THE ROLE OF PROSTAGLANDIN E2 IN THROMBOCYTE PHARMACOLOGY

血栓素合成酶(TX-SYN)抑制剂作为药物或 针对各种心血管疾病状态的预防药物已经被 提倡，特别是针对血栓性疾病和其他疾病 哪些是血小板聚集或黏附的图形。在这样的待遇下 血小板激活仍然会产生PGH2，它会经历 非酶转化为PGE2，并可能导致花生四烯酸分流 脂氧合酶途径。一种血小板PGE2受体现在已经 证明(在华盛顿大学的研究中)和PGE2已知 成为一名促凝剂。本提案的目标是： 1)完成PGE结合部位的鉴定 并确定其药理作用。 有效受体占有率，2)确定其交叉反应性 PGE2和其他前列腺素结合位点，以及3)搜索 特异性PGE2受体阻滞剂。 PGE2的另一个潜在作用是调节血栓素合成酶。 酶动力学和花生四烯酸产物分布研究旨在 对这一角色的测试提出了建议。将探索的一个假说 PGE2可以在它的两个结合位点之一上取代PGH2 TX同步。该模型假设TX-SYN对PGH2具有较高的亲和力， 并在存在的情况下更有效地转化为血栓素A2 PGE2。前列腺素与TX-SYN结合的磁共振实验 也提出了一些建议。 为了确定前列腺素E_2是否具有潜在的血小板作用 TX-SYN抑制治疗中的注意事项，以下方案 实验建议：1)测定前列腺素E_2水平(和其他 抑制TX-SYN后花生四烯酸代谢分布的变化 和2)花生四烯酸产物分布的测定(和 外源性前列腺素H_2)对PG和非PG刺激下的血小板活化的影响 有无PGE2水平升高。 建议的研究应该有助于阐明 TX-SYN抑制剂，并确定TX-SYN抑制是否是 心血管医学中预防和治疗的防御性策略。

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.