Receptors and Channels, 10: 147–157, 2004 Copyright c  Taylor & Francis Inc. ISSN: 1060-6823 print / 1543-5334 online DOI: 10.1080/10606820490936141 Effects of Losartan on Blood Pressure, Oxidative Stress, and Nitrate/Nitrite Levels in the Nitric Oxide Deficient Hypertensive Rats Mahmoud Khattab, Mobasher Ahmad, Othman A. Al-Shabanah, and Muhammad Raza Department of Pharmacology, College of Pharmacy, King Saud University, Kingdom of Saudi Arabia Losartan, an angiotensin II type-1 receptor (AT 1 ) antagonist, was used to investigate whether it can offer protection against the sustained hypertension, cardiac hypertrophy, and renal damage induced by chronic inhibition of nitric oxide (NO) by N ω -nitro-L- arginine methyl ester (L-NAME). We studied the involvement of both NO metabolism and oxidative stress in L-NAME-induced hy- pertension, and how AT 1 receptor antagonism may interact. Male Wistar albino rats were subjected to NO synthesis inhibition by the use of L-NAME (60 mg/kg/day), and the effects of losartan (10 mg/kg/day) in drinking water for six weeks were observed. After six weeks, animals were subjected to the measurements for systolic, mean, and diastolic blood pressure (BPs, BPm, and BPd, respectively). Under light ether anesthesia blood was withdrawn for ACE activity, NO x and creatinine determinations. Heart and kid- neys were weighed, and organ indices were calculated comparing to their body weights. These tissues were immediately preserved for GSH, MDA, NO x estimations. Chronic L-NAME treatment raised BPs, BPm, and BPd, respectively, above the normal. Treatment also increased NO x in plasma, significantly decreased it in the heart, and tended to increase it in kidney. L-NAME caused GSH depletion in the heart and kidney tissues with a concomitant increase in MDA contents in both the tissues. Plasma creatinine doubled in L-NAME- treated animals. Plasma ACE activity showed a nonsignificant de- crease below control. Concurrent treatment with losartan almost completely inhibited any rise in blood pressure. Losartan replen- ished the partly depleted cardiac and renal antioxidant GSH and ameliorated the increase of oxidative stress damage index, MDA. However, losartan alone did not change appreciably the plasma level or cardiac and renal contents of NO x . Losartan plus L-NAME treatment caused an increase in plasma ACE activity above control. Furthermore, losartan ameliorated the L-NAME induced increase in creatinine back to value nonsignificantly different from control. Keywords Glutathione, Hypertension, L-NAME, Losartan, Nitrate/ nitrite, Nitric oxide, Oxidative stress Address correspondence to Muhammad Raza, Department of Phar- macology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Kingdom of Saudi Arabia. E-mail: mrsheikhus@ yahoo.com INTRODUCTION A decade ago, it was reproducibly shown that chronic in- hibition of nitric oxide (NO) synthesis leads to sustained hy- pertension together with evident renal damage (Ribeiro et al. 1992; Baylis et al. 1992). Most of the data indicate that NO- deficient hypertension is brought about, at least in part, by acti- vation of the rennin-angiotensin-aldosterone system (RAS). The main characteristics of this experimental hypertension model are myocardial remodeling, including hypertrophy and fibrosis, as well as cardiovascular remodeling (Takemoto et al. 1997a, 1997b; Devlin et al. 1998). Increased activity and content of tis- sue angiotensin converting enzyme (ACE) were shown to be the markers for vascular and myocardial remodeling in NO deficient hypertensive rats (Takemoto et al. 1997b). Furthermore, both angiotensin II (ANG II), produced by ACE, and ANG II type-1 (AT 1 ) receptors, the main two cascades of RAS were shown to be crucial factors for myocardial hypertrophy (Mazzolai et al. 2000; Paradis et al. 2000). Llinas et al. (1997) demonstrated that renal vasoconstriction and increased proximal sodium reabsorption during NO deficit (or prostaglandin deficiency) are produced through increased endogenous ANG II levels. Acute hypertension induced by in- travenous infusion of ANG II by aortic occlusion was accompa- nied by an increase in plasma nitrate. The authors demonstrated that an augmented systemic production of NO, measured as an increase in plasma nitrate, occurs after acute hypertension, and suggested that an increase in NO generation occurs when ANG II hypertension exceeds a certain limit, below which the basal production of NO is sufficient to compensate the vasoconstric- tion (Nava et al. 2000). In the present investigation, the aim is to investigate the efficacy of the AT 1 receptor antagonist losartan on the renal damage and cardiac hypertrophy induced by chronic NO syn- thesis inhibition. Secondly it was of interest to monitor the effect of L-NAME induced chronic hypertension on NO metabo- lites. Furthermore, it became important to study the influence of 147