TCV-116 stimulates eNOS and caveolin-1 expression and improves coronary microvascular remodeling in normotensive and angiotensin II-induced hypertensive rats.

Angiotensin II (Ang II) plays an important role as a modulator of vascular structure and function in arterial hypertension. This study investigated the effects of an Ang II type 1 receptor antagonist, TCV-116, on endothelial nitric oxide synthase (eNOS) mRNA and protein expression, and NOS activity and eNOS regulatory protein caveolin-1 protein expression in the left ventricle of Wistar-Kyoto rats treated for 2 weeks with Ang II (200 ng/kg/min) and evaluated these relations to myocardial remodeling. Rats given Ang II alone (ANGII) were compared with rats also receiving TCV-116 (ANGII-TCV). The eNOS mRNA and protein levels, and NOS activity and caveolin-1 protein expression in the left ventricle were significantly decreased in ANGII compared with control rats (CON), and were significantly increased in ANGII-TCV compared with ANGII. Moreover, compared with CON, the eNOS and caveolin-1 expression was significantly greater in CON treated with TCV-116. ANGII showed a significant increase of the wall-to-lumen ratio, perivascular and myocardial fibrosis, and type I collagen mRNA expression, with all these parameters being significantly improved by TCV-116. Thus, coronary microvascular and myocardial remodeling in normotensive and Ang II-induced hypertensive rats was significantly ameliorated by a subdepressor dose of TCV-116, which may be at least in part mediated by an increase in local eNOS mRNA and protein expression, and NOS activity in the left ventricle.