To determine whether the antihypertensive effect of captopril (CAP) is related to an alteration in brain angiotensin II (AII) stores, metabolism, or receptor binding and whether changes in vascular reactivity baroreflex activity, and sympathetic tone associated with the blood pressure lowering effect of CAP are related to changes in brain AII. We will carry out the following specific aims:
Aim 1 : To test the hypothesis that the antihypertensive effect of CAP in SHR is related to, or accompanied by alterations in brain AII synthesis and/or metabolism and/or decreased number, affinity or altered regulation of brain AII receptors. Brain AII will be characterized biochemically (RIA and HPLC immunocytochemically and functionally in CAP-treated and control SHR and WKY. Radioligand binding studies will be used to characterize AII binding in brain and vascular tissue.
Aim II : To test the hypothesis that increased vascular reactivity in SHR is related to brain AII stimulation of ACTH-corticosterone and/or VP and that the decreased vascular reactivity in CAP treated rats is relate to a diminution in brain AII-induced release of these hormones. Vascular reactivity will be assessed in the whole animal and in the isolated artificially perfused renal vascular bed. These studies will be done in control and CAP treated rats before and after subpressor iv or intra- arterial (ia) infusions of VP an corticosterone or subpressor icv infusions of AII or Sar(1)Thr(8)AII.
Aim III : To test the hypothesis that baroreceptor reflex resetting in SHR is related to a direct central action of brain AII on neural centers controlling the reflex and/or an All induced alteration in VP release and that CAP induced enhancement of baroreflex sensitivity is related to alterations in brain AII mechanisms. Baroreflex control of heart rate and sympathetic activity will be assessed in control and CAP treated SHR and WKY rats, before and after central administration of AII, VP and Sar(1)Thr(8)AII.
Aim I V: To test the hypothesis that increased sympathetic tone in SHR is related to an affect of brain AII on neural centers controlling sympathetic outflow and/or an AII induced alteration in VP release and that the depressed sympathetic tone in CAP treated rats is related to an alteration in brain All mechanisms. We will assess cardiovascular and sympathetic nerve responses to posterior hypothalamic stimulation and to microinjection of AII or VP into areas of the brain thought to regulate sympathetic outflow in control and CAP treated WKY and SHR. We will also study central AII and VP-catecholamine interactions using catecholaminergic lesioning and microiontophoresis techniques. Experiments will be performed in SHR and WKY rats treated icv with CAP and with lifetime peripheral administration of CAP.
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