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The synergy between ANG II and aldosterone (Aldo) in the induction of salt appetite, extensively studied in rats, has been tested in baboons. ANG II was infused intracerebroventricularly at 0.5 or 1.0 microg/h; Aldo was infused subcutaneously at 20 microg/h. Separate infusions over 7 days had no significant effect on the daily intake of 300 mM NaCl. Concurrent infusions, however, increased daily NaCl intake approximately 10-fold and daily water intake approximately 2.5-fold. In addition, the combined infusions caused 1) a reduction in daily food intake, 2) changes in blood composition indicative of increased vasopressin release, and 3) changes of urinary excretion rates of cortisol and Aldo indicative of increased ACTH release. Arterial blood pressure, measured in two baboons, rose during concurrent ANG II and Aldo treatment. These results indicate a potent synergy between central ANG II and peripheral Aldo in stimulating salt appetite in baboons. At the same time, other ANG II-specific brain mechanisms concerned with water intake, food intake, vasopressin release, ACTH release, and blood pressure regulation appear to have been activated by the same type of synergy. These central enhancement processes have never been previously demonstrated in primates.

Stress is a large stimulus of Na appetite in rabbits, rats, and mice. This study investigated the influence of some peptides implicated in stress, i.e., adrenocorticotropin (ACTH), corticotropin-releasing factor (CRF), and the recently discovered member of the CRF family, urocortin, on the ingestive behavior of sheep. Intracerebroventricular infusion of these peptides over 4 days decreased the need-free Na intake of Na-repleted sheep. Intracerebroventricular infusion of urocortin, however, did not alter Na intake of Na-depleted sheep. Systemic infusion of ACTH increased, whereas systemic infusion of either urocortin or CRF decreased, Na intake of Na-repleted sheep. The increase in Na intake caused by the peripheral infusion of ACTH was blocked by concurrent i.v. infusion of urocortin, substantiating the inhibitory role of this peptide on Na appetite. Central administration of all peptides and i.v. administration of urocortin or urocortin and ACTH combined decreased food intake. Water intake was not directly influenced by the peptides. Rather, decreased water intake, when observed, was secondary to decreased food intake, as determined by pair-feeding experiments. Whereas systemic infusion of ACTH mimics the increase in Na intake observed in several different stressful situations, CRF and urocortin actually inhibit Na intake, indicating a direct central action overriding any effect of these peptides on ACTH release. Indeed, the inhibition of Na intake by urocortin occurred despite its stimulation of ACTH release and the subsequent increase in peripheral level of cortisol. Thus it would appear that hormones associated with stress have both excitatory and inhibitory influences on Na intake. Presumably, other physiological processes entrained by stress also will be important in determining the quantitative outcome on Na appetite.

A main vector of the effects of stress is secretion of corticotrophin releasing factor (CRF), adrenocorticotrophin (ACTH), and adrenal steroids. Systemic administration of ACTH (2.8 microgram/day sc) for 7 days in BALB/c mice caused a very large increase of voluntary intake of 0.3 M NaCl equivalent to turnover of total body sodium content each day. Intracerebroventricular infusion of ACTH (20 ng/day) had no effect. Intracerebroventricular infusion of ovine CRF (10 ng/h for 7 days) caused an increase of sodium intake. The large sodium appetite-stimulating effect of systemic ACTH was not influenced by concurrent systemic infusion of captopril (2 mg/day). Induction of stress by immobilization of mice on a running wheel caused an increase in Na appetite associated with a 50% decrease of thymus weight, indicative of corticosteroid effects. The present data suggest that stress and the hormone cascade initiated by stress evoke a large sodium appetite in mice, which may be an important survival mechanism in environmental conditions causing stress.

