We propose to determine the distinct biological and chemical properties, and to pharmacologically manipulate the synthesis and actions of thromboxanes, endoperoxides, prostacyclins, and prostaglandins in several biological systems. 1. This proposal will attempt to delineate the intrinsic pathophysiological roles and interactions between components of the arachidonic acid metabolic pathway in blood vessels and platelets in the regulation and function of vascular tone and thrombosis. 2. We propose to establish (in intact animals) the selective vulnerability to inhibition of vascular prostacyclin production versus platelet thromboxane production. In addition, we intend to study the mechanism of action and utility of anti-thrombotic drugs. 3. We propose to study the potential role of intrinsic hydroperoxy fatty acids as modulators of prostacyclin synthesis and its impact in the regulation of vascular tone. 4. We will characterize the structural determinants for the fatty acid, prostaglandins, prostacyclin and thromboxane synthetic enzymes and for receptor recognition and activation in platelets and blood vessels. 5. Finally, we propose to continue our studies of the triene prostaglandins. We will also evaluate the role and potential of PGD3 as an anti-thrombotic agent, as well as characterize the utility and mechanism of eicosapentaenoate as a competitor of arachidonate on synthetic enzymes. Ultimately, we plan to utilize dietary manipulation to increase eicosapentaenoate and reduce arachidonate tissue and platelet levels in an attempt to manipulate in vivo platelet-blood vessel interactions such as thrombosis and vasospasms.
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