Cytochrome P-450 arachidonate metabolite inhibition improves renal function in Lyon hypertensive rats.
The present study evaluated the effects of miconazole, a selective inhibitor of epoxygenase activity, on renal hemodynamics and the pressure-natriuresis response of saline-drinking, uninephrectomized Lyon hypertensive (LH) and Lyon low blood pressure (LL) rats. Infusion of miconazole (final concentration, 1 micromol/L) into the renal artery had no effect on the renal function of LL rats over a range of renal perfusion pressures (RPP) from 100 to 140 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 sodium excretion (6.4 +/- 1.2 v 4.2 +/- 0.8 micromol/min/g, P < .05) in LH rats at a RPP of 140 mm Hg. To determine whether the effects of epoxyeicosatrienoic acids were dependent on activation of the thromboxane A2-prostaglandin H2 (TP) receptor, we studied the effects of a TP receptor antagonist, GR 32191B (0.1 mg/kg/min), on the renal response to an infusion of miconazole into the renal artery in LH rats. GR 32191B decreased basal RVR and prevented the dilation induced by miconazole. It did not, however, alter its natriuretic 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 micromol/L) reduced epoxygenase activity similarly, by approximately 60%, in both strains. These results suggest that endogenously formed P450 metabolites of arachidonic acid may serve as a substrate for the formation of vasoconstrictor endoperoxides that interact with TP receptors in LH rats and contribute to the enhanced renal vascular tone but not the blunted pressure-natriuresis response.
Messer-Létienne
I
I
Département de Physiologie et Pharmacologie Clinique, CNRS ESA 5014, Faculté de Pharmacie, Lyon, France. letienne@rockefeller.univ-lyon1.fr
Bernard
N
N
Roman
R J
RJ
Sassard
J
J
Benzoni
D
D
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008825:Miconazole / Q000494:pharmacology*; D009318:Natriuresis / Q000187:drug effects; D010477:Perfusion; D011312:Pressure; D051381:Rats; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D012016:Reference Values
D001713:Biphenyl Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D006538:Heptanoic Acids; D017482:Receptors, Thromboxane; D016718:Arachidonic Acid; D008825:Miconazole; D003577:Cytochrome P-450 Enzyme System; C060013:vapiprost