THE ROLE OF PROSTAGLANDIN E2 IN THROMBOCYTE PHARMACOLOGY

血栓烷合成酶（TX-SYN）抑制剂作为药物或 用于各种心血管疾病状态的药物已经被 提倡，特别是血栓性疾病和其他条件， 血小板聚集或粘附图。 在这种待遇下 血小板活化仍然会产生PGH 2， 非酶促转化为PGE 2，并可能导致花生四烯酸被分流 脂肪氧合酶途径。 血小板PGE 2受体现已被 证明（在华盛顿大学的研究中）和PGE 2是已知的 成为一个促进聚合的代理人 本提案的目标是： 1)为了完成PGE结合位点的表征， 人血小板，并确定药理学后果 有效的受体占有率，2）确定交叉反应性 PGE 2与其他前列腺素结合位点，和3）寻找 特异性PGE 2受体阻断剂。 血栓素合成酶的调节是PGE 2的另一个潜在作用。 酶动力学和花生四烯酸产物分布研究， 提出了对这种作用测试。 我们将探讨的一个假设是 PGE 2可以在PGH 2的两个结合位点之一取代PGH 2， TX-SYN。 该模型假定TX-SYN对PGH 2具有更高的亲和力， 并在存在下更有效地转化为血栓烷A2， 前列腺素E2。 探测前列腺素类与TX-SYN结合的磁共振实验 也提出了。 为了确定PGE_2的血小板作用是否具有潜在的 TX-SYN抑制治疗期间的问题，以下方案 实验提出：1）测定PGE 2水平（和其他 花生四烯酸代谢分布的变化） 和2）测定来自花生四烯酸（和 外源性PGH 2）在PG和非PG刺激的血小板活化后， 存在和不存在升高的PGE 2水平。 拟议的研究应有助于阐明 TX-SYN抑制剂，并确定TX-SYN抑制是否是TX-SYN抑制剂。 预防和治疗心血管疾病的防御策略。

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.