The effect of sodium intake on the reproductive performance of BALB/C mice was assessed in four groups of 11 or 12 mice that received ad lib access to low or higher sodium food (LSF 4-5, HSF 120-143 mmol Na+/kg). The two groups that received HSF had (mean values) 100% matings, 83 and 91% litters, 5.9 pups/litter, pups weighing 2.05 and 2.22 g (3 days after birth) and 10.47 and 10.96 g at weaning (19 days). One of the HSF groups that also had 300 mM NaCl to drink did not show any benefit. Two groups received LSF, and one of them also received 30 mM NaCl. The group given LSF only had 83% matings, 20% litters, 1.5 pups/litter, and pups that were significantly smaller at birth and at weaning. However, the LSF group given 30 mM NaCl to drink performed almost as well as the two HSF groups. The results show that (a) the daily sodium requirement for optimal reproduction was > or = 400 (micromol/day, based on voluntary sodium intake late in gestation and lactation; (b) sodium deficiency was the cause of reproductive deficiency in mice on LSF; (c) severe sodium deficiency suppressed reproduction primarily at the gestation step; (d) this deficiency could be prevented by the voluntary sodium intake of mothers with access to salt solution; and (e) pups on the LSF showed an avid innate salt appetite when offered salt solution at 12 days of age.

The roles of ANG II in the brain mechanisms subserving thirst and Na appetite in baboons were investigated by chronic intracerebroventricular infusions of ANG II and AT1-receptor antagonists using subcutaneous miniosmotic pumps and by oral administration of captopril. ANG II at 3 or 5 micrograms/h for 7 days increased water intake from 2,455 +/- 107 to 7,052 +/- 562 ml/day by day 6 and 300 mM NaCl intake from 8.3 +/- 1.1 to 275 +/- 87 mmol/day by day 5. Concurrent intracerebroventricular losartan (300 micrograms/h) did not substantially reduce these responses, but they were abolished by intracerebroventricular ZD-7155 (50 micrograms/h). The increase of 300 mM NaCl intake when it was offered after intramuscular injection of furosemide, 2 mg . kg-1 . day-1 for 3 days, was unaltered by intracerebroventricular losartan (300 micrograms/h) but was reduced by intracerebroventricular ZD-7155 (50 micrograms/h) infused throughout Na depletion/repletion; oral captopril (1 g, 3 and 18 h before access to 300 mM NaCl) also reduced NaCl intake. Restriction of water intake to 25% of daily intake for 3 days caused a high intake of water on day 4, and this was reduced by intracerebroventricular losartan (300 micrograms/h) infused throughout the period of water restriction/rehydration. These novel results in a primate species suggest that brain ANG II is involved in both thirst and Na appetite, acting via AT1 receptors.

Previous experiments indicated that the Na appetite of Na-deplete sheep is decreased by systemically administered captopril. The assumption that captopril does not readily cross the blood-brain barrier, lead to the conclusion that circulating ANG II acting in brain areas without a blood-brain barrier, i.e., circumventricular organs such as the subfornical organ or organum vasculosum of the lamina terminalis, contributes to Na appetite induced by Na depletion. The present experiments investigated the possibility that systemically administered captopril does, in fact, cross the blood-brain-barrier and thereby influence brain angiotensin II formation and that brain angiotensin II contributes to Na depletion-induced Na appetite of sheep. The results showed that systemically administered captopril blocked water intake caused by intracerebroventricular infusion of angiotensin I, and that Na depletion induced Na appetite was not decreased by intracerebroventricular infusion of various antagonists of the renin-angiotensin system. Thus, the results suggest that although captopril crosses the blood-brain-barrier and can influence the formation of brain angiotensin II, brain angiotensin II is not involved in the Na appetite of Na-deplete sheep.

