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Nitric oxide inhibits renal cytochrome P450‐dependent epoxygenases in the rat
Author(s) -
Oyekan Adebayo
Publication year - 2002
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1046/j.1440-1681.2002.03762.x
Subject(s) - epoxygenase , sodium nitroprusside , chemistry , arachidonic acid , cytochrome p450 , nitric oxide , vasodilation , endocrinology , kidney , medicine , epoxyeicosatrienoic acid , pharmacology , biochemistry , metabolism , biology , enzyme
Summary 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 µg. Sodium nitroprusside (SNP; 100 µmol/L), an NO donor, blunted the basal and AA‐stimulated efflux of epoxides. 3. Sodium nitroprusside at 10 and 100 µmol/L inhibited renal microsomal conversion of [ 14 C]‐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 µmol/L)‐treated kidney, AA at 5, 10 and 25 µg elicited vasodilation that was blunted by miconazole (2 µmol/L), 80 mmol/L KCl, tetraethylammonium (10 mmol/L), a K + channel blocker, or SNP (100 µmol/L). 5. Vasodilation induced by AA, but not 5,6‐epoxide, was reduced in rats treated with LPS, an effect that was abolished by N ω ‐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.