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(Hypertension. 2009;54:633.)
© 2009 American Heart Association, Inc.

Original Articles

Aliskiren Enhances the Protective Effects of Valsartan Against Cardiovascular and Renal Injury in Endothelial Nitric Oxide Synthase–Deficient Mice

Eiichiro Yamamoto; Keiichiro Kataoka; Yi-Fei Dong; Taishi Nakamura; Masaya Fukuda; Yoshiko Tokutomi; Shinji Matsuba; Hisato Nako; Naomi Nakagata; Takehito Kaneko; Hisao Ogawa; Shokei Kim-Mitsuyama

From the Departments of Pharmacology and Molecular Therapeutics (E.Y., K.K., Y.-F.D., T.N., M.F., Y.T., S.M., H.N., S.K.-M.) and Cardiovascular Medicine (H.O.), Kumamoto University Graduate School of Medical Sciences, Honjyo, Kumamoto, Japan; Division of Reproductive Engineering (N.N., T.K.), Institute of Resource Development and Analysis, Kumamoto University, Honjo, Kumamoto, Japan.

Correspondence to Shokei Kim-Mitsuyama, Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjyo, Kumamoto 860-8556, Japan. E-mail kimmitsu{at}gpo.kumamoto-u.ac.jp

The protective effect of aliskiren, a direct renin inhibitor, against hypertensive cardiovascular and renal injury remains to be defined. This study was undertaken to examine the protective effects of the combination of aliskiren and valsartan, an angiotensin receptor blocker, against cardiovascular and renal injury. Endothelial NO synthase–deficient mice, subjected to cuff injury of femoral artery, were divided into 5 groups and were treated with the following: (1) vehicle; (2) aliskiren (25 mg/kg per day); (3) valsartan (8 mg/kg per day); (4) combined aliskiren (12.5 mg/kg per day) and valsartan (4 mg/kg per day); and (5) hydralazine (10 mg/kg per day) for 4 weeks. Aliskiren and valsartan alone markedly and similarly suppressed cardiac hypertrophy, inflammation and fibrosis, and coronary remodeling; prevented cuff injury–induced arterial intimal thickening; and reduced urinary albumin excretion, glomerular inflammation, and glomerulosclerosis in endothelial NO synthase–deficient mice. These beneficial effects of aliskiren and valsartan were associated with the significant attenuation of oxidative stress in these tissues. Hence, aliskiren and valsartan markedly exert the protective effects against cardiovascular and renal injury through the reduction of oxidative stress. Furthermore, compared with monotherapy with aliskiren or valsartan, the combination of a half dose of these drugs more greatly improved the above-mentioned cardiovascular and renal injuries of endothelial NO synthase–deficient mice, which were associated with greater attenuation of tissue oxidative stress by the combination therapy. Thus, the combination of aliskiren and valsartan exerts the synergistic organ-protective effects through synergistic attenuation of oxidative stress. The combination of aliskiren and valsartan seems to be a promising therapeutic strategy for hypertensive organ injury caused by endothelial NO synthase dysfunction.

Key Words: eNOS • oxidative stress • combination therapy • synergistic effect • inflammation