Terashita Z, Imura Y, Nishikawa K
Pharmaceutical Research Laboratories I, Pharmaceutical Group Takeda chemical Industries, Ltd, Osaka, Japan.
J Lipid Mediat Cell Signal. 1996 Jan;13(1):1-8. doi: 10.1016/0929-7855(95)00009-7.
In rabbit platelet-rich plasma, a specific TXA2 synthase inhibitor, CV-4151 (isbogrel) alone modestly inhibited the platelet aggregation induced by arachidonic acid (AA); even at 10(-4) M the inhibition was less than 50% (IC40 value: 8.1 x 10(-5) M). Aspirin-treated rat aortic rings alone inhibited the AA-induced platelet aggregation by 7%. However, CV-4151 exhibited a potent antiplatelet action in the presence of the aortic rings and its IC40 value was 8.3 x 10(-8) M. Thus, the aortic rings caused 1000-fold enhancement of the antiplatelet action of CV-4151. Next, we investigated the effect of CV-4151 on the production of two highly biologically active prostanoids, TXA2 and PGI2, and the contribution of these prostanoids to the antiplatelet action of CV-4151. TXA2 and PGI2 were measured by a radioimmunoassay of their stable metabolites, TXB2 and 6-keto-PGF1 alpha, respectively. Under the experimental conditions, CV-4151 simultaneously inhibited TXA2 generation and enhanced PGI2 generation. There was a positive linear relationship (r = 0.975, p < 0.01) between % inhibition of platelet aggregation and PGI2 generation and a significant negative linear relationship (r = 0.994, p < 0.001) between % inhibition of platelet aggregation and TXA2 generation. CV-4151 exhibits a potent antiplatelet action in the presence of PGI2 synthase, which is the in vivo situation, by simultaneously inhibiting TXA2 generation and enhancing PGI2 generation.
在富含血小板的兔血浆中，一种特异性血栓素A2合成酶抑制剂CV - 4151（异波格雷）单独使用时，对花生四烯酸（AA）诱导的血小板聚集有一定程度的抑制作用；即使在10⁻⁴ M浓度下，抑制率也小于50%（IC40值：8.1×10⁻⁵ M）。单独用阿司匹林处理的大鼠主动脉环对AA诱导的血小板聚集的抑制率为7%。然而，在存在主动脉环的情况下，CV - 4151表现出强大的抗血小板作用，其IC40值为8.3×10⁻⁸ M。因此，主动脉环使CV - 4151的抗血小板作用增强了1000倍。接下来，我们研究了CV - 4151对两种具有高度生物活性的前列腺素——血栓素A2（TXA2）和前列环素（PGI2）生成的影响，以及这些前列腺素对CV - 4151抗血小板作用的贡献。TXA2和PGI2分别通过对其稳定代谢产物血栓素B2（TXB2）和6 - 酮 - 前列腺素F1α（6 - keto - PGF1α）的放射免疫测定来检测。在实验条件下，CV - 4151同时抑制TXA2的生成并增强PGI2的生成。血小板聚集抑制率与PGI2生成之间存在正线性关系（r = 0.975，p < 0.01），而血小板聚集抑制率与TXA2生成之间存在显著的负线性关系（r = 0.994，p < 0.001）。在存在PGI2合成酶的情况下（这是体内的情况），CV - 4151通过同时抑制TXA2生成和增强PGI2生成，表现出强大的抗血小板作用。
