Thiol repletion prevents venous thrombosis in rats by nitric oxide/prostacyclin-dependent mechanism: Relation to the antithrombotic action of captopril

Clinical and experimental data have recently accumulated for antithrombotic action of angiotensin-converting enzyme inhibitors (ACE-Is). We have shown previously that captopril (which contains a thiol group in the moiety) exe rts more pronounced antithrombotic activity than does an equipotent dose of enalapril (the drug devoid of the thiol group). To clarify the relative im portance of the presence of the thiol group in the molecule versus angioten sin-converting enzyme (ACE) inhibitory properties in the antithrombotic act ion of captopril, rats were treated with captopril (5 mg/kg twice daily; CA P), epicaptopril (stereoisomer of captopril devoid of ACE-inhibitory proper ties; 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 th e ENA-treated groups when compared with control rats. The effect of CAP, EP I, and ACC was accompanied by a marked reduction of euglobulin clot lysis t ime and, with the exception of ACC, by an increase in prothrombin time in t he blood collected from the site of the thrombus formation. Antithrombotic activity of EPI was completely abolished by nitric oxide synthase inhibitor NG-nitro-L-arginine methyl eater (L-NAME) or indomethacin, with the parall el reversal of fibrinolytic and coagulation parameters toward normal. Activ ated partial thromboplastin time, mean blood pressure, and bleeding time we re not altered by either of the administered drugs. Thus, we demonstrated t hat thiol compounds exert antithrombotic activity by increasing fibrinolysi s and/or suppression of the extrinsic pathway of the coagulation cascade in a nitric oxide/prostacyclin-dependent manner.