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(Hypertension. 2006;48:972.)
© 2006 American Heart Association, Inc.

Original Articles

Soluble Guanylate Cyclase Stimulation on Cardiovascular Remodeling in Angiotensin II–Induced Hypertensive Rats

Hiroyuki Masuyama; Toshihiro Tsuruda; Johji Kato; Takuroh Imamura; Yujiro Asada; Johannes-Peter Stasch; Kazuo Kitamura; Tanenao Eto

From the Department of Internal Medicine (H.M., T.T., J.K., T.I., K.K., T.E.), Circulatory and Body Fluid Regulation, and Department of Pathology (Y.A.), Faculty of Medicine, University of Miyazaki, Miyazaki, Japan; the Department of Nutrition Management (T.T.), Faculty of Health and Nutrition, Minami-Kyushu University, Miyazaki, Japan; and PharmD at Cardiovascular Research (J-P.S.), Bayer HealthCare, Wuppertal, Germany.

Correspondence to Toshihiro Tsuruda, Department of Internal Medicine, Circulatory and Body Fluid Regulation, Faculty of Medicine, University of Miyazaki, 5200 Kihara Kiyotake, Miyazaki 889-1692, Japan. E-mail ttsuruda{at}med.miyazaki-u.ac.jp

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-ß1 (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.

Key Words: hypertension • fibrosis • soluble guanylate cyclase • cGMP • extracellular matrix

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