Platelet activation in hypertension associated with hypercholesterolemia: Effects of irbesartan

Abstract

Aim: The aim of this study was to determine the effect of simultaneous hypertension and hypercholesterolemia on platelet activation, nitric oxide (NO) production and oxidative stress, and to evaluate the role of irbesartan, an angiotensin II type 1 receptor antagonist. Methods: Golden Syrian hamsters were divided into three groups: controls, C (fed a standard diet); hypertensive-hypercholesterolemic, HH (fed a diet enriched in 3% cholesterol, 15% butter and 8% NaCl, for 4 months); and hypertensive-hypercholesterolemic treated with irbesartan, HHI (fed as HH group, plus irbesartan 10 mg kg-1 per day, for 4 months). Results: Compared with the C group, platelets isolated from the HH group showed: morphological modifications; increased integrin β3 exposure and protein expression of P-selectin, FAK, PI3K, Akt and Src; reduced eNOS protein expression and NO production; higher generation of ROS, mostly produced by NADPH-oxidase, cyclooxygenase-1 (COX-1) and 12-lipoxygenase; and enhanced NAD(P)H oxidase activity and protein expression of gp91phox and p22phox subunits, 12-lipoxygenase, COX-1, cPLA2 and PKC. Compared with the HH group, the treatment with irbesartan (HHI group) significantly attenuates the changes in all the molecules tested, reduces platelet aggregation, and improves intraplatelet redox balance. Conclusions: Experimental hypertension associated with hypercholesterolemia produces major changes in morphology, signaling mechanisms and oxidative stress in blood platelets. These changes were significantly diminished by irbesartan administration, which functions as an antioxidant on platelets. © 2010 International Society on Thrombosis and Haemostasis.