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 th e 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 ventr icle of Wistar-Kyoto rats treated for 2 weeks with Ang II (200 ng/kg/min) a nd evaluated these relations to myocardial remodeling. Rats given Ang II al one (ANGII) were compared with rats also receiving TCV-116 (ANGII-TCV). The eNOS mRNA and protein levels, and NOS activity and caveolin-1 protein expr ession in the left ventricle were significantly decreased in ANGII compared with control rats (CON), and were significantly increased in ANGII-TCV com pared with ANGII. Moreover, compared with CON, the eNOS and caveolin-1 expr ession was significantly greater in CON treated with TCV-116. ANGII showed a significant increase of the wall-to-lumen ratio, perivascular and myocard ial fibrosis, and type I collagen mRNA expression, with all these parameter s 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. (C) 2001 Elsevier Scie nce Ireland Ltd. All rights reserved.