Sodium appetite in sheep induced by cerebral ventricular infusion of angiotensin: comparison with sodium deficiency.

Intraventricular administration of supraphysiological amounts of renin, nerve growth factor preparation, or angiotensin II greatly increased the consumption of water and hypertonic sodium bicarbonate solution by sheep. These effects were antagonized by intraventricular administration of drugs that prevent the formation of angiotensin II or block its receptors. The fact that these angiotensin-blocking drugs did not change the sodium intake of sodium-deficient sheep challenges the idea that central angiotensin action is involved in sodium appetite due to a deficiency.

Localization of angiotensin II receptor binding in rabbit brain by in vitro autoradiography.

Binding of 125I-[Sar1,Ile8] angiotensin II (AII) to sections of brains from both wild and laboratory rabbits was determined by in vitro autoradiography. In the forebrain, specific high density binding was observed in the olfactory bulb, organum vasculosum of the lamina terminalis (OVLT), subfornical organ, median eminence, lateral septum, median preoptic nucleus and hypothalamic paraventricular, supraoptic and arcuate nuclei. In the midbrain, binding of the radioligand was observed in the interpeduncular and parabrachial nuclei, in the locus coeruleus, and ventrolateral pons. In the hind brain, there was dense binding of 125I-[Sar1,Ile8] AII to the nucleus of the solitary tract (NTS) and to both rostral and caudal parts of the reticular formation of the ventrolateral medulla oblongata. Weaker specific binding of the radioligand to the molecular layer of the cerebellum, to the nucleus of the spinal trigeminal tract, dorsal motor nucleus of the vagus, area postema, and to a band of tissue connecting the NTS to the ventrolateral medulla was also observed. Binding of the ligand to circumventricular organs such as the OVLT, subfornical organ, and median eminence suggests that these are sites in the brain of the rabbit at which blood-borne AII may exert influences on the central regulation of fluid balance and pituitary hormone secretion, although AII of neuronal origin could also act at these sites. Binding of the radioligand in several other brain regions suggests that angiotensin II of cerebral origin may be involved in a number of different aspects of brain function in the rabbit. The finding of dense binding in the NTS and ventrolateral medulla, which are involved in autonomic activity and are also sites of catecholamine-containing neurons, raises the possibility of angiotensin interaction with these neurons and involvement in autonomic function.

Hyperaldosteronism in the sodium-depleted rat: mechanism of aldosterone stimulation by peritoneal dialysis with glucose solution.

Peritoneal dialysis with 5% glucose solution was carried out in dexamethasone-pretreated rats. Dialysis brought about a severe loss of sodium and a slight loss of potassium into the peritoneal fluid. This kind of sodium depletion took place without any decrease in total body-water space, thus it evoked a severe fall in plasma sodium concentration. Plasma renin activity and the serum concentration of aldosterone increased in response to dialysis. Peak values in renin activity were attained within 60 min, whereas aldosterone concentrations exhibited a continuous rise until at least 120 min. Despite the correlation of renin and aldosterone values, neither the administration of an angiotensin I converting enzyme inhibitor (SQ 20,881) nor the reduction of plasma renin activity by indomethacin could reduce hyperaldosteronism evoked by peritoneal dialysis. Therefore, it is assumed that there is no causal relationship between renin and aldosterone in this kind of acute, severe sodium depletion.

Hyperaldosteronism in the sodium-depleted rat: mode of aldosterone-stimulating action of frusemide.

The mechanism of diuretic-induced hyperaldosteronism was examined in dexamethasone-pretreated rats. The diuretic drug frusemide brought about a rapid increase in plasma renin activity and aldosterone concentration in serum. Half an hour after the administration of frusemide the mean concentration of aldosterone was 25 times higher than in vehicle-treated control animals. Administration of SQ 20,881, an inhibitor of angiotensin converting enzyme, prevented the adrenal response to frusemide. The response of aldosterone was completely blocked by indomethacin. This drug reduced renin release and probably also inhibited the effect on the adrenal glands of angiotensin, released in response to frusemide. Our results indicate that the effects of diuretics on the adrenal glomerulosa cells are mediated by the renin-angiotensin system also in the rat. Hyperaldosteronism is dependent on the maintenance of prostaglandin synthesis. ACTH has no essential role in this response.

