Effects of valsartan and valeryl 4-hydroxy valsartan on human platelets: a possible additional mechanism for clinical benefits.

Valsartan selectively blocks angiotensin II binding to the AT 1 receptor. ince platelet activation plays a key role in the pathogenesis of vascular disease, and because AT 1 receptors are present on the platelet surface, we assessed the in vitro effects of valsartan and its metabolite, valeryl 4-hydroxy valsartan (V4HV), on platelets in 30 subjects with multiple risk factors for cardiovascular disease. Platelet characteristics in blood samples pretreated and incubated with 10 nmol to 100 μmol concentrations of valsartan and V4HV were assessed by aggregometry, rapid platelet analyzers, and by flow cytometry. Pretreatment of blood with valsartan and V4HV resulted in inhibition of conventional plasma (ADP, P = 0.0001, valsartan; epinephrine, P = 0.0001, V4HV) and whole blood collagen-induced (P = 0.01, valsartan; P =.0001, V4HV) platelet aggregation. Closure time was delayed (P = 0.02, valsartan; P = 0.03, 4VHV), indicating platelet inhibition in whole blood under high shear conditions. Expression of many surface platelet receptors, namely GP IIb/IIIa antigen, and activity, vitronectin, p-selectin, and LAMP-1 was significantly reduced compared with autologous baseline activity. Intensity of platelet-leukocyte formation and other platelet activation markers remained unchanged. Platelet inhibition was not dose dependent and was more potent for 4VHV than valsartan in the therapeutic range. Valsartan and 4VHV exhibited significant in vitro inhibition of human platelets. Their antiplatelet properties, especially more potent activity of the metabolite appear to be independent of those of other antiplatelet agents. Whether valsartan reduces vascular ischemic events via additional pathways of platelet inhibition in patients with myocardial infarction and ischemic stroke requires further clinical research.