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Am J Physiol Renal Physiol 291: F612-F618, 2006. First published April 18, 2006; doi:10.1152/ajprenal.00032.2006
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Cyclooxygenase-2 inhibition normalizes arterial blood pressure in CYP1A1-REN2 transgenic rats with inducible ANG II-dependent malignant hypertension

Allison L. Opay,1 Cynthia R. Mouton,1 John J. Mullins,2 and Kenneth D. Mitchell1

1Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana; and 2Centre for Cardiovascular Science, University of Edinburgh Medical School, Edinburgh, United Kingdom

Submitted 26 January 2006 ; accepted in final form 11 April 2006

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.

renal hemodynamics; nimesulide; meclofenamate; kidney; renin-angiotensin system; glomerular filtration rate; renal plasma flow


Address for reprint requests and other correspondence: K. D. Mitchell, Dept. of Physiology, Tulane Univ. Health Sciences Center, 1430 Tulane Ave., SL39, New Orleans, LA 70112 (e-mail: kdmitch{at}tulane.edu)




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