We hypothesized that increased superoxide contributes to mean arterial pressure (MAP) regulation in male Sprague-Dawley rats fed a high-salt diet and/or during endothelin (ETB) receptor blockade. Four groups on either a normal- or a high-salt diet were studied for 1 week: (1) control; (2) tempol, a superoxide dismutase mimetic, in their drinking water (1 mmol/L); (3) A-192621, an ETB antagonist, in their food (10 mg/kg daily); or (4) both tempol and A-192621. Without ETB blockade, tempol had no effect on MAP (telemetry) in rats on the normal-salt diet but significantly reduced MAP in rats on the high-salt diet (100±3 vs 112±2 mm Hg, P<0.05). On the normal-salt diet, A-192621 increased MAP with or without tempol. Under high-salt conditions, tempol attenuated the increase in MAP produced by A-192621, but only during the initial days of treatment. Plasma 8-isoprostanes were increased in all rats on the high-salt diet and were further increased after 3 days of A-192621 but not after 7 days; tempol inhibited the increase produced by A-192621 but had no influence on the increase produced by high salt. H2O2 excretion was significantly higher in rats on a high-salt diet for the 7-day drug treatment compared with those on a normal-salt diet. Tempol further increased H2O2 excretion in rats on a high-salt diet, an effect accelerated in A-192621-treated rats. These data suggest that blood pressure lowering by tempol in rats on a high-salt diet may be unrelated to reductions in superoxide and that renal H2O 2 may account for the limited ability of tempol to attenuate hypertension produced by ETB receptor blockade.