Our long term goals are to expand our knowledge concerning mechanisms regulating brain microcirculation. These mechanisms are vitally important in providing appropriate flow to the brain, whose function is especially sensitive to impaired delivery of oxygen and nutrients. Present studies focus on the role of endothelium in controlling diameter of arterioles, and on the ways in which endothelial damage can derange flow. Two groups of studies are planned. All are relatively unique because they are conducted on microcirculation in vivo. Surface arterioles on the mouse brain are observed by intravital microscopy. The first group of studies investigates the role of endothelium in producing relaxing or constricting factors (EDRFs, EDCFs) when stimulated by selective vasoactive agonists or during autoregulation to an increase in blood pressure. Endothelial injury, produced in situ by helium neon laser/Evans blue causes a focus of lost capacity to produce EDRFs or EDCFs and provides a method for testing which agonists are dependent upon such an endothelial mechanism for their action. Pharmacologic probes, followed by chemical measurements will be used to determine the chemical nature of the endothelium derived mediators (e.g. prostanoids, other eicosanoids). We will also use pharmacologic probes to determine the role of protein kinase C, and of guanylate or adenylate cyclase and of L-arginine in mediating the synthesis, release or effects of the endothelium derived mediators. The second group of studies concerns the production of platelet aggregation by endothelial injury in the arterioles. Pharmacologic probes will be used to study the role of altered synthesis/release of an antiaggregant endothelium derived relaxing factor in promoting local platelet adhesion/aggregation at a site injured by light/dye. The capture of embolizing platelets at such a site will be studied for its relevance to repetitive symptoms of transient ischemic attacks. Pharmacologic probes will be used to assess the role of increased release of such an EDRF in decreasing platelet aggregation when flow and shear are increased. The role of L-arginine in regulating the antiaggregating and antiadhesive properties of this EDRF will be investigated.
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