COX-1 and COX-2-derived prostanoids participate in the regulation of renal hemodynamics and blood pressure in normotensive states, but their role in hypertensive states remains uncertain. This study was performed to determine the effects of COX-1 and COX-2 inhibition on blood pressure and renal hemodynamics in hypertensive transgenic rats with inducible expression of the Ren2 renin gene [strain name: TGR(Cyp1a1Ren2)]. Male Cyp1a1-Ren2 rats (n = 7) were fed normal rat food containing the aryl hydrocarbon, indole-3-carbinol (I3C, 0.3%) for 6-9 days to induce malignant hypertension. Mean arterial pressure (MAP) and renal hemodynamics were measured in pentobarbital-anesthetized Cyp1a1-Ren2 rats during control conditions, following administration of the COX-2 inhibitor, nimesulide (3 mg/kg, IV), and following administration of the nonspecific COX inhibitor meclofenamate (5 mg/kg, IV). Rats induced with I3C had higher MAP than noninduced rats (188 ± 6 vs. 136 ± 4 mm Hg, p < .01). There was no difference in RPF or GFR between induced and noninduced rats. Nimesulide induced a larger decrease in MAP in hypertensive rats (188 ± 6 to 140 ± 8 mm Hg, p < .01) than in normotensive rats (136 ± 4 to 113 ± 8 mm Hg, p < .01). Additionally, nimesulide decreased GFR (0.9 ± 0.13 to 0.44 ± 0.05 mL/min.g, p < .05) and RPF (2.79 ± 0.27 to 1.35 ± 0.14 mL/min.g, p < .05) in hypertensive rats but did not alter GFR or RPF in normotensive rats. Meclofenamate further decreased MAP in hypertensive rats (from 140 ± 8 mm Hg to 115 ± 10 mm Hg) but did not decrease MAP in normotensive rats. Meclofenamate did not alter GFR or RPF in either normotensive or hypertensive rats. These findings demonstrate that COX-1- and COX-2-derived prostanoids contribute importantly to the development of malignant hypertension in Cyp1a1-Ren2 transgenic rats. The data also indicate that COX-2-derived vasodilatory metabolites play an important role in the maintenance of RPF and GFR following induction of malignant hypertension in Cyp1a1-Ren2 rats.
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