The contribution of brain angiotensin II (ANG II) to thirst and Na+ appetite of sheep was evaluated. Thirst was stimulated by water deprivation, intracarotid or intracerebroventricular infusion of ANG II, or intracarotid or intracerebroventricular infusion of hypertonic solution. Intracerebroventricular infusion, over 1-3 h, of the ANG II type 1 (AT1) receptor antagonist, losartan, decreased or abolished water intake caused by all of the stimuli tested. Intracerebroventricular infusion of ZD-7155, another AT1-receptor antagonist, blocked ANG II-induced water intake. Neither losartan nor ZD-7155 infused intracerebroventricularly altered the Na+ appetite of Na(+)-depleted sheep. Intracerebroventricular infusion of losartan over 3 h, however, did block the increase in water intake and the decrease in Na+ intake caused by intracerebroventricular infusion of hypertonic NaCl in Na(+)-depleted sheep. Intracerebroventricular infusion of the ANG II type 2 (AT2) receptor antagonist, PD-123319, over 1-3 h, did not alter ANG II-induced water intake or Na+ depletion-induced Na+ intake. These results are consistent with the proposition that brain ANG II, working via AT1 receptors, is involved in the neural system controlling some aspects of physiological thirst and Na+ appetite. A role for AT2 receptors in physiological thirst or Na+ appetite is not supported by the present results.

Experiments in cattle compared the effects of intracerebroventricular (i.c.v.) infusions of losartan and PD-123319 on water intake caused by water restriction, i.c.v. infusion of hypertonic NaCl, or i.c.v. infusion of angiotensin II (ANG II). The effects of these receptor antagonists on sodium intake caused by sodium depletion were also examined. Losartan infusion caused dose-dependent inhibition of the high water intake caused by the physiological stimulus of water restriction or by ANG II infusion but did not affect salt appetite. PD-123319 infused at equimolar or greater (in ANG II experiments) doses did not affect water intake or salt intake due to sodium depletion. The results of these i.c.v. infusion experiments confirm our earlier proposal that the physiological regulation of water intake in cattle may be mediated by ANG II acting centrally via AT1 receptors. The dose of losartan that inhibited thirst in cattle did not inhibit sodium appetite, nor did an equimolar dose of PD-123319.

The role of brain angiotensin II (ANG II) in water, Na and food intake of rats was studied. Intracerebroventricular (i.c.v.) infusion (100 micrograms/h) of the non-peptide ANG II receptor antagonist losartan (type 1), but not PD123319 (type 2), completely blocked water intake caused by i.c.v. infusion of ANG II at 50 ng/h. Following food deprivation, food intake was reduced by PD123319 and associated water intake was decreased by losartan or PD123319. Neither water intake after water deprivation nor Na intake after Na depletion was altered by losartan or PD123319. In conclusion, evidence was consistent with a role for brain ANG II in both food and water intake after food deprivation but not in thirst subsequent to water deprivation or Na intake after Na depletion alone.

From the outset, the study of angiotensin II (Ang II) in body fluid homeostasis has been both complicated and intriguing. Since the publication of an early report of the dipsogenic action of this peptide, the pursuit of the role of Ang II in thirst and Na appetite has continued for the last 25 years. This pursuit captured the attention of all workers interested in the behavioural/physiological regulation of body fluid balance, with major contributions being made by James T. Fitzsimons and his colleagues. In spite of its powerful dipsogenic actions, delineation of its precise role in physiological thirst has been elusive and difficult to demonstrate. The influence of Ang II on Na intake took longer to show convincingly. However, in contrast to thirst, the role of Ang II in physiological Na appetite has been demonstrated clearly. The technological advances made during the recent years have greatly increased our ability to delineate the neurobiological context of Ang II-mediated responses. Thus, the future is promising in regard to illuminating the subtleties of the role of Ang II in body fluid balance.

