Published Online
on September 18, 2006

A more recent version of this article appeared on November 1, 2006

This Article Full Text (PDF) Data Supplement All Versions of this Article: 48/5/972    most recent 01.HYP.0000241087.12492.47v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Masuyama, H. Articles by Eto, T. Search for Related Content PubMed PubMed Citation Articles by Masuyama, H. Articles by Eto, T. Related Collections Hypertension - basic studies

Submitted on May 18, 2006
Revised on June 6, 2006

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; and 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.

^* To whom correspondence should be addressed. E-mail: ttsuruda{at}med.miyazaki-u.ac.jp.

Abstract--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-1 (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

This article has been cited by other articles:

				T. Tsuruda, K. Hatakeyama, H. Masuyama, Y. Sekita, T. Imamura, Y. Asada, and K. Kitamura Pharmacological stimulation of soluble guanylate cyclase modulates hypoxia-inducible factor-1{alpha} in rat heart Am J Physiol Heart Circ Physiol, October 1, 2009; 297(4): H1274 - H1280. [Abstract] [Full Text] [PDF]

				M. P. Ruiz-Torres, M. Griera, A. Chamorro, M. L. Diez-Marques, D. Rodriguez-Puyol, and M. Rodriguez-Puyol Tirofiban increases soluble guanylate cyclase in rat vascular walls: pharmacological and pathophysiological consequences Cardiovasc Res, April 1, 2009; 82(1): 125 - 132. [Abstract] [Full Text] [PDF]

				T. Nagayama, M. Zhang, S. Hsu, E. Takimoto, and D. A. Kass Sustained Soluble Guanylate Cyclase Stimulation Offsets Nitric-Oxide Synthase Inhibition to Restore Acute Cardiac Modulation by Sildenafil J. Pharmacol. Exp. Ther., August 1, 2008; 326(2): 380 - 387. [Abstract] [Full Text] [PDF]

				B. Williams The Year in Hypertension J. Am. Coll. Cardiol., May 6, 2008; 51(18): 1803 - 1817. [Full Text] [PDF]

				B. Kemp-Harper and R. Feil Meeting Report: cGMP Matters Sci. Signal., March 4, 2008; 1(9): pe12 - pe12. [Abstract] [Full Text] [PDF]

				D. A. Heaton, D. Li, S. C. Almond, T. A. Dawson, L. Wang, K. M. Channon, and D. J. Paterson Gene Transfer of Neuronal Nitric Oxide Synthase into Intracardiac Ganglia Reverses Vagal Impairment in Hypertensive Rats Hypertension, February 1, 2007; 49(2): 380 - 388. [Abstract] [Full Text] [PDF]

				V. Franco and S. Oparil Is There a New Treatment for Hypertensive Disease in the Horizon?: Role of Soluble Guanylate Cyclase Hypertension, November 1, 2006; 48(5): 822 - 823. [Full Text] [PDF]