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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:556.)
© 2007 American Heart Association, Inc.

Vascular Biology

Pravastatin Enhances Beneficial Effects of Olmesartan on Vascular Injury of Salt-Sensitive Hypertensive Rats, via Pleiotropic Effects

Eiichiro Yamamoto; Takuro Yamashita; Tomoko Tanaka; Keiichiro Kataoka; Yoshiko Tokutomi; Zhong-Fang Lai; Yi-Fei Dong; Shinji Matsuba; Hisao Ogawa; Shokei Kim-Mitsuyama

From the Departments of Pharmacology and Molecular Therapeutics (E.Y., T.Y., T.T., K.K., Y.T., Z.-F.L., Y.-F.D., S.M., S.K.-M.) and Cardiovascular Medicine (H.O.), Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan.

Correspondence to Shokei Kim-Mitsuyama, MD, PhD, 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

Objective— This work was undertaken to investigate comparative effect of AT1 receptor blocker (ARB), 3-hydroxy-3-methylglutaryl (HMG) coenzymeA (CoA) reductase inhibitor (statin), and their combination on vascular injury of salt-sensitive hypertension.

Methods and Results— Salt-loaded Dahl salt-sensitive hypertensive rats (DS rats) were treated with (1) vehicle, (2) hydralazine (5 mg/kg/d), (3) olmesartan (0.5 mg/kg/d), (4) pravastatin (100 mg/kg/d), and (5) combined olmesartan and pravastatin for 4 weeks. Olmesartan or pravastatin significantly and comparably improved vascular endothelium-dependent relaxation to acetylcholine, coronary arterial remodeling, and eNOS activity of DS rats. Olmesartan prevented vascular eNOS dimer disruption or the downregulation of dihydrofolate reductase (DHFR) more than pravastatin, whereas Akt phosphorylation was enhanced by pravastatin but not olmesartan, indicating differential pleiotropic effects between olmesartan and pravastatin. Add-on pravastatin significantly enhanced the improvement of vascular endothelial dysfunction and remodeling by olmesartan in DS rats. Moreover, pravastatin enhanced the increase in eNOS activity by olmesartan, being associated with additive effects of pravastatin on phosphorylation of Akt and eNOS.

Conclusions— Olmesartan and pravastatin exerted beneficial vascular effects in salt-sensitive hypertension, via differential pleiotropic effects. Pravastatin enhanced vascular protective effects of olmesartan. Thus, the combination of ARB with statin may be the potential therapeutic strategy for vascular diseases of salt-sensitive hypertension.

Olmesartan, pravastatin, and their combination were compared on vascular effects in salt-sensitive hypertensive rats (SS rats). Olmesartan or pravastatin improved vascular injury of SS rats, via different pleiotropic effects. Pravastatin enhanced vascular effect of olmesartan, via Akt and eNOS. ARB combined with statin is useful for treatment of salt-sensitive hypertension.

Key Words: eNOS dimers • DHFR • oxidative stress • vascular injury • combined ARB and statin

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