Pawlak R, Chabielska E, Matys T, Kucharewicz I, Rółkowski R, Buczko W
Department of Pharmacodynamics, Medical University of Białystok, Poland.
J Cardiovasc Pharmacol. 2000 Oct;36(4):503-9. doi: 10.1097/00005344-200010000-00014.
Clinical and experimental data have recently accumulated for antithrombotic action of angiotensin-converting enzyme inhibitors (ACE-1s). We have shown previously that captopril (which contains a thiol group in the moiety) exerts more pronounced antithrombotic activity than does an equipotent dose of enalapril (the drug devoid of the thiol group). To clarify the relative importance of the presence of the thiol group in the molecule versus angiotensin-converting enzyme (ACE) inhibitory properties in the antithrombotic action of captopril, rats were treated with captopril (5 mg/kg twice daily; CAP), epicaptopril (stereoisomer of captopril devoid of ACE-inhibitory properties; 5 mg/kg twice daily; EPI), N-acetylcysteine (3.75 mg/kg twice daily; ACC), enalapril (3 mg/kg once daily; ENA), or distilled water (VEH) for 10 days, per os. After ligation of the vena cava, the incidence of the venous thrombosis and/or the thrombus weight decreased significantly in all but the ENA-treated groups when compared with control rats. The effect of CAP, EPI, and ACC was accompanied by a marked reduction of euglobulin clot lysis time and, with the exception of ACC, by an increase in prothrombin time in the blood collected from the site of the thrombus formation. Antithrombotic activity of EPI was completely abolished by nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) or indomethacin, with the parallel reversal of fibrinolytic and coagulation parameters toward normal. Activated partial thromboplastin time, mean blood pressure, and bleeding time were not altered by either of the administered drugs. Thus, we demonstrated that thiol compounds exert antithrombotic activity by increasing fibrinolysis and/or suppression of the extrinsic pathway of the coagulation cascade in a nitric oxide/prostacyclin-dependent manner.
最近，有关血管紧张素转换酶抑制剂（ACE-1s）抗血栓形成作用的临床和实验数据不断积累。我们之前已经表明，卡托普利（其分子部分含有巯基）比等剂量的依那普利（不含巯基的药物）具有更显著的抗血栓形成活性。为了阐明分子中巯基的存在与血管紧张素转换酶（ACE）抑制特性在卡托普利抗血栓形成作用中的相对重要性，将大鼠经口给予卡托普利（5mg/kg，每日两次；CAP）、依匹卡托普利（卡托普利的立体异构体，无ACE抑制特性；5mg/kg，每日两次；EPI）、N-乙酰半胱氨酸（3.75mg/kg，每日两次；ACC）、依那普利（3mg/kg，每日一次；ENA）或蒸馏水（VEH），持续10天。腔静脉结扎后，与对照大鼠相比，除ENA治疗组外，所有组的静脉血栓形成发生率和/或血栓重量均显著降低。CAP、EPI和ACC的作用伴随着优球蛋白凝块溶解时间的显著缩短，除ACC外，血栓形成部位采集的血液中凝血酶原时间延长。一氧化氮合酶抑制剂N(G)-硝基-L-精氨酸甲酯（L-NAME）或吲哚美辛可完全消除EPI的抗血栓形成活性，同时纤溶和凝血参数平行恢复正常。活化部分凝血活酶时间、平均血压和出血时间均未因所给药物而改变。因此，我们证明了巯基化合物通过以一氧化氮/前列环素依赖的方式增加纤溶和/或抑制凝血级联的外源性途径发挥抗血栓形成活性。
