Nitric oxide inhibits renal cytochrome P450-dependent epoxygenases in the rat.
1. Nitric oxide (NO), or peroxynitrite, is known to inhibit haemoproteins, including cytochrome P450 mono-oxygenases. The present study explores the functional correlates of the inhibition by NO of renal epoxygenase on the vascular responses to arachidonic acid (AA) in the perfused kidney. 2. Control kidneys produce measurable amounts of epoxyeicosatrienoic acids (epoxides), which were increased from 0.6 +/- 0.2 to 1.8 +/- 0.9 ng/min (P < 0.05) following the addition of AA 5 micro g. Sodium nitroprusside (SNP; 100 micro mol/L), an NO donor, blunted the basal and AA-stimulated efflux of epoxides. 3. Sodium nitroprusside at 10 and 100 micro mol/L inhibited renal microsomal conversion of [14C]-AA to epoxides and its hydration products dihydroxyeicosatrienoic acid (diols). Microsomes harvested from rats 3 h after treatment with Escherichia coli endotoxin (lipopolysaccharide; LPS) also inhibited renal epoxygenase activity (81 +/- 8%; P < 0.05). 4. In the phenylephrine-preconstricted and indomethacin (2.8 micro mol/L)-treated kidney, AA at 5, 10 and 25 micro g elicited vasodilation that was blunted by miconazole (2 micro mol/L), 80 mmol/L KCl, tetraethylammonium (10 mmol/L), a K+ channel blocker, or SNP (100 micro mol/L). 5. Vasodilation induced by AA, but not 5,6-epoxide, was reduced in rats treated with LPS, an effect that was abolished by Nomega-nitro-l-arginine (100 mg/kg in drinking water for 10 days). 6. These data suggest that NO inhibits renal epoxygenase activity and inhibits epoxide-mediated AA-induced vasodilation in the rat kidney.
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D065607:Cytochrome P-450 Enzyme Inhibitors; D004852:Epoxy Compounds; D016718:Arachidonic Acid; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System