Valsartan improves l-NAME-exacerbated cardiac fibrosis with TGF-β inhibition and apoptosis induction in spontaneously hypertensive rats

SummaryThis 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 NG-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-β1 (TGF-β1) 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-β1. 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-β1 inhibition in the development of interstitial fibrosis in severe hypertension rat model.