Matsumoto Y, Marukawa K, Okumura H, Adachi T, Tani T, Kimura Y
Thrombosis and Vascular Research Laboratory, Department of Advanced Pharmacology, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
Thromb Res. 1999 Jul 1;95(1):19-29. doi: 10.1016/s0049-3848(98)00189-3.
Among various categories of antiplatelet drugs, cAMP-elevating agents and GP IIb/IIIa antagonists have been reported to inhibit platelet aggregation stimulated by a wide variety of platelet agonists. To clarify the qualitative difference between these two agents, their effects on various platelet responses in washed platelets evoked by thrombin (0.05 U/mL) were compared in vitro. Two types of cAMP-elevating drugs, cilostazol (a phosphodiesterase III inhibitor) and prostaglandin E1 (an adenylate cyclase activator), both inhibited platelet aggregation, thromboxane A2 formation, and platelet factor 4 release in a concentration-dependent manner. In addition, both agents suppressed intracellular Ca++ elevation induced by thrombin. However, two classes of GP IIb/IIIa antagonists, abciximab (Fab fragment of antibody) and tirofiban (a synthetic compound), showed no inhibitory effects against thromboxane A2 formation and platelet factor 4 release, although these drugs inhibited platelet aggregation. Essentially the same results were obtained in platelet-rich plasma stimulated with high concentration (100 microM) of thrombin receptor activating peptide. In contrast to these different profiles on thromboxane A2 formation and release reaction, both cAMP-elevating agents and GP IIb/IIIa antagonists potently suppressed procoagulant activity in thrombin-stimulated platelets. These results suggest that the development of platelet procoagulant activity induced by thrombin is exclusively dependent on platelet aggregation or aggregation-dependent processes. These observations also indicate that cAMP-elevating agents possess wider inhibitory effects on platelet responses evoked by strong agonists than GP IIb/IIIa antagonists.
在各类抗血小板药物中，据报道，环磷酸腺苷（cAMP）升高剂和糖蛋白IIb/IIIa拮抗剂可抑制多种血小板激动剂刺激引起的血小板聚集。为了阐明这两种药物之间的质性差异，我们在体外比较了它们对凝血酶（0.05 U/mL）诱导的洗涤血小板中各种血小板反应的影响。两种类型的cAMP升高药物，西洛他唑（一种磷酸二酯酶III抑制剂）和前列腺素E1（一种腺苷酸环化酶激活剂），均以浓度依赖性方式抑制血小板聚集、血栓素A2形成和血小板因子4释放。此外，这两种药物均抑制凝血酶诱导的细胞内钙离子升高。然而，两类糖蛋白IIb/IIIa拮抗剂，阿昔单抗（抗体的Fab片段）和替罗非班（一种合成化合物），尽管抑制血小板聚集，但对血栓素A2形成和血小板因子4释放无抑制作用。在用高浓度（100 microM）凝血酶受体激活肽刺激的富血小板血浆中也获得了基本相同的结果。与这些在血栓素A2形成和释放反应上的不同表现相反，cAMP升高剂和糖蛋白IIb/IIIa拮抗剂均有效抑制凝血酶刺激的血小板中的促凝活性。这些结果表明，凝血酶诱导的血小板促凝活性的发展完全依赖于血小板聚集或聚集依赖性过程。这些观察结果还表明，与糖蛋白IIb/IIIa拮抗剂相比，cAMP升高剂对强激动剂引起的血小板反应具有更广泛的抑制作用。
