PREVENTION OF STROKE AND KIDNEY DYSFUNCTION BY ACE

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This is a proposal to investigate the role of the renin-angiotensin system (RAS) in the pathogenesis of renal vascular disease and stroke in stroke- prone spontaneously hypertensive rats (SHRSP). The proposal is based on our recent work demonstrating that treatment of saline-drinking SHRSP with either ACE inhibitors (enalapril, captopril, and ceranopril) or an ANG II receptor antagonist, Dup 753, results in prevention of renal vascular disease and stroke with minimal or no effect on blood pressure. Importantly, the renal vascular protective effect of ACE inhibitors in saline-drinking SHRSP could be reversed by chronic infusion of ANG II. Accordingly, the vascular protective effect of ACE inhibitors and DuP 753 is attributable to inhibition of the synthesis or blockade of the vasculotoxic actions of ANG II. Implied in this conclusion is that ANG II plays a pathophysiologic role in the development of vascular lesions that accompany salt feeding in SHRSP. The aim of this project is to determine the sequence of events relating changes in the RAS to the development of hypertension, albuminuria, vascular permeability, renal function and vascular lesions. The time-course and organ specificity for vascular permeability changes as an early marker for vascular damage will be determined in SHRSP and WKY on normal- and high-salt intake. The influence of ACE inhibitor or ANG II receptor antagonist treatment on the time-course and organ specificity for vascular permeability changes will be determined. The time-course for alterations in the RAS will be determined and correlated with the development of hypertension, albuminuria, renal dysfunction, vascular permeability and vascular lesions. Whether the ability of ACE inhibitor treatment to affect these changes is due to reductions in ANG II levels will be examined. We will also determine whether ANG II administration, either by systemic infusion or direct microperfusion into brain cerebral cortex, can reverse the protective effects of ACE inhibitor therapy in saline-drinking SHRSP and the responsiveness compared with saline-drinking WKY. Our studies will provide important information relevant to ANG II and the pathogenesis of vascular disease.