ANGIOTENSIN EFFECTS IN HYPOTHALAMUS AND ADRENAL MEDULLA

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Angiotensin II (Ang II) is a potent mediator of numerous effects related to cardiovascular regulation and body fluid homeostasis. Substantial evidence indicates: 1) that angiotensin receptors may be classified into two or more subtypes, and 2) that other angiotensin peptides in addition to Ang II may act upon angiotensin receptors. Particular interest has focused on the neuronal effects of angiotensins, but interpretation of such experiments has proven difficult because of the relatively rapid metabolism and low concentration of Ang II in the brain. These limitations underscore the possibility that other angiotensin peptides may locally mediate some effects apparently mediated by Ang II. Thus, the research proposal is designed to test the following hypothesis: that the renin-angiotensin system interacts with two or more subclasses of neuronal angiotensin receptors via selective generation of two or more physiologically active angiotensin peptides. Toward this objective, the proposal will address two specific aims: 1) To characterize the interaction of angiotensin peptides with the rat hypothalamoneurohypophysial system in the control of arginine vasopressin release; 2) To characterize the interaction of angiotensin peptides with the rat adrenal medulla in the control of epinephrine release. For each specific aim, three sets of experiments nave been planned: 1) To compare the relative potencies of Ang 11, Ang-(2-8) and Ang- (1-7) in promoting hormonal release; 2) To study the effects of Ang I or Ang II on release of the hormone in the presence of inhibitors which block angiotensin peptidases; 3) To directly evaluate the effect of these peptidase inhibitors on the metabolism of Ang I or Ang II in the tissue. In addition, the renin-angiotensin system of the brain will be further tested by studying release of angiotensin peptides (Ang I, Ang II, Ang-(2-8), and Ang-(1-7)) from the in vitro perifused hypothalamo-neurohypophysial system. The evidence obtained from the proposed studies may have significant implications concerning the treatment of diseases in which angiotensin plays a role, since better characterization of the enzymes and receptors which interact with angiotensin peptides could lead to the development of enzyme inhibitors and receptor antagonists which selectively block particular effects of the renin-angiotensin system.