title: Blockade of cytochrome P-450 epoxygenase pathway attenuates the natriuresis of N(G)-monomethyl-L-arginine infusion in the spontaneously hypertensive rat.
abstract: Previous studies demonstrated that there is increased renal synthesis of cytochrome P-450-dependent arachidonic acid metabolites in the vasculature and tubules of the Okamoto spontaneously hypertensive rat (SHR). It has also been shown that the natriuretic response of the SHR to NG-monomethyl-L-arginine (L-NMMA) infusion is exaggerated compared with that of the normotensive Wistar-Kyoto rat. The purpose of this study was to determine the roles of cytochrome P-450 epoxygenase and cyclooxygenase pathways in the natriuresis that is observed with the systemic infusion of a high dose of L-NMMA to inhibit nitric oxide synthesis in the SHR and the Wistar-Kyoto rats. After a control clearance period of 20 minutes groups of adult SHR (n = 14) were given L-NMMA (15 mg/kg bolus followed by 500 microg/kg/min continuous infusion). In other groups of SHR either ketoconazole (0.5 mg/kg, n = 9) to inhibit the renal activity of cytochrome P-450 epoxygenase pathway or indomethacin (3 mg/kg, n = 7) to inhibit cyclooxygenase activity was administered intravenously 20 minutes before the control clearance period. After the control clearance period L-NMMA was infused as previously described. Infusion of L-NMMA in the control group of SHR resulted in a significant increase in fractional excretion of sodium (FE Na from 1.78% +/- 0.24% to 6.90% +/- 0.61%). In the ketoconazole-treated group of SHR, L-NMMA infusion resulted in a significant natriuresis (from 2.22% +/- 0.58% to 4.70% +/- 0.93%); however, the natriuretic response was significantly attenuated compared with that of the control group of SHR that received only L-NMMA (delta FE Na, 2.47% +/- 0.40% vs 5.24% +/- 0.55%). Indomethacin administration did not affect the natriuretic response to L-NMMA infusion in the SHR. In conclusion, the natriuretic response to L-NMMA infusion in the SHR is significantly attenuated by administration of ketoconazole but not indomethacin. This result suggests that the natriuretic effect of L-NMMA infusion in the SHR is mediated at least partly by cytochrome P-450 metabolites of the epoxygenase pathway.
authors.affiliation: Department of Obstetrics and Gynecology, University of Illinois at Chicago, 60612-7313, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Khraibi
authors.forename: K H
authors.initials: KH
authors.lastname: Taylor
authors.forename: C R
authors.initials: CR
authors.lastname: Ramsey
authors.forename: T J
authors.initials: TJ
authors.lastname: Berndt
mesh_terms: D000367:Age Factors; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004231:Diuresis / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007213:Indomethacin / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D009399:Nephrons / Q000187:drug effects / Q000201:enzymology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010105:Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012964:Sodium / Q000652:urine*; D019323:omega-N-Methylarginine / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D012964:Sodium; D010105:Oxygenases; D000090762:Cytochrome P-450 CYP2J2; D011451:Prostaglandin-Endoperoxide Synthases; D007654:Ketoconazole; D007213:Indomethacin