The effects of adrenal steroid hormones on sodium appetite were determined in female Balb/c mice by the subcutaneous implantation for 7 days of slow-release pellets containing aldosterone, corticosterone, deoxycorticosterone (DOC) or 11-deoxycortisol, separately or in a "cocktail" combination. Placebo pellets were also implanted. The daily intake of 0.3 M NaCl was increased for 2 days by aldosterone (calculated 2.9 micrograms/day released) or corticosterone (240 micrograms/day) and for 7 days by DOC (4.8 micrograms/day). The combination of these steroids plus 11-deoxycortisol (95 micrograms/day) increased daily sodium intake nine-fold (days 3-7) and also increased water intake 1.5-fold. Placebo pellets had small effects on water intake on three days. Subcutaneous infusion of ACTH (Synacthen) at 2.8 micrograms/day for 7 days by mini-osmotic pump increased sodium intake five-fold and water intake three- or four-fold. Thus, several adrenal steroids evoked sodium appetite in Balb/c mice, DOC being the most potent at the doses used. The effects of individual steroids are consistent with their contribution to the effect of ACTH on sodium appetite.

The influence of systemic or intracerebroventricular (icv) administration of angiotensin II on the intakes of NaCl solution, water, and food was investigated in BALB/c mice. Systemic administration of angiotensin II had little, if any, influence on these ingestive behaviors. On the other hand, icv infusion of angiotensin II at 70 ng/day increased (P less than 0.05) intakes of NaCl solution and water by the third day of infusion. The amount of NaCl ingested daily during the infusion was two to three times body sodium content. The mean daily water intake increased to 40-60% of body weight. The vast increase in NaCl intake was not secondary to a natriuresis caused by the icv infusion of angiotensin II. The results suggest that angiotensin II has a direct effect on neural systems involved in sodium appetite in this species.

BALB/c mice were allowed free access to water, food, and 0.3 M NaCl. Intracerebroventricular infusion of 0.7 M mannitol in artificial cerebrospinal fluid (CSF) was used to reduce CSF sodium concentration. The infusion was made at 24 microliters/day, which was similar on a body weight basis to the rate that evoked a large increase in sodium appetite in sheep. Reduction of CSF sodium concentration did not increase the voluntary sodium intake of sodium-replete mice or furosemide-treated, sodium-depleted mice. Thus, in contrast to findings in sheep and cattle and similar to the findings in the laboratory rat and wild rabbits, changes in cerebral sodium concentration are apparently not involved in the sodium appetite of mice.

The role of angiotensin II (ANG II) in Na-depletion-induced Na appetite of mice was investigated. Intraperitoneal injection of the angiotensin-converting enzyme inhibitor captopril at 1.7 mg/mouse (high dose) decreased the Na intake of the Na-depleted (furosemide-treated) mice by 80-85%. The decrease in Na intake was restored to the initial level by concurrent subcutaneous infusion of ANG II. High dose of captopril also decreased the Na intake of fluid-deprived, Na-depleted mice. High dose of captopril did not alter water intake in any of the four conditions examined, i.e., in fluid-replete, Na-depleted, water-deprived, or fluid-deprived, Na-depleted mice. Low dose of captopril (1.7 microgram/mouse) tended to or significantly enhanced Na intake of Na-depleted mice. Low dose of captopril, however, did not enhance water intake in any of the conditions examined. Both high- and low-dose captopril treatment decreased food intake in water-deprived mice, whether or not the mice were Na depleted as well. The addition of captopril (0.1 or 1.0 mg/ml) to the drinking water did not influence Na or food intake. Water intake was enhanced during treatment with the low but not with the high dose of captopril. The results are consistent with the proposition that ANG II is involved in the Na appetite of Na-depleted mice. ANG II does not appear to have a role in water intake of Na-depleted or water-deprived mice, but neural mechanisms in which angiotensin has a role may influence food intake of water-deprived mice.

The present study reports the effects of ICV administered eledoisin, the most potent anti/dipsogenic member of the tachykinin family, in three species. Sheep with chronic parotid fistula lost daily 200-400 mmol sodium in 3-4 l of saliva. During ICV infusion of eledoisin, 2 to 50 ng/min, a decrease in sodium intake was observed. If water was withheld for 22 hours, sheep normally drank 5.4 l water on presentation. During ICV infusion of eledoisin, 50 ng/min, water intake increased significantly. Wild rabbits lost 5 mmol sodium in 50 ml of urine after injection of furosemide. During ICV infusion of eledoisin, 30 ng/min, a decrease in sodium intake and an increase in water drinking was observed. Cows prepared with parotid fistula had access to sodium solution every other day to replace salivary sodium loss. During ICV infusion of eledoisin, 50 and 150 ng/min, a decrease in sodium intake occurred, and water intake was unaffected. These results confirm that central administration of eledoisin specifically influences ingestive behaviour in mammals and draws attention to some species differences in the observed effects.

