Thromboxane (Tx)A2, the predominant cyclooxygenase product of arachidonic acid, is a potent vasoconstrictor and platelet agonist in vitro. However, elucidation of the role of this eicosanoid in vivo has been constrained by its chemical instability. We have recently identified the major metabolites formed from TxB2 in the human circulation. In the first specific aim we shall explore the utility of this approach to the study of Tx biosynthesis in vivo. In particular, we wish to investigate the origin of the 11-dehydro metabolite of TxB2 in human urine and plasma. Combined analysis of this compound with 2,3-dinor-TxB2 reflects both major routes of Tx metabolism and can be used to discriminate alterations in biosynthesis from changes in metabolism. In the second specific aim, we shall combine studies of biosynthesis and interventions with defined pharmacological probes to explore the role of eicosanoids in the evolution of vascular disease in the cholesterol-fed pigtail monkey and in a newly developed canine model of coronary thrombosis. Recent analytical developments also permit us to explore the effects of pharmacological interventions on eicosanoid biosynthesis at the platelet-vascular interface in man and seek definitive evidence of trienoic thromboxane formation in vivo during omega-3 fatty acid administration. Finally, in the third specific aim we shall combine these approaches to focus on the role of TxA2 in human pathophysiology. We shall relate biochemical events to functional outcome following pharmacological interventions in human models of platelet activation; severe atherosclerosis, unstable angina and following vascular angioplasty. These studies will expand and develop our previous investigation of the role of eicosanoids in the regulation of platelet-vessel wall interactions.
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