428 Interactive Effects of Neuronal Nitric Oxide Synthase and Cyclooxygenase-2 on Renal Hemodynamics in Cyp1a1-Ren2 Transgenic Rats With Malignant Hypertension

Abstract

Neuronal nitric oxide synthase (nNOS)-derived NO and cyclooxygenase (COX)-2 metabolites exert pronounced renal vasodilator influences in transgenic rats [strain name: TGR(Cyp1a1Ren2] with ANG II-dependent malignant hypertension. This study was performed to determine if the renal vasodilator effects of COX-2 metabolites in hypertensive Cyp1a1-Ren2 rats are dependent on nNOS activity. Male Cyp1a1-Ren2 rats (n = 7) were fed a normal diet containing indole-3-carbinol (0.3%) for 7-9 days to induce malignant hypertension. Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital-anesthetized Cyp1a1-Ren2 rats during infusion of the nNOS inhibitor S-methyl-L-thiocitruline (L-SMTC, 1 mg/hr, iv) and following administration of the COX-2 inhibitor, nimesulide (3 mg/kg, iv). During infusion of L-SMTC, hypertensive rats had higher MAP (182 ± 2 vs. 153 ± 3 mm Hg, p < .01) than normotensive rats (n = 5). There were no differences in RPF (1.9 ± 0.2 vs. 2.0 ± 0.2 mL/min.g) and GFR (0.86 ± 0.07 vs. 1.00 ± 0.02 mL/min.g) between groups. Administration of nimesulide during continued L-SMTC infusion decreased MAP in both hypertensive and normotensive rats (182 ± 2 to 170 ± 3 mm Hg and 153 ± 3 to 140 ± 3 mm Hg, respectively, p < .01). Nimesulide also decreased RPF (1.9 ± 0.2 to 0.8 ± 0.1 mL/min.g, p < .01) and GFR (0.86 ± 0.07 to 0.40 ± 0.05 mL/min.g, p < .01) in hypertensive rats but did not alter RPF or GFR in normotensive rats. The present study confirms that COX-2 metabolites contribute to the elevated arterial pressure and exert pronounced renal vasodilator influences in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension. The data also demonstrate that the renal vasodilator effects of COX-2-derived prostanoids in hypertensive Cyp1a1-Ren2 transgenic rats are not dependent on nNOS activity.