1. ¹Pharmacology & Toxicology, Morehouse School of Medicine, Atlanta, Georgia
2. ²Merck & Co, Inc., Endocrinology and Atherosclerosis, New Point, New Jersey

Correspondence: Dr. Mohamed A. Bayorh, Department of Pharmacology/Toxicology, Morehouse School of Medicine, 720 Westview Drive, S.W., Atlanta, GA 30310-1495 E-mail: bayorh@msm.edu

^*This study was supported, in part, by NIH grant S06GM08248-12 and NASA grant NCC9-112.

Received 4 January 2005; Revised 14 April 2005; Accepted 12 May 2005.

Abstract

Background: The renin-angiotensin-aldosterone system and oxidative stress play a major role in the pathogenesis of hypertension.

Methods: We examined the effects of simvastatin, an HMG-CoA inhibitor, and losartan, an angiotensin type 1 receptor antagonist, in Dahl rats fed a high salt diet (8% NaCl), and treated with either simvastatin (3 mg/kg/d), losartan (10 mg/kg/d), or their combination using the drinking water as vehicle, for 3 weeks. Mean blood pressure (MAP) was measured by tail–cuff plethysmography. Plasma levels of nitric oxide (NO) and prostanoids, as well as plasma and tissue angiotensin II (Ang II) and aldosterone (ALDO) were analyzed by enzyme immunoassay. Renal and aortic superoxide production was determined by fluorescence spectrometry. Vascular reactivity of second-order mesenteric arteries was assessed in vitro.

Results: Simvastatin, losartan, and the drug combination attenuated the salt-induced increase in MAP. Plasma NO was elevated by simvastatin, losartan, and the combination, whereas plasma thromboxane was reduced by losartan. Simvastatin, losartan, and the combination reduced renal Ang II, but only the combination reduced cardiac Ang II. Heart and renal ALDO were reduced by simvastatin, losartan, and the combination. Aortic and renal NADPH-dependent superoxide production was reduced by simvastatin, losartan, and the combination. The response to acetylcholine, in mesenteric arteries preconstricted with norepinephrine, was greater in the losartan group.

Conclusions: Thus, treatment with simvastatin and losartan lowered oxidative stress and improved endothelial function. Simvastatin significantly reduced the effect of losartan on vascular reactivity in mesenteric arteries, suggesting that their combination may be contraindicated.