The long-term goal of this project is to elucidate the pathogenesis of hypertensive cardiovascular disease. It is generally accepted that the complications of hypertension result from the increase in wall stress secondary to the elevated blood pressure. Work from this laboratory during the previous project period has shown that vascular and myocardial lesions can develop in circulations (cerebral and coronary) protected from the elevated blood pressure. We have also shown recently that increased nonlysosomal and lysosomal proteases are associated with the myocardial necrosis of hypertensive cardiomyopathy. It is our working hypothesis that these vascular alterations are mediated by neurohumoral agents that modify the normal balance between vasoconstrictor-vasodilator processes, and thereby initiate a cascade of cellular events that result in overt injury in hypertension, while the myocyte proteases are involved in the initiation and progression of cardiac necrosis. In order to test this hypothesis we plan: 1) to evaluate by radioligand binding techniques the interaction between noradrenergic, angiotensin II and muscarinic receptors in isolated cerebral cortical microvessels from Wistar rats (WR) with short term two-kidney, one clip Goldblatt hypertension: 2) to assess in cerebral cortical microvessels the effects of noradrenergic, angiotensin II and muscarinic cholinergic stimulation on calcium uptake, phosphorylation of myosin light chain, and generation of cyclic nucleotides; 3) to measure the biological activity of relaxing substance released by muscarinic agonists from cerebral cortical microvessels, and determine how the release of this relaxing substance is modulated by noradrenergic agonists and angiotensin II, and how it is affected in hypertension; 4) to study the involvement of an ATP-dependent alkaline protease in myofibrillar protein breakdown in hypertensive cardiomyopathy using a case-inolytic assay; 5) to correlate development of myocardial necrosis with protease activity following administration of lysosomal inhibitors and a calcium channel blocker in hypertensive cardiomyopathy; and 6) to explore the initiation of cardiac myocyte necrosis by studying protease activities in a system [acute(angiotensin II-induced) hypertension] where lesions develop over a few hours, and adrenoreceptor blockade permits a discrimination between the effects of elevated blood pressure and vasoactive agents on myocardium.
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