The proposed research program focuses on diacylglycerol formation in vascular smooth muscle. Diacylglycerol (DG), one of the major putative second messengers of the phosphoinositide system, will be measured in both cultured vascular smooth muscle cells (VSMC) and intact rat aorta. Biochemical and physiological mechanisms controlling agonist-induced DG formation will be defined, and the role of DG in sustaining vascular smooth muscle contraction will be examined. Radioisotopic labelling, subcellular fractionation, and chromatogtaphic separation will be used to quantitate and localize lipids, and measurement of isometric force developed by ring segments of aorta will be used to quantitate contraction.
Specific aims i nclude: 1) determining the ionic and endocytotic mechanisms controlling sustained angiotensin II-induced DG formation in VSMC; 2) characterizing angiotensin II- and norepinephrine-stimulated phosphoinositide hydrolysis and DG production in intact rat aorta and comparing it with that produced by angiotensin II in VSMC; 3) determining the physiological or biochemical bases for any observed differences in phosphoinositide metabolism between cultured cells and intact aorta; and 4) determining whether DG/protein kinase C has a role in sustaining vascular smooth muscle contraction. These studies should provide important basic information on the cellular mechanisms controlling the sustained phosphoinositide response in vascular smooth muscle and their relationship to contraction. Understanding the mechanisms of normal vascular responsiveness should provide insight into the pathophysiology of hypertension and atherosclerosis.
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