Increasing evidence suggests that the brain renin-angiotensin system may play a role in the development of hypertension in the spontaneously hypertensive rat (SHR). Of great importance is the finding that chronic intra-cerebroventricular (icv) treatment of SHR with the converting enzyme inhibitor, captopril, at doses which have no effect when given intravenously significantly attenuates the development of hypertension. The mechanisms underlying this antihypertensive action of captopril and the role of the brain renin-angiotensin system in spontaneous hypertension are not known with certainty. The present research plan proposes to define the role of brain angiotensin II (AII) in SHR and identify its mechanism(s) of action. This proposal will test the hypothesis that brain AII participates in SHR by producing the functional abnormalities in vascular reactivity, baroreflex activity and/or sympathetic drive which characterize this strain. To this end we will employ captopril to block the brain renin-angiotensin system and study the effects of this blockade on the development of functional abnormalities in SHR. Brain angiotensin may produce alterations in vascular reactivity through its ability to affect the release of ACTH and vasopressin. Peripheral vascular reactivity studies (conscious whole animal using Doppler flow probes and isolated perfused vascular beds) will be performed to determine whether corticosterone and/or vasopressin participates in the induction of increased vascular reactivity in SHR and whether the inhibitory effects of centrally administered captopril are due to inhibition of ACTH and/or vasopressin. Brain angiotensin may participate in SHR by altering baroreflex function. This will be tested by assessing the effect of captopril treatment of SHR on baroreflex control of heart rate and vascular resistance and determining whether the effects of captopril are reversed by administration of AII or vasopressin. Finally, brain AII may produce alterations in sympathetic function in SHR. This will be testedly assessing the effects of inhibition of brain AII on sympathetic function and the ability of central AII administration to reverse the effects of blockade. The results of these experiments should provide fundamental information on the role of brain AII in normal cardiovascular regulation as well as in the pathogenesis of hypertension.
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