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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS003469-25
Application #
3393294
Study Section
Biopsychology Study Section (BPO)
Project Start
1974-09-01
Project End
1992-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
25
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Galaverna, O; Nicolaidis, S; Yao, S Z et al. (1995) Endocrine consequences of prenatal sodium depletion prepare rats for high need-free NaCl intake in adulthood. Am J Physiol 269:R578-83
Black, R M; Weingarten, H P; Epstein, A N et al. (1992) Transection of the stria terminalis without damage to the medial amygdala does not alter behavioural sodium regulation in rats. Acta Neurobiol Exp (Wars) 52:9-15
Galaverna, O; De Luca Jr, L A; Schulkin, J et al. (1992) Deficits in NaCl ingestion after damage to the central nucleus of the amygdala in the rat. Brain Res Bull 28:89-98
Chow, S Y; Sakai, R R; Witcher, J A et al. (1992) Sex and sodium intake in the rat. Behav Neurosci 106:172-80
Epstein, A N (1992) Control of salt intake by steroids and cerebral peptides. Pharmacol Res 25:113-24
De Luca Jr, L A; Galaverna, O; Schulkin, J et al. (1992) The anteroventral wall of the third ventricle and the angiotensinergic component of need-induced sodium intake in the rat. Brain Res Bull 28:73-87
Thompson, C I; Epstein, A N (1991) Salt appetite in rat pups: ontogeny of angiotensin II-aldosterone synergy. Am J Physiol 260:R421-9
Frankmann, S P; Ulrich, P; Epstein, A N (1991) Transient and lasting effects of reproductive episodes on NaCl intake of the female rat. Appetite 16:193-204
Epstein, A N (1991) Neurohormonal control of salt intake in the rat. Brain Res Bull 27:315-20
Yang, Z F; Epstein, A N (1991) Blood-borne and cerebral angiotensin and the genesis of salt intake. Horm Behav 25:461-76

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