Cyclooxygenase-2 inhibition normalizes arterial blood pressure in CYP1A1-REN2 transgenic rats with inducible ANG II-dependent malignant hypertension.
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.
Opay
Allison L
AL
Department of Physiology, Tulane University Health Sciences Center, 1430 Tulane Ave., SL39, New Orleans, LA 70112, USA.
Mouton
Cynthia R
CR
Mullins
John J
JJ
Mitchell
Kenneth D
KD
D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006974:Hypertension, Malignant / Q000503:physiopathology*; D008297:Male; D008469:Meclofenamic Acid / Q000494:pharmacology; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects
D052246:Cyclooxygenase 2 Inhibitors; D013449:Sulfonamides; D000804:Angiotensin II; D008469:Meclofenamic Acid; D019363:Cytochrome P-450 CYP1A1; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C012655:nimesulide