Small doses of systemic mineralocorticoid (DOCA or aldosterone) combined with infusions of low doses of angiotensin II into the cerebral ventricles of the sodium replete rat induce a rapid, reliable, and robust appetite for salt, and the salt appetite of the sodium deplete rat is suppressed by interference with the cerebral actions of angiotensin II with drugs that prevent its synthesis or block its receptors. These findings support the hypothesis that excess sodium intake is provoked by a synergy of action in the brain of the two hormones of renal sodium conservation - angiotensin II (Ang II) and aldosterone (ALDO). Endogenous Ang I, Ang II, and ALDO will be measured by radioimmune assay in the sodium deficient, the adrenalectomized, and the drug or hormone treated rat to evaluate the hypothesis directly. Blockade of synthesis of endogenous Ang II with orally self-administered captopril (Squibb) will test the idea that in the adrenalectomized rat, in which angiotensin must act without aldosterone, the appetite for salt is completely dependent on angiotensin. The role of endogenous ALDO will be evaluated in the intact rat by varying the salt content of its diet and by using a new mineralocorticoid receptor blocker (RU 28318) that is potent and specific. Renin-angiotensin systems exist both in the periphery and in the brain. Their potencies for arousal of salt appetite by synergy with ALDO will be compared by contrasting the results of intravenous infusion of Ang II or of competitive antagonists of Ang II with those already obtained with intracranial infusion of the same agents. In addition, the neurological mechanisms that may mediate the synergistic effect of the hormones will be studied with emphasis on the circumventricular organs, as will the effects of the synergy treatment and the excess salt intake that it produces on the rat's blood pressure. The ontogeny of the appetite will be studied in newborn rats, and its phylogeny will be studied in the pigeon. Excess salt intake is implicated in the etiology of hypertensive disease. An understanding of its hormonal causes could lead to rational chemical therapies and to reductions of salt intake in humans at risk for hypertension.
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