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.
Kobayashi
N
N
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. a-fukuda@dokkyomed.ac.jp
Mori
Y
Y
Nakano
S
S
Tsubokou
Y
Y
Kobayashi
T
T
Shirataki
H
H
Matsuoka
H
H
D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000473:pathology; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D051242:Caveolin 1; D022461:Caveolins / Q000096:biosynthesis*; D024042:Collagen Type I / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000473:pathology; D015870:Gene Expression; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; C495537:Cav1 protein, rat; D051242:Caveolin 1; D022461:Caveolins; D024042:Collagen Type I; D009573:Nitrites; D012333:RNA, Messenger; D013777:Tetrazoles; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; C077793:candesartan cilexetil