Renoprotective effects of neuronal NOS-derived nitric oxide and cyclooxygenase-2 metabolites in transgenic rats with inducible malignant hypertension

Abstract

The present study was performed to determine the effects of neuronal nitric oxide synthase (nNOS) and cyclooxygenase-2 (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/h). 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 noninduced rats (124 ± 9 to 149 ± 9 mmHg, P < 0.01, n = 5). Additionally, l-SMTC decreased renal plasma flow (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−1·g−1, respectively, P < 0.01) but did not alter glomerular filtration rate (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 noninduced 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−1·g−1, P < 0.01) and GFR (0.9 ± 0.1 to 0.4 ± 0.1 ml·min−1·g−1, P < 0.01) in hypertensive rats but did not alter RPF or GFR in noninduced 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.