Effect of reduced extracellular sodium concentration on the function of adrenal zona glomerulosa: studies in conscious rats.

The present experiments were designed to study the effect extracellular hyponatraemia on aldosterone secretion. Hyperaldosteronism was induced by peritoneal dialysis with 5% glucose solution in dexamethasone-pretreated rats. In the narrow physiological range of 135-142 mmol/l, as well as in the whole range of the study (122-142 mmol/l), the plasma concentration of sodium showed a close negative correlation with the serum concentration of aldosterone (r = -0.71 and -0.83, respectively). Plasma renin activity increased after peritoneal dialysis; however, no close correlation was observed either between sodium concentration and plasma renin activity or plasma renin activity and serum aldosterone concentration within the dialysed group. The ratio of serum concentration of aldosterone to plasma renin activity showed no considerable change between 132 and 142 mmol/l but rose steeply below 132 mmol sodium/l suggesting that a factor(s) other than angiotensin may also contribute to the induction of hyperaldosteronism.U

Effect of CRF, ACTH and adrenal steroids on sodium intake and excretion of rabbits.

The effect of CRF, ACTH and adrenal steroid hormones on the sodium intake and excretion of wild and laboratory rabbits was studied in our laboratory in detail. All these hormones are known to play important roles in the initiation and maintenance of stress-reaction. Intracerebroventricular (icv) infusion of CRF increased both sodium intake and excretion of rabbits on the day of the infusion, and the stimulated sodium turnover persisted for several days after the infusion stopped. Systemic administration of the same dose of CRF did not influence sodium intake or excretion. Icv infusion of CRF was accompanied by a rise in plasma cortisol and plasma corticosterone concentration. Plasma sodium concentration was unchanged despite the increased turnover. The elevated plasma concentration of adrenal steroid hormones indicates that icv infused CRF resulted in ACTH and consequent cortisol and corticosterone release. Earlier studies in our laboratory established that ACTH, and similarly cortisol and corticosterone, when injected systemically, also elicited increased sodium intake, which was accompanied by increased sodium excretion. The rise in sodium turnover occurred on the second or third day of ACTH or steroid administration. The difference in the time of onset of sodium appetite between icv CRF and ACTH or adrenal steroids indicates that CRF influences sodium intake by other mechanisms as well. These other contributing mechanisms are probably activated by the binding of CRF to the specific binding sites demonstrated earlier in the rabbit's brain. Its is possible, that the small natriuresis accompanying icv infusion of CRF has some role in the initiation of the sodium appetite.(ABSTRACT TRUNCATED AT 250 WORDS)

Water and sodium intake of wild and New Zealand Rabbits following angiotensin.

Two rabbit strains, New Zealand (laboratory) rabbits and Australian wild rabbits, both members of the Oryctolagus cuniculus genus were studied. New Zealand rabbits under control conditions consumed 2-5 times more water and 8-30 times more 0.5 M NaCl/kg body weight than wild rabbits. Single injections of angiotensin II or III administered ICV did not induce water drinking in either strain. Acute ICV infusion of angiotensin II also did not influence water intake, but after several days of administration, induced increased sodium intake. Intravenous infusion of graded doses of angiotensin II induced diuresis only at the higher doses in both strains. In New Zealand rabbits, this was accompanied by a commensurate and concurrent increase in water intake. Intravenous infusion of angiotensin II also induced urinary sodium loss that was either accompanied or followed by increased sodium intake. The development of salt appetite in both strains was preceded by sodium loss.

Role of brain angiotensin in thirst and sodium appetite of rats.

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.

Atrial natriuretic peptide inhibits water and sodium intake in rabbits.

