Human platelets and blood vessels can synthesize prostaglandins and thromboxanes which have potent biological activities. Platelets produce thromboxane A2 which induces platelet aggregation and is a vasoconstrictor, as well as prostaglandin D2 which inhibits platelet aggregation. Blood vessels produce prostaglandin I2 which inhibits aggregation and is a vasodilator and recently 7e have shown that they also produce thromboxane A2. The precursor of these potent aggregating and inhibiting agents is arachidonic acid which can induce platelet aggregation in vitro and in vivo in association with prostaglandin and thromboxane synthesis. The purpose of this work is to investigate further the synthesis of prostaglandins by platelets and blood vessels and elucidate its significance in hemostasis, thrombosis and atherosclerosis. We propose to continue to investigate the mechanisms whereby arachidonic acid and other fatty acids are incorporated into the platelet phospholipids and released to become substrate for the platelet enzymes of the lipoxygenase and cyclooxygenase pathways. This study includes isolation and characterization of the lipoxygenase and the phospholipase A2 which releases arachidonic acid. We shall continue our studies on the binding of prostaglandin to platelets to characterize the receptor. We shall study the ultrastructural and biochemical responses of arteries and veins to agents which can damage these vessels or stimulate production of prostaglandin I2. Finally, we shall search for abnormal prostaglandin or thromboxane synthesis by the platelets of selected patients. The methods employed include tests of platelet aggregation and the release action, determination of phospholipase activity, transmission and scanning electron microscopy of blood vessels and qualitative determination of prostaglandins and thromboxanes by thin layer chromatography, bioassay and, radioimmunoassay.
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