Cows depleted of Na by loss of saliva from a parotid fistula for 46 h had an avid appetite for Na solution. They drank 21.0 +/- 1.6 liter of 0.3 M NaHCO3-NaCl solution during 2 h of access but little or no water during that time. Solutions of angiotensin II or captopril were infused for 3 h intravenously or into a lateral ventricle (intracerebroventricular) beginning 1 h before access to Na solution. Intravenous angiotensin II increased Na intake (to 26.8 +/- 2.9 liter, P less than 0.01) but did not alter water intake. Intracerebroventricular angiotensin II increased water intake but did not alter Na intake. Intravenous captopril reduced Na intake (to 11.0 +/- 2.1 liter, P less than 0.001) and concurrent intravenous angiotensin II prevented the reduction but concurrent intracerebroventricular angiotensin II did not. Intracerebroventricular captopril did not alter Na or water intake. Intravenous captopril reduced to zero the water intake during the hour before Na access, and concurrent intravenous angiotensin II prevented that reduction also. The dipsogenic action of intracerebroventricular angiotensin II was potentiated by intravenous captopril. The results of these experiments suggest that if angiotensin II receptors involved in the mechanism regulating Na appetite are in the brain, they are accessible only from the blood, e.g., in circumventricular organs. Thirst was inhibited by reduction of angiotensin II in blood but was stimulated only by angiotensin II acting inside the blood-brain barrier.

Cows having free access to water (hydrated) or deprived of water for 26.5 h (dehydrated) were infused for 3 h with angiotensin II or captopril solutions intravenously (iv) or intracerebroventricularly (icv) beginning 1 h before access to 0.3 M NaHCO3/NaCl solution for 2 h. The results agree with the results of the experiments with the same agents and doses in Na-deficient cows. Only iv infusion of angiotensin II stimulated Na appetite and only icv infusion of angiotensin II stimulated thirst. Therefore, barriers to the penetration of angiotensin II in the brain determined the particular site of action and elicited response. Dehydration did not stimulate Na appetite and, as shown previously, Na deficiency did not stimulate thirst, but both behaviors seem to be influenced by angiotensin-related mechanisms in the brain. The inability of iv angiotensin II to stimulate Na appetite in hydrated cows might be explained by the lack of a response caused by, and common to, Na deficiency and dehydration, e.g., upregulation of angiotensin II receptors, or reduced extracellular fluid volume.

Cows depleted of phosphorus by loss of saliva from a parotid fistula and low dietary phosphate developed an avid appetite for bones. The behaviour is innate and predominantly cued by olfactory stimuli. Meat, blood or fat were not attractive and bones became more attractive after aging for 1.5-2.0 years. The appetite was also shown for guano-derived rock phosphate and bird excreta. There was no interest in inorganic calcium and phosphate salts or ashed bone. The attractant is therefore an organic constituent of aging bone and was found to be at highest concentration in the marrow fraction. Water, ether and vacuum distillation extracts of old bone or marrow, added to unattractive materials e.g., ashed bone, rendered them attractive. The residues of such extraction were of diminished interest. The attractiveness of the fractionated extracts was highest in the neutral fraction. The bone appetite was abolished by increasing the phosphate concentration in plasma but not in cerebrospinal fluid. The phosphate concentration in the blood appears, therefore, to regulate the bone appetite. The sensors could be in brain regions without a blood-brain barrier. Chronic severe phosphorus deficiency was associated with bone resorption, reduced osteoblastic and hemopoietic activities, and abnormal blood progesterone cycles.