BENEFICIAL EFFECT OF?COMBINED SPIRONOLACTONE AND?QUINAPRIL TREATMENT ON THROMBOSIS AND HEMOSTASIS IN?2K1C HYPERTENSIVE?RATS

摘要

A strong correlation between raised aldosterone levels and increased risk of thrombotic disorders has been provided. Clinical studies have demonstrated the benefits of the addition of the aldosterone receptor antagonist to the standard therapy with angiotensin-converting enzyme inhibitor in the reduction of cardiovascular events in patients. We suggest that the benefits of this dual renin-angiotensin-aldosterone system (RAAS) blockade may be related to the drug’s effects on the hemostatic and oxidative balance. Thus, we investigated the effect of combined spironolactone (SPIRO) and quinapril (QUIN) administration on thrombosis, hemostasis and oxidative stress in hypertensive rats. A two-kidney, one-clip model of renovascular hypertension in Wistar rats was used. QUIN, SPIRO, or QUIN + SPIRO were administered for 10 days. Venous thrombosis was induced by vena cava ligation. Thrombus weight and incidences of thrombosis were assessed. Bleeding time, platelet adhesion, tissue factor (TF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), thrombin activatable fibrynolysis inhibitor (TAFI), malonyl dialdehyde, and hydrogen peroxide plasma levels were assayed. Aortic expression of NADPH oxidase and superoxidase dismutase were measured. We observed significant RAAS activation associated with hypercoagulability and oxidative stress augmentation in renovascular hypertensive rats. Thrombosis was reduced only in rats treated with QUIN + SPIRO. In all groups, decreases in TF, PAI-1, and TAFI levels were observed, however in the QUIN + SPIRO group those changes were more pronounced. The inhibition of platelet adhesion was also stronger in rats treated with QUIN + SPIRO. The oxidative stress parameters were markedly reduced in rats treated with QUIN or SPIRO, although the most evident changes were observed in the QUIN + SPIRO group. Dual RAAS blockade with aldosterone receptor antagonist and angiotensin-converting enzyme inhibitor provides additional benefits for experimental thrombosis associated with the antiplatelet, anticoagulative, profibrinolytic, and antioxidative effects in renovascular hypertensive rats.