THE ROLE OF PROSTAGLANDIN E2 IN THROMBOCYTE PHARMACOLOGY

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The use of thromboxane synthetase (TX-SYN) inhibitors as medicinals or prophylactics for a variety of cardiovascular disease states has been advocated, particularly for thrombotic diseases and other conditions in which platelet aggregation or adhesion figure. Under such treatment platelet activation will still produce PGH2 which would undergo non-enzymatic conversion to PGE2 and could cause arachidonate to be shunted to lipoxygenase pathways. A platelet PGE2 receptor has now been demonstrated (in studies at the University of Washington) and PGE2 is known to be a proaggregatory agent. The objectives of the present proposal are: 1) to complete the characterization of PGE binding sites in and on the human platelet and to determine the pharmacological consequences of efficacious receptor occupancy, 2) to determine the cross-reactivities of PGE2 with other prostaglandin binding sites, and 3) to search for a specific PGE2 receptor blocker. Regulation of thromboxane synthetase is another potential role of PGE2. Enzyme kinetics and arachidonate product distribution studies designed to test for such a role are proposed. One hypothesis which will be explored is that PGE2 can take the place of PGH2 at one of its two binding sites at TX-SYN. This model presupposes that TX-SYN has higher affinity for PGH2, and gives a more efficient conversion to thromboxane A2, in the presence of PGE2. Magnetic resonance experiments probing prostanoid binding to TX-SYN are also proposed. In order to ascertain whether the platelet actions of PGE2 are of potential concern during TX-SYN inhibition therapy, protocols for the following experiments are proposed: 1) determination of PGE2 levels (and other changes in arachidonate metabolic distribution) upon inhibition of TX-SYN and 2) determination of product distributions from arachidonate (and exogenous PGH2) upon platelet activation with PG and non-PG stimuli in the presence and absence of elevated PGE2 levels. The studies proposed should serve to elucidate possible side-effects of TX-SYN inhibitors and to determine whether TX-SYN inhibition is a defensible strategy for prophylaxis and therapy in cardiovascular medicine.