title: Escape from tolerance of organic nitrate by induction of cytochrome P450.
abstract: The mechanism of organic nitrate tolerance is poorly defined. We studied the rat P450-catalyzed conversion of organic nitrate to nitric oxide (NO) by purified P450 isoforms relationship between