1. ¹Department of Pharmacology and ToxicologyAtlanta, Georgia, USA
2. ²Space Medicine and Life Sciences Research CenterAtlanta, Georgia, USA
3. ³Clinical Research Center, Morehouse School of Medicine, Atlanta, Georgia, USA

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

^*This work was supported, in part, by National Institutes of Health grants S06GM08248-12 (MAB) and P20RR11104-07 (IKA).

Received 8 October 2002; Revised 19 November 2002; Accepted 8 January 2003.

Abstract

Background: Hypertension induced by oxidative stress has been demonstrated in normal rats. In the current study, we investigated the effect of the oral AT₁ receptor blocker losartan (10 mmol/kg/day) on oxidative stress, induced by glutathione (GSH) depletion (using buthionine-sulfoximine, BSO, 30 mmol/L/day in the drinking water), in Sprague-Dawley rats.

Methods: Mean arterial pressure (MAP) was measured by tail–cuff plethysmography and the plasma levels of total 8-isoprostane, nitric oxide, prostacyclin, thromboxane A₂, angiotensin II, aldosterone, and aortic cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were determined by enzyme immunoassay. Plasma, heart, and kidney GSH were analyzed by high-performance liquid chromatography. Aortic and renal superoxide production was determined by fluorescence spectrometry.

Results: In the BSO-treated group, MAP, angiotensin II, isoprostane, thromboxane A₂, and superoxide were elevated; whereas prostacyclin, GSH, cAMP, and cGMP were reduced, compared to control. Losartan alone reduced MAP, and increased renal GSH, plasma nitric oxide, angiotensin II, aldosterone, and aortic cGMP. When administered concurrently with BSO, losartan reversed the BSO-induced elevation of MAP, superoxide, and thromboxane A₂ as well as the reduction in prostacyclin and aortic cAMP levels, but did not significantly alter the reduction in GSH or the elevation in angiotensin II and aldosterone.

Conclusions: Losartan attenuates BSO-induced hypertension, which appears to be mediated, in part, by angiotensin II and the prostanoid endothelium-derived factors.