Losartan metabolite EXP3174 reduces the weight of formed thrombus in 2K1C hypertensive rats.

The aim of the study was to evaluate the effect of an active metabolite of losartan - EXP3174 - on a performed venous thrombus in hypertensive rat. The contribution of coagulation and fibrinolytic systems as well as platelets in the EXP3174 action was also determined. Male Wistar rats with renovascular hypertension (2K1C) were used in the study. Stasis-induced venous thrombus was allowed to age for 7 hours before intravenous injection of EXP3174 (10 mg/kg and 30 mg/kg). Thrombus reduction was then evaluated as the difference in thrombus weight 1 hour after drug or its vehiculum administration (8 h-aged thrombus). Euglobulin clot lysis time (ECLT), overall hemostasis potential (OHP), overall coagulation potential (OCP), the time to fibrin generation (TFG), and thrombin amidolytic activity were measured in blood. Collagen-induced platelet aggregation was measured in whole blood. Bleeding time (BT) and systolic blood pressure (SBP) were measured 1 hour after drug administration. EXP3174 in hypotensive doses caused a marked, dose-dependent decrease in venous thrombus weight. Shortened ECLT and decreased OCP, OHP and thrombin amidolytic activity were also observed. Platelet aggregation was significantly decreased after a higher dose of EXP3174, while no changes in BT were observed. Our study provides evidence for reduction of the weight of a formed venous thrombus by losartan metabolite - EXP3174 - in the mechanism involving enhancement of plasma fibrinolytic activity as well as reduced platelet reactivity and coagulation inhibition in 2K1C hypertensive rats.