Thiol Repletion Prevents Venous Thrombosis in Rats by Nitric Oxide/Prostacyclin-Dependent Mechanism: Relation to the Antithrombotic Action of Captopril

Abstract

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.

Captopril and Lisinopril Decrease Acetaldehyde Effects upon the Prothrombin Time

“…Captopril, an antihypertensive drug which contains a thiol moiety (or functional group), has been employed in pre-clinical studies on rats, as well as in clinical applications, with some mixed results. Some laboratories have reported a prolonged PT and/or APTT, while other accounts indicate a lack of effect upon APTT [9,10,12]. In this current investigation, it has been observed that coagulation response to captopril varied with captopril concentration, whereby 4.25 · 10 -3 M captopril exhibited a procoagulant effect.…”

“…Some investigations have reported anticoagulant effects of captopril [9,10]. Others, however, have seen no effect or a procoagulant effect [11,12].…”

Antithrombotic Effect of Captopril and Losartan Is Mediated by Angiotensin-(1-7)

“…[17][18][19] This striking similarity in the mode of action of both RAS blockers suggests a common mechanism leading to the liberation of NO/PGI 2 after the inhibition of RAS. Because the concentration of Ang-(1-7)-which liberates NO/PGI 2 -increases during treatment with RAS blockers 20,21 and because Ang-(1-7) may mediate some of beneficial effects of these drugs, 22,35 we thought that this peptide might be responsible for their antithrombotic action.…”

“…[52][53][54] Because the activation of this receptor is crucial for platelet aggregation, its blockade may also contribute to the antithrombotic effect of LOS. As for captopril, we have shown recently that a thiol group of this drug is important for its antithrombotic action, 19 most probably by trapping and stabilizing endogenous NO in stable S-nitroso compounds.…”

Captopril, an Angiotensin-Converting Enzyme Inhibitor, Attenuates the Severity of Acute Pancreatitis in Rats by Reducing Expression of Matrix Metalloproteinase 9

“…Previous evidence suggested that captopril can also improve the severity of inflammation through the following pathways: First, it inhibited endothelial derived growth factor (EDGF) /nitric oxide (NO) degradation through eliminating oxygen free radicals, and reinforced EDGF/NO function (Soggard et al 1996;Kanno et al 2001). Secondly, it improved microcirculatory disturbance through promoting the synthesis of vascular endothelial cell and the release of prostacyclin (Pawlak et al 2000). Thirdly, it reduced endothelin release to attenuate tissue injury (Plusczyk et al 1999).…”