The effect of atrial natriuretic peptide (ANP) on water and sodium intake was investigated in wild rabbits, a species which does not drink water following i.c.v. or i.v. administration of angiotensin II but develops sodium appetite following i.c.v. infusion of angiotensin II. ANP was given during or after depletion of extracellular fluid volume: hemorrhage, fluid deprivation and administration of furosemide. Systemically administered ANP reduced the water, but not the sodium intake of wild rabbits. I.c.v. administration of ANP inhibited both water and sodium intake. The suppression of thirst following both i.v. and i.c.v. administration of ANP indicates that inhibition of the effect of angiotensin II is not the exclusive mechanism and the circumventricular organs are probably not the exclusive sites of action for ANP. The inhibition of sodium appetite in wild rabbits was consistent with earlier proposals that ANP acts through the inhibition of the effects of angiotensin II. Reduction of food intake coincident with administration of ANP was also noted, but dose-dependent decrease was not observed.

The role of angiotensin II in ingestive behaviour: a brief review of angiotensin II, thirst and Na appetite.

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.

Effect of ICV infusion of CRF on blood pressure and adrenal steroids in rabbits.

The effect of prolonged, 22 h long, intracerebroventricular (i.c.v.) infusion of corticotropin-releasing hormone (CRF) on plasma cortisol, corticosterone and electrolyte concentrations, mean arterial blood pressure (MAP) and heart rate (HR) were investigated in conscious rabbits. During i.c.v. infusion of CRF, 1 and 3 micrograms/h, at a rate of 17 microliters/h, plasma cortisol and corticosterone concentrations rose to the level noted after ACTH stimulation in rabbits. Plasma [Na] did not change, but plasma [K] was reduced and plasma osmolality increased during the infusion of CRF, 3 micrograms/h. MAP and HR, recorded continuously during i.c.v. infusion of CRF, changed only with the higher dose of CRF: MAP was elevated during the first 5 h of infusion, and then returned to the control level. HR was lower than control at the end of the first hour of infusion and again between 9 and 15 h of infusion. The prolonged rise of CRF concentration in the brain induced a sustained rise in circulating adrenal steroid hormones. MAP did not increase to the level noted after bolus i.c.v. injection of CRF and the rise in MAP was not sustained.

Corticotropin-releasing factor enhances sodium and water intake/excretion in rabbits.

Sodium and water intake and excretion of wild rabbits was studied during intracerebroventricular (icv) infusion of corticotropin-releasing factor (CRF). Icv infusion of 200 and 600 pmol/h for 22 h induced changes in the ingestive and general behavior of animals. Increased consumption of 0.5 M NaCl solution was observed during the day of infusion, accompanied by increased sodium excretion, and food intake was decreased. The rabbits maintained the high sodium turnover, together with a high water turnover, for 2-3 days after the icv infusion stopped. Icv infusion of CRF induced strange behaviour in wild rabbits, they appeared to react with fright to normal daily events around them. The strange behaviour started about two hours after the beginning of icv infusion and disappeared immediately after the infusion stopped. On the basis of present and earlier observations, that systemic administration of adrenocorticotropin (ACTH) and adrenal steroid hormones induce increased sodium turnover, it is proposed that changes in the sodium and water metabolism might constitute part of the general stress reaction of the body.

Cerebral sodium sensors in the sodium-deplete sheep.

The sodium intake of sodium deplete sheep was studied during local, push-pull perfusion of different solutions within the third cerebral ventricle. Sheep were made sodium deplete by continuous loss of parotid saliva, and were allowed access to 0.6 M NaHCO3 solution for 2 h daily. Local perfusion within the third cerebral ventricle was performed before and during the access to sodium solution. Four perfusion sites were used: anterior dorsal and ventral, and posterior dorsal and ventral. Perfusion of 200 mM Na-csf caused a decrease in sodium intake at each perfusion site. Perfusion of ouabain, 10(-6) M, caused a reduction in sodium intake only during perfusions within the anterior portion of the third ventricle. The results may indicate that specific neuronal elements sensitive to changes in intracellular sodium concentration are located around the anterior portion of the third cerebral ventricle. These neurones, however, are not exclusive sites from where sodium intake of sodium deplete sheep can be influenced.

Corticotropin-releasing factor receptors in the rabbit brain visualized by in vitro autoradiography.

Corticotropin-releasing factor (CRF) binding sites were visualized in the rabbit brain by in vitro autoradiography using the radioligand 125I-[Tyr0]ovine CRF. The radioligand binding to sections of rabbit cingulate cortex were competed for by ovine and rat CRF with inhibitory constants (Ki) of 26 and 37 nM, respectively, whereas sauvagine and alpha-helical CRF9-41 were approximately 10-fold less potent. In the rabbit brain, the highest densities of binding sites for CRF are found in the pineal gland and the choroid plexus. The cerebral cortex is labelled throughout, with the highest concentration of binding sites in the piriform and primary olfactory divisions. In the cerebellar cortex, the granular layer is more intensely labelled than the molecular layer. The distribution of CRF binding sites in the hippocampus follows a laminar pattern; the molecular layer of the dentate gyrus is intensely labelled, the oriens, radiatum and lacunosum moleculare layers of Ammon's horn contain moderate densities of binding and no binding is observed in the granular layer of the dentate gyrus and the pyramidal cell layer. The ventral subnucleus of the lateral septum, the zonal and superficial layers of the superior colliculus contain high densities of receptors. A moderate concentration of binding sites is observed in the caudate nucleus, putamen, bed nucleus of the stria terminalis, paraventricular, anterodorsal and anteroventral thalamic nuclei and the medial nucleus of the mammillary body.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid sodium concentration and salt appetite.

Infusion into a lateral brain ventricle (IVT) of different hypertonic (0.7 M) saccharide solutions decreased [Na+] of cerebrospinal fluid (CSF). Increased Na appetite of moderately Na-deplete sheep was observed during infusion of mannitol, L-glucose or L-fucose, while no change was observed during infusion of D-glucose, D-fucose, D-mannose, 2-deoxy-D-glucose, 3-O-methyl-glucose or fructose. In other experiments, increased Na appetite was observed during infusion of 2.3 mM phlorizin (a relatively specific blocker of Na-coupled glucose transport into cells) or 2.3 mM phlorizin plus 0.7 M D-glucose. In addition, phlorizin eliminated the characteristic decrease in Na appetite but did not affect the increase in water intake caused by IVT infusion of hypertonic NaCl which increased [Na+] of CSF. The results suggest that: (a) there are sensors within the neuropil which respond to change of [Na+] and influence Na appetite, and that these changes of [Na+] are induced deep within the neuropil by those saccharides which do not cross the blood-brain barrier or enter cells; change of CSF[Na+] alone is not sufficient to alter appetite but a change in brain extracellular fluid (ECF)[Na+] is probably necessary; (b) the theory is advanced that the stimulus for altered Na intake could be altered brain ECF[Na+] producing a change in cerebral intracellular fluid (ICF)[Na+] of the sensors; and (c) phlorizin, in reducing or blocking Na-coupled glucose transport, could increase Na appetite by producing a fall in ICF[Na+] of the specific neurones subserving sodium appetite or prevent a decrease in Na appetite caused by IVT infusion of hypertonic NaCl by preventing an increase in ICF[Na+] of this same neuronal system.

Central administration of somatostatin suppresses the stimulated sodium intake of sheep.

The effect of intracerebroventricular (i.c.v.) infusion (50 micrograms/h over 3 h) of somatostatin (SOM) on Na and water intake of sheep was determined. In Na-deplete sheep, infusion of SOM-(28) but not SOM-(14) decreased (P less than 0.05) Na intake, while both SOM-(28) and SOM-(14) increased water intake. I.c.v. infusion of SOM-(28) did not significantly affect Na or water intake of Na-replete sheep. I.c.v. infusion of SOM-(28) decreased (P less than 0.01) Na intake but did not alter the high water intakes of water-deprived sheep or sheep infused i.c.v. with angiotensin II. The results are compatible with an inhibitory action of somatostatin on stimulated brain mechanisms subserving Na appetite but not on stimulated brain mechanisms subserving thirst. Somatostatin may antagonize the inhibition of thirst in Na-deplete sheep. The results suggest that somatostatin may have a regulatory role in ingestive behavior concerned with body fluid and Na homeostasis. The difference between SOM-(14) and SOM-(28) in decreasing the Na intake of Na-deplete sheep may be due to a difference in potency or mechanism of action.

Central administration of atrial natriuretic peptide suppresses sodium and water intake of sheep.

The effect of intracerebroventricular (i.c.v.) infusion (20 micrograms/h) over 3 h) of human alpha-atrial natriuretic peptide (ANP) on Na and water intake of sheep was studied. I.c.v. infusion of ANP decreased (p less than 0.01) Na and water intakes of water-deprived sheep but did not affect significantly Na or water intakes of Na and water-replete sheep. In addition, i.c.v. infusion of ANP decreased (P less than 0.05) Na and water intakes of sheep infused i.c.v. with angiotensin II. The results suggest that ANP may act on brain mechanisms concerned with both Na appetite and thirst. These mechanisms may involve action on the angiotensin II component of sodium appetite but effects on other factors determinant of appetite cannot be excluded at present.

Decrease of brain extracellular fluid [Na] and its interaction with other factors influencing sodium appetite in sheep.

It has been shown previously in sheep that physiological increase of cerebrospinal fluid (CSF) [Na] by infusion of 0.5 M NaCl artificial CSF causes a large reduction of sodium appetite of the sodium-deplete animal. Equivalent increase of CSF osmotic pressure caused by infusion 0.7 M mannitol artificial CSF which lowers CSF [Na] causes a doubling of sodium appetite. The results of the experiments here show that simple dilution of CSF [Na] with isotonic mannitol CSF, as distinct from use of hypertonic 0.7 M mannitol CSF, is an equally effective strong stimulus of sodium appetite. Lowering CSF [Na] concentration stimulates salt appetite in the severely sodium-deplete as well as in the mild to moderately sodium-deplete animal, and the effect of decrease of CSF [Na] on sodium appetite is sustained over 48 h. In addition, i.c.v. infusion of angiotensin II for the preceding 22 h at a rate which is an effective stimulus of both water and sodium solution intake in the sodium-replete animal, in fact, significantly decreased the sodium appetite stimulating effect of reduction of CSF [Na] in the Na-deplete animal.

Thirst induced by increasing brain sodium concentration is mediated by brain angiotensin.

Thirst, the longing or compelling desire to drink, arises physiologically by two main mechanisms-extracellular and cellular dehydration. The hormone angiotensin II has been implicated in the former but not in the latter brain mechanism. To test this apparent difference, experiments in 5 mammalian species examined the effect of intracerebroventricular infusion of losartan, an angiotensin II type I receptor antagonist, on the third induced by intracerebroventricular infusion of an artificial cerebrospinal fluid made hypertonic by the inclusion of 500 mM NaCl. The losartan infusion reduced the water intake due to increased brain sodium concentration in all 5 species, cattle, sheep, rabbits, rats and mice. Thus, the thirst evoked by cellular dehydration, as well as the thirst evoked by extracellular dehydration, may be mediated by angiotensin II.

Sodium/water intake of rabbits following administration of hormones of stress.

Intracerebroventricular (ICV) infusion of CRF, for 22 h, induced five- to seven-fold increase in the daily intake of sodium chloride solution in wild rabbits. The increased sodium intake persisted for 3 days after the infusion stopped and was accompanied by increased sodium excretion, water turnover and decreased food intake. ICV infusion of CRF also induced a change in the general behaviour of the animals, which lasted throughout the infusion only. Systemic, but not ICV administration of ACTH, similar to systemic administration of adrenal steroid hormones (demonstrated in earlier studies), induced gradual increases in the daily sodium intake and excretion of rabbits, as did restraint by tight jackets. The increased sodium intake was accompanied by increased sodium excretion and water turnover, and lasted as long as the administration of hormones. Together these results lead to the hypothesis that increased sodium intake might be an integral part of the stress reaction of the body and not the consequence of distortions of other regulatory functions.