The aim of this study was to evaluate the effect of cyclosporine (CsA) on oxidative stress as well as the use of a nitric oxide (NO) donor, the organic nitrate isosorbide-5-mononitrate (Is-5-Mn), to prevent or reverse CsA-induced toxicity, namely on the vascular NO-cGMP pathway or on oxidative equilibrium. The following rat groups (n = 8) were tested: (1) a control group; (2) the CsA group (5 mg/kg/d for 7 weeks); (3) the Is-5-Mn group (150 mg/kg/d, twice a day for 7 weeks); (4) the preventive group (Is-5-Mn + CsA) treated for 2 weeks with Is-5-Mn only, and thereafter with both drugs for 7 weeks; (5) the curative group (CsA + Is-5-Mn) beginning 7 weeks after CsA, and following thereafter with both drugs for 5 weeks. The following parameters were evaluated: aortic cNOS activity and cGMP content; plasma levels of lipid peroxidation (malondialdehyde [MDA] levels); antioxidant capacity (glutathione peroxidase [GPx] and superoxide dismutase [SOD] activities, total antioxidant status, and vitamins A, C, and E); and peroxynitrite formation (3-nitrotyrosine [3-NT] content). Is-5-Mn + CsA therapy showed, when compared with the CsA group, total prevention of CsA-induced NO and cGMP attenuation, and no relevant influence on antioxidant indices, as well as on MDA and 3-NT levels. However, when compared with this CsA group, the curative group (CsA + Is-5-Mn) showed NO-cGMP values only partially reversed, and an enhancement in lipid peroxidation (5.6 +/- 1.4 vs 12.78 +/- 3.63 mumol/L; P < .05) and in peroxynitrite formation (16.7% incidence of positives vs 83.3% incidence of positives). Our data suggested that nitrate therapy may provide a valid choice to prevent CsA-induced NO-cGMP decrease, without a negative influence on the oxidative equilibrium. However, when the local environment is adverse, as occurs after CsA therapy, Is-5-Mn seemed to enhance the CsA-induced oxidative stress, promoting even worse deleterious effects, probably through the generation of the cytotoxic ROS peroxynitrite.