The present study was performed to determine the effects of nNOS and COX-2 inhibition on blood pressure and renal hemodynamics in transgenic rats with inducible ANG II-dependent malignant hypertension [strain name: TGR(Cyp1a1Ren2)]. Male Cyp1a1-Ren2 rats (n=7) were fed a normal diet containing indole-3-carbinol (I3C; 0.3%) for 6-9 days to induce malignant hypertension. Mean arterial pressure (MAP) and renal hemodynamics were assessed in pentobarbital sodium-anesthetized Cyp1a1-Ren2 rats before and during intravenous infusion of the nNOS inhibitor S-methyl-L-thiocitrulline (L-SMTC, 1 mg/hr). In hypertensive Cyp1a1-Ren2 rats, L-SMTC increased MAP from 169±3 to 188±4 mmHg (P<0.01), which was a smaller increase than in non-induced rats (124±9 to 149±9 mmHg, P<0.01, n=5). Additionally, L-SMTC decreased RPF to a similar extent (-34±13% vs. -35±12%) in the hypertensive and normotensive rats (4.1±0.2 to 2.7±0.5 and 3.1±0.3 to 2.0±0.3 ml/min.g, respectively, P<0.01) but did not alter GFR in either group. In additional experiments, administration of the COX-2 inhibitor, nimesulide (3 mg/kg iv), during simultaneous infusion of L-SMTC decreased MAP in both hypertensive and non-induced rats (182±2 to 170±3 mmHg and 153±3 to 140±3 mmHg, respectively, P<0.01). Nimesulide also decreased RPF (1.9±0.2 to 0.8±0.1 ml/min.g, P<0.01) and GFR (0.9±0.1 to 0.4±0.1 ml/min g, P<0.01) in hypertensive rats but did not alter RPF or GFR in non-induced rats. The present findings demonstrate that both nNOS-derived NO and COX-2 metabolites exert pronounced renal vasodilator influences in hypertensive Cyp1a1-Ren2 rats. The data also indicate that the renal vasodilator effects of COX-2-derived prostanoids in hypertensive Cyp1a1-Ren2 rats are not dependent on nNOS activity.