Valsartan improves L-NAME-exacerbated cardiac fibrosis with TGF-ß inhibition and apoptosis induction in spontaneously hypertensive rats.
This study was designed to investigate whether chronic angiotensin II type 1 receptor blockade inhibits ventricular interstitial fibrosis with the induction of programmed cell death (apoptosis) in prolonged nitric oxide synthase (NOS) inhibition using N(G)-nitro-l-arginine methyl ester (L-NAME) in spontaneously hypertensive rats (SHR). Four groups of 20-week-old male SHR were studied for 3 weeks: the control group; the L-NAME group given 80 mg/L L-NAME in drinking water; and the groups given 1 or 30 mg/(kg day) of valsartan, respectively, with L-NAME. The L-NAME group showed marked cardiac tissue injuries with elevated blood pressure such as interstitial fibrosis, intimal thickening of small arteries, and myocardial necrosis. Caspase-3, an apoptosis inducer, immunoreactivity was increased in interstitial cells, and the tissue RNA expression of transforming growth factor-ß(1) (TGF-ß(1)) was also increased in the L-NAME group. Low-dose valsartan treatment did not affect blood pressure or cardiac weight but alleviated the L-NAME-induced interstitial fibrosis with increased mRNA level of caspase-3 in interstitial fibroblasts. High-dose valsartan significantly lowered blood pressure and decreased the mRNA levels of caspase-3 and TGF-ß(1). These data suggest that low-dose valsartan inhibits interstitial fibrosis by promoting apoptosis of the fibroblasts without blood pressure changes, which may provide the TGF-ß(1) inhibition in the development of interstitial fibrosis in severe hypertension rat model.
Akashiba
Akira
A
Department of Hypertension and Cardiorenal Medicine, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan.
Ono
Hidehiko
H
Ono
Yuko
Y
Ishimitsu
Toshihiko
T
Matsuoka
Hiroaki
H
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000494:pharmacology; D005355:Fibrosis; D006973:Hypertension / Q000473:pathology*; D008297:Male; D009206:Myocardium / Q000473:pathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D012313:RNA / Q000032:analysis; D051381:Rats; D011918:Rats, Inbred SHR; D013777:Tetrazoles / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D020257:Ventricular Remodeling / Q000187:drug effects*
D047228:Angiotensin II Type 1 Receptor Blockers; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D012313:RNA; D000068756:Valsartan; D053148:Caspase 3; D014633:Valine; D019331:NG-Nitroarginine Methyl Ester