Cyclooxygenase-2 inhibition normalizes arterial blood pressure in CYP1A1-REN2 transgenic rats with inducible ANG II-dependent malignant hypertension

Allison L. Opay, Cynthia R. Mouton, John J. Mullins, Kenneth D. Mitchell

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Abstract

The present study was performed to determine the effects of cyclooxygenase (COX)-1 and COX-2 inhibition on blood pressure and renal hemodynamics in transgenic rats with inducible malignant hypertension [ strain name: TGR(Cyp1a1Ren2)]. Male Cyp1a1-Ren2 rats (n = 7) were fed a normal diet 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 sodium-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 ( n = 7; 188 +/- 6 vs. 136 +/- 4 mmHg, P < 0.01). There was no difference in renal plasma flow (RPF) or glomerular filtration rate (GFR) between induced and noninduced rats. Nimesulide elicited a larger decrease in MAP in hypertensive rats ( 188 +/- 6 to 140 +/- 8 mmHg, P < 0.01) than in normotensive rats ( 136 +/- 4 to 113 +/- 8 mmHg, P < 0.01). Additionally, nimesulide decreased GFR ( 0.9 +/- 0.13 to 0.44 +/- 0.05 ml (.) min(-1) (.) g(-1), P < 0.05) and RPF (2.79 +/- 0.27 to 1.35 +/- 0.14 ml (.) min(-1) (.) g(-1), P < 0.05) in hypertensive rats but did not alter GFR or RPF in normotensive rats. Meclofenamate further decreased MAP in hypertensive rats ( to 115 +/- 10 mmHg, P < 0.05) but did not decrease MAP in normotensive rats. Meclofenamate did not alter GFR or RPF in either group. 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 transgenic rats.

Original languageEnglish
Pages (from-to)F612-F618
Number of pages7
JournalAmerican Journal of Physiology - Renal Physiology
Volume291
Issue number3
DOIs
Publication statusPublished - Sep 2006

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