Stroke constitutes a major health problem in our society. One approach to its prophylaxis and treatment has been to alter prostaglandin synthesis by administering drugs which modify arachidonic acid (AA) metabolism in platelets (plt) and blood vessels. We propose to study the mechanisms regulating the metabolism of AA in cultures of component cells of cerebral and other vessels following the addition of plt contents and circulating vasoactive su stances. We have observed a marked stimulation of PGI2 synthesis (as measured by 6-keto PGF1 Alpha) after the addition of plt derived growth factor (PDGF), to endothelial and smooth muscle cells in culture. Serotonin (5HT) also stimulated PGI2 production by smooth muscle cells, an effect which appeared due to a specific 5HT receptor-mediated interaction. The ability of 5HT to stimulate PGI2 synthesis became markedly enhanced by the presence of PDGF. Specific issues which we propose to address include: A) a characterization of cyclooxygenation and lipoxygenation products made by vascular cells harvested from cerebral and peripheral large and small blood vessels from bovine and human species (RIA and HPLC) B) a description of the smooth muscle 5 HT receptor and its modulation by PDGF using pharmacological and ligand binding techniques. C) a description of the changes in phospholipids and membrane components that follow receptor activation by 5HT and PDGF (HPLC). By so doing, we will test the hypothesis that plt products and other circulating and tissue-derived molecules are important receptor-mediated regulators of AA metabolism in vascular cells. It is important to study the regulation of AA metabolism in endothelium and smooth muscle from cerebral and periphral vessels since the administration of prostaglandins (and related compounds) or drugs which alter their production represents a potentially important therapeutic strategy to reduce the propensity of vessels to thrombose or undergo spasm. Moreover, recent evidence indicates that lipoxygenation products are important vasocactive molecules which also possess both chemotactic and chemokinetic properties; hence a study of AA metabolism by vascular cells from a """"""""stroke- and trauma-prone"""""""" organ such as the brain appears even more compelling.
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