It is unknown whether long-term pharmacological stimulation of soluble guanylate cyclase (sGC), elevating intracellular cGMP levels, has a beneficial effect on hypertension. The purpose of this study is to investigate the effects of BAY41-2272, an orally available sGC stimulator, on cardiovascular remodeling in hypertensive rats. Eight-week-old male Wistar rats with hypertension induced by angiotensin II infused subcutaneously at 250 ng/kg per minute were treated orally with a low ([L] 2 mg/kg per day) or high ([H] 10 mg/kg per day) dose of BAY41-2272 for 14 days. BAY41-2272-H partially suppressed the rise in blood pressure and reduced the heart weight (4.20±0.34 versus 3.68±0.20 mg/g; P<0.01), whereas BAY41-2272-L had no effect. However, both doses decreased the angiotensin II–induced left ventricular accumulation of collagen in the perivascular area (L, −20%, P<0.05; H, −30%, P<0.01) and myocardial interstitium (L, −21%, P<0.05; H, −38%, P<0.01), reducing the number of activated fibroblasts surrounding coronary arteries (L, −74%; H, −79%; P<0.05). BAY41-2272 downregulated the angiotensin II–induced left ventricular gene expression of type 1 collagen (L, −41%, P<0.05; H, −49%, P<0.01) and transforming growth factor-β1 (L, −49%, P<0.05; H, −65%, P<0.01). cGMP levels were elevated by BAY41-2272 not only in the left ventricle, but also in cultured cardiac fibroblasts, resulting in reduced thymidine incorporation into the cells. Thus, stimulation of sGC by BAY41-2272 attenuates fibrosis of the left ventricle in rats with angiotensin II–induced hypertension partly in a pressure-independent manner, suggesting an important role for sGC generating cGMP in inhibiting cardiovascular remodeling.