E. Tarjan

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.

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.

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.

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.

Evidence for cerebral sodium sensors involved in water drinking in sheep.

Abstract Evidence supporting cerebral Na sensors in the initiation of thirst is the greater water drinking which occurs with intracerebroventricular (ICV) infusion of hypertonic NaCl than with ICV hypertonic saccharide solution. However, ICV infusion of hypertonic saccharide solution causes a reduction in CSF [Na], even though the saccharide is made in solution with normal [Na] of 150 mM. To prevent this, ICV infusion of hypertonic sucrose in high Na solution was made. The ICV infusion of 0.3 M sucrose/0.3 M NaCl-CSF caused water intake of 416 ± 173 ml (mean ± SEM) in 6 sheep, and CSF [Na] was 151 ± 0.9 mM, but ICV infusion of equiosmolar 0.45 M NaCl-CSF caused greater water intake of 1097 ± 202 ml and CSF [Na] increased to 178.8 ± 3.6 mM. Control ICV isotonic CSF did not cause drinking and CSF [Na] was 150.5 ± 0.8 mM whereas ICV 0.6 M sucrose-CSF ([Na]=150 mM) caused water intake of 132 ± 63 ml with CSF [Na] falling to 139.3 ± 1.3 mM. These results indicate specific brain NaCl sensors involved in thirst. Osmoreceptors may also exist because some drinking occurred with ICV sucrose despite reduced CSF [Na].

Water and salt intake of wild rabbits (Oryctolagus cuniculus (L)) following dipsogenic stimuli.

Wild rabbits trapped in their natural habitat and adapted to laboratory conditions were studied. Food, water and electrolyte (0.5 M‐NaCl, 0.5 M‐KCl, 0.25 M‐MgCl2 and 0.25 M‐CaCl2) consumption, urinary volume and sodium losses were monitored daily following stimuli which were found dipsogenic in other species. Water drinking was observed immediately after the intravenous injection of 1 M‐NaCl (3 ml/kg), and following withdrawal of a mean of 13.9% of calculated blood volume. Daily intake of water decreased during intracerebroventricular (I.C.V.) infusion of 0.3 M‐NaCl in artificial cerebrospinal fluid (c.s.f.), during I.C.V. infusion of 0.9 M‐mannitol c.s.f., both at a rate of 17 microliters/h, following peritoneal dialysis with 5% (w/v) glucose solution, and during food restriction. Water intake was not affected following intravenous administration of acetazolamide (10 mg/kg). Daily intake of 0.5 M‐NaCl solution was increased following peritoneal dialysis with 5% (w/v) glucose solution, which caused hyponatraemia, but not after haemorrhage which caused about the same sodium deficit as peritoneal dialysis, but as an isosmotic loss. Administration of two different angiotensin II analogues, systemically or I.C.V., failed to induce water drinking. However, urinary sodium excretion and intake of 0.5 M‐NaCl were increased during the 5 days of I.C.V. infusion of angiotensin II (10 pmol/h). Infusion for 1 day of angiotensin II (500 pmol/h) led to increased urinary sodium excretion which was followed by increased intake. The intake of other electrolyte solutions was not significantly affected by any of the treatments detailed above. The mechanisms participating in initiation of thirst in wild rabbits are very sensitive to decrease in blood volume, in contrast to other species studied in laboratories. Angiotensin II at the doses and routes administered was not dipsogenic in wild rabbits. The increased intake of 0.5 M‐NaCl solution observed during and after the long‐term intraventricular administration of angiotensin II in the wild rabbit appears predominantly a response to sodium deficit caused by natriuresis. The persistence of appetite after the cessation of infusion is indicative of a residual effect on central mechanisms of salt appetite.

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.

Stress, ACTH, salt intake and high blood pressure.

Epidemiological evidence supports the thesis that high salt intake is involved in the aetiology of hypertension. If sodium intake is not causal, it appears other factors do not cause high blood pressure in unacculturated societies with low sodium intake. In this context, it is potentially important that stress causing ACTH release, as well as other neurohumoral effects, causes increased salt appetite and can impair renal sodium excretion.

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.

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.