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

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(CyplalRen2)]. Male Cyplal-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 Cyplal-Ren2 rats before and during intravenous infusion of the nNOS inhibitor S-methyl-L-thiocitrulline (L-SMTC; 1 mg/h). In hypertensive Cyplal-Ren2 rats, L-SMTC increased MAP from 169 [+ or -] 3 to 188 [+ or -] 4 mmHg (P < 0.01), which was a smaller increase than in noninduced rats (124 [+ or -] 9 to 149 [+ or -] 9 mmHg, P < 0.01, n = 5). Additionally, L-SMTC decreased renal plasma flow (RPF) to a similar extent (-34 [+ or -] 13 vs. -35 [+ or -] 12%) in the hypertensive and normotensive rats (4.1 [+ or -] 0.2 to 2.7 [+ or -] 0.5 and 3.1 [+ or -] 0.3 to 2.0 [+ or -] 0.3 ml x [min.sup-1] x [g.sup.-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 [+ or -] 2 to 170 [+ or -] 3 mmHg and 153 [+ or -] 3 to 140 [+ or -] 3 mmHg, respectively, P < 0.01). Nimesulide also decreased RPF (1.9 [+ or -] 0.2 to 0.8 [+ or -] 0.1 ml x [min.sup.-1] x [g.sup.-1], P < 0.01) and GFR (0.9 [+ or -] 0.1 to 0.4 [+ or -] 0.1 ml x [min.sup.-1] x [g.sup.-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 Cyplal-Ren2 rats. The data also indicate that the renal vasodilator effects of COX-2-derived prostanoids in hypertensive Cyplal-Ren2 rats are not dependent on nNOS activity. kidney; nimesulide; S-methyl-L-thiocitrulline; renal hemodynamics; renin-angiotensin system; glomerular filtration rate; renal plasma flow