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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL023603-15
Application #
3337310
Study Section
Pathology A Study Section (PTHA)
Project Start
1978-07-01
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1994-06-30
Support Year
15
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Wayne State University
Department
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Kumar, M; Grammas, P; Giacomelli, F et al. (1996) Selective expression of c-mas proto-oncogene in rat cerebral endothelial cells. Neuroreport 8:93-6
Wiener, J; Lombardi, D M; Su, J E et al. (1996) Immunohistochemical and molecular characterization of the differential response of the rat mesenteric microvasculature to angiotensin-II infusion. J Vasc Res 33:195-208
Grammas, P; Diglio, C; Giacomelli, F et al. (1994) Growth properties and receptor expression in vascular smooth muscle cells from hypertensive rats. Clin Exp Hypertens 16:207-27
Diglio, C A; Liu, W; Grammas, P et al. (1993) Isolation and characterization of cerebral resistance vessel endothelium in culture. Tissue Cell 25:833-46
Grammas, P; Giacomelli, F; Bessert, D et al. (1991) Angiotensin II and atrial natriuretic factor receptor interactions at the blood-brain barrier. Brain Res 562:93-7
Grammas, P; Caspers, M L (1991) The effect of aluminum on muscarinic receptors in isolated cerebral microvessels. Res Commun Chem Pathol Pharmacol 72:69-79
Caspers, M L; Kwaiser, T M; Grammas, P (1990) Control of [3H]ouabain binding to cerebromicrovascular (Na+ + K+)-ATPase by metal ions and proteins. Biochem Pharmacol 39:1891-5
Mooradian, D L; Diglio, C A (1990) Effects of epidermal growth factor and transforming growth factor-beta 1 on rat heart endothelial cell anchorage-dependent and -independent growth. Exp Cell Res 186:122-9
Grammas, P; Dereski, M O; Diglio, C et al. (1989) Autonomic receptor interactions in isolated cardiac myocytes from hypertensive rats. J Mol Cell Cardiol 21:807-15
Grammas, P; Diglio, C; Giacomelli, F et al. (1989) Cerebrovascular angiotensin II receptors in spontaneously hypertensive rats. J Cardiovasc Pharmacol 13:227-32

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