PHYSIOLOGICAL ACTIONS OF THE RENIN-ANGIOTENSIN SYSTEM

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The purpose of this project is to study physiological and pathological aspects of the renin-angiotensin system, with emphasis on its role on circulatory homeostasis and development. During the past year studies have focused on a) the role of type-1 angiotensin II (Ang II) receptors located in parvicellular CRH and CRH/VP cells in the hypothalamic paraventricular nucleus (PVN), b) the control of mineralocorticoid secretion during development. a) Previous studies of this group showed that AT1 receptors in the PVN are located in neurons expressing corticotropin releasing hormone (CRH) in the parvicellular subdivision. To determine the physiological role of these receptors, the effects of acute stress on the hypothalamic pituitary adrenal (HPA) axis and sympathetic activity were studied in rats subjected to icv injection of Losartan. Central AT1 receptor blockade had no effect on stress-induced elevations in plasma ACTH and corticosterone, CRH mRNA and CRH receptor mRNA in the PVN. However, the increases in plasma epinephrine and norepinephrine in response to stress were significantly smaller in Losartan injected rats. b) In the adult, mineralocorticoid secretion in the adrenal zona glomerulosa is characterized by: 1) high dependance on Ang II, 2) biphasic effects of ACTH, with stimulation after initial exposure followed by inhibition, and 3) minor inhibition by glucocorticoids. Studies during development showed that while aldosterone responses in 7-day old rats are markedly insensitive to Ang II in vivo, they are similar to those in adults in vitro. Aldosterone responses to ACTH are normal in vivo and in vitro. This indicates that the steroidogenic capacity of the adrenal is normal in immature rats, but an endogenous factor inhibits the Ang II action. A novel finding was that glucocorticoids markedly inhibit aldosterone secretion in vivo but not in vitro. This effect is mediated by inhibition of aldosterone synthetase expression, and it was not prevented by ACTH injection. These studies show marked developmental changes in the mechanism of regulation of aldosterone secretion.