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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL030400-07
Application #
3341430
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1983-04-01
Project End
1992-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Kunitada, S; FitzGerald, G A; Fitzgerald, D J (1992) Inhibition of clot lysis and decreased binding of tissue-type plasminogen activator as a consequence of clot retraction. Blood 79:1420-7

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