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

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.

Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II

“…We observed that COX-2 inhibition does not elicit significant alterations of RPF and GFR under NS conditions. This finding is consistent with previous in vivo studies under NS conditions that have not demonstrated a discernible consequence of acutely attenuated prostaglandin biosynthesis on renal hemodynamics (11,26,30). Furthermore, afferent arteriolar diameters of juxtamedullary nephrons in NS rats were not changed by COX-2 inhibition with NS-398 (16).…”

“…During elevated intrarenal ANG II, the addition of meclofenamate, a nonselective COX inhibitor, augmented nimesulide-mediated reductions in blood pressure but did not alter nimesulide-induced reductions in renal vascular resistances, GFR, or RPF (26). Also, in studies using selective COX-1 (genetic deletion and pharmacological) inhibition, COX-1-augmented ANG II increases in systemic resistances were not apparent in the vascular resistances that influence CBF or MBF (29).…”

“…Next, injection of a bolus of the selective COX-2 inhibitor nimesulide (3 mg/kg body wt) or a 50 mM sodium carbonate vehicle (1 ml/kg body wt) was followed by a 15-min delay. Nimesulide has been previously shown to be selective for COX-2 (4,34) and to elicit alterations in renal function (26,30,31). The third and fourth 30-min urine samples were collected during COX-2 inhibition.…”

Renal vascular and tubulointerstitial inflammation and proliferation in Cyp1a1-Ren2 transgenic rats with inducible ANG II-dependent malignant hypertension

“…Accordingly, this model allows induction of ANG II-dependent hypertension of graded severity using a benign and naturally occurring dietary supplement without the need for surgical intervention, dietary salt manipulation, or the administration of steroids (23,27). In essence, the Cyp1a1-Ren2 transgenic rat model is particularly advantageous because of the ease and reproducibility of genetically clamping expression of the Ren2 gene and inducing increases in plasma renin activity, plasma and intrarenal ANG II levels, and hypertension of graded severity (22,27,28,31,32).We have demonstrated that at a dose of 0.3% (wt/wt), chronic dietary administration of I3C induces malignant hypertension in Cyp1a1-Ren2 transgenic rats (27,28,31,32). Malignant hypertension is a severe form of hypertension characterized by rapidly increasing blood pressure, pressure diuresis and natriuresis, severe renal vasoconstriction and ischemia, activation of the renin-angiotensin system, microangiopathy, hemolytic anemia, and development of retinopathy (23,47,48).…”

“…We have demonstrated that at a dose of 0.3% (wt/wt), chronic dietary administration of I3C induces malignant hypertension in Cyp1a1-Ren2 transgenic rats (27,28,31,32). Malignant hypertension is a severe form of hypertension characterized by rapidly increasing blood pressure, pressure diuresis and natriuresis, severe renal vasoconstriction and ischemia, activation of the renin-angiotensin system, microangiopathy, hemolytic anemia, and development of retinopathy (23,47,48).…”