. Posmol (whose r values ranged from 0.79 to 0.99), very reproducible before and after pregnancy, were similar at 5-8 and 10-12 wk, but were markedly reduced in the third trimester (P less than 0.001). These volunteers had randomly undergone an additional infusion before conception (both tests in the luteal phase of the menstrual cycle) when 10,000 IU of human chorionic gonadotrophin (hCG) had been given intramuscularly over a 5-d period. Serum hCG values between 0.2 and 3.3 U.ml-1 were lower than usually seen in pregnancy, but the osmotic thresholds for AVP release and thirst decreased by 3 and 4 mosmol.kg-1, respectively (P less than 0.05). Finally we studied a patient with a molar pregnancy in whom thresholds for hormone release and thirst were both decreased to values resembling normal gestation and remained so for approximately 6 wk postevacuation, only normalizing when hCG had virtually disappeared from her serum. In contrast, thresholds increased within the first two puerperal weeks in two women with normal pregnancies. These data demonstrate (a) osmotic thresholds for both AVP release and thirst decrease within the very first gestational weeks; (b) increment in PAVP per unit increase in Posmol is reduced late in gestation; and (c) hCG may be involved in the osmoregulatory changes of pregnancy.

The aim of this study was to investigate if atrial natriuretic peptide (ANP) plays a role in the control of water balance in goats and whether ANP affects the increase in mean arterial blood pressure (MAP) which accompanies drinking in water-deprived animals. Bilateral intracarotid infusions were made in female adult goats deprived of water for 48 h. ANP (1.5 micrograms min-1, n = 5, or 4.75 micrograms min-1, n = 5) was infused for 40 min. In control experiments isotonic saline (n = 7) was infused. The goats got access to water 35 min after the start of the infusions. During saline infusions they drank 2.9 +/- 0.4 litres, during the low dose of ANP 1.9 +/- 0.6 litres (n.s. vs saline), and during the high dose of ANP 0.6 +/- 0.2 litres (P less than 0.01 vs saline). Plasma vasopressin concentration did not change during saline infusions until after drinking, when it decreased. The vasopressin concentration increased in one goat after infusion of the low dose of ANP and in two goats after the high dose of ANP. The low dose of ANP caused no change in MAP in four goats, but MAP dropped in the one in which vasopressin concentration increased. MAP fell in all goats infused with the high dose (P less than 0.01), with the largest changes occurring in animals showing increased vasopressin concentration. During the act of drinking a temporary increase of MAP was observed when saline or the low dose of ANP was infused, but this response was attenuated during infusions of the high dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Subcutaneous injection of polyethylene glycol (PEG) solution produced a progressive sequestration of extracellular fluid at the injection site. Appropriately, PEG-treated rats showed both thirst and sodium appetite. However, water intake began within 1 to 2 hr after the injections, whereas consumption of NaCl solution did not start until 3-4 hr later. Then rats ingested both fluids alternately until plasma volumes were restored, whereupon saline intake became even more prominent while water was consumed due to induced osmoregulatory needs. These three phases were seen regardless of the dose of PEG that was administered or the concentration of saline that was available. In contrast, after maintenance on a sodium-deficient diet for 2-4 days, or after bilateral adrenalectomy, rats increased their intake of saline immediately after PEG treatment. These and other findings suggest that the delayed onset of sodium appetite after PEG treatment that occurs when rats are maintained on standard sodium-rich chow results from the buffer provided by surplus extracellular fluid in those animals. They further suggest that sodium appetite is not directly associated with decreases in plasma volume or sodium concentration but instead may be stimulated by decreased availability of sodium in the brain.

The effect of intravenous infusion of hypertonic NaCl at three different rates (series I, 4.0 mmol/min; series II, 8.0 mmol/min; series III, 16.0 mmol/min) on osmotic thirst threshold and postloading restitution of plasma osmolality (Posm) has been determined in dogs. Osmotic thirst threshold increased proportionally to the rate of delivery of the osmotic load. Relative suppression of osmotic thirst at the higher rates of infusion was temporary and largely disappeared within 10 min after the end of hypertonic infusion. During the postloading period excretion of osmotic load and water intake was proportional to the magnitude of the load administered. However, the animals with high osmotic thirst threshold stopped drinking at a higher Posm than those with a low osmotic thirst threshold. In series I and II, Posm decreased during 1 h to a level not significantly different from the preloading value. In each series renal excretion of osmotic load was more important than water intake for restitution of Posm during 1 h. Amount of water ingested during this period was significantly smaller than that theoretically required to restore resting Posm when excretion of osmotic load was not taken into account. However, total amount of water intake and osmotic load excreted during 1 h were together well adjusted to restore preloading Posm.

The effects of self-administered iv infusion of hypertonic NaCl, mannitol, glucose, urea, or isotonic NaCl on Na appetite were studied. Sodium-depleted sheep were trained to bar press in order to replace Na deficits of 300-500 mmol. During basal conditions, each delivery to a drinking cup was 15 ml of .6 M NaHCO3 (9 mmol). In the experimental situation, an iv infusion (10 ml) was given automatically with each delivery to the drinking cup. The ingestion of NaHCO3 solution was significantly reduced by all of the hypertonic solutions, the largest decrease being caused by hypertonic NaCl or mannitol. The decreased intake was observed within 10 (with infusion of hypertonic NaCl, mannitol, or glucose) or 20-40 (with urea infusion) min irrespective of whether water was concurrently available to drink. At 20 min, plasma Na concentration was increased by hypertonic NaCl, decreased by mannitol or glucose, and not changed by urea. Cerebrospinal fluid (CSF) Na concentration was increased by all of the hypertonic solutions. Isotonic NaCl had no effect on the ingestion of NaHCO3 solution, plasma, or CSF composition. In regard to the "turn-off" of Na appetite by systemic infusion, these data are consistent with the theory of neural cells within the blood-brain barrier responsive to changes of Na concentration or osmolality in their environment. In contrast, water intake was stimulated by hypertonic NaCl or mannitol but not by urea or glucose, results suggestive that the sensors involved in thirst (e.g., osmoreceptors) are in an area of the brain lacking the blood-brain barrier.