Cytochrome P-450 arachidonate metabolite inhibition improves renal function in Lyon hypertensive rats

The present study evaluated the effects of miconazole, a selective inhibito r of epoxygenase activity, on renal hemodynamics and the pressure-natriures is response of saline-drinking, uninephrectomized Lyon hypertensive (LH) an d Lyon low blood pressure (LL) rats. Infusion of miconazole (final concentr ation, 1 mu mol/L) into the renal artery had no effect on the renal functio n of LL rats over a range of-renal perfusion pressures (RPP) from 100 to 14 0 mm Hg. In contrast, miconazole lowered renal vascular resistance (RVR, 17 .9 +/- 1.1 v 26.3 +/- 1.5 mm Hg/mL/min/g, P < .01) and increased urinary so dium excretion (6.4 +/- 1.2 v 4.2 +/- 0.8 mu mol/min/g, P < .05) in LH rats at a RPP of 140 mm Hg. To determine whether the effects of epoxyeicosatrie noic acids were dependent on activation of the thromboxane A2-prostaglandin H2 (TP) receptor, we studied the effects of a TP receptor antagonist, GR 3 2191B (0.1 mg/kg/min), on the renal response to an infusion of miconazole i nto the renal artery in LH rats. GR 32191B decreased basal RVR and prevente d the dilation induced by miconazole. It did not however, alter its natriur etic effect. The renal metabolism of arachidonic acid was also compared in LH and LL rats. The production of epoxygenase metabolites was 25% lower in microsomes prepared from the renal cortex of LH versus LL rats. Miconazole (1 mu mol/L) reduced epoxygenase activity similarly, by approximately 60%, in both strains. These results suggest that endogenously formed P450 metabo lites of arachidonic acid may serve as a substrate for the formation of vas oconstrictor endoperoxides that interact with TP receptors in LH rats and c ontribute to the enhanced renal vascular tone but not the blunted pressure- natriuresis response. (C) 1999 American Journal of Hypertension, Ltd.