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1 Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana, United States
2 Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, United Kingdom
* To whom correspondence should be addressed. E-mail: aopay{at}tulane.edu.
The present study was performed to determine the effects of 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 non-specific COX inhibitor, meclofenamate (5 mg/kg, iv). Rats induced with I3C had higher MAP than non-induced rats (n=7; 188±6 vs.136±4 mmHg, P<0.01). There was no difference in RPF or GFR between induced and non-induced 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 (0.90±0.13 to 0.44±0.05 ml/min.g, P<0.05), and RPF (2.79±0.27 to 1.35±0.14 ml/min.g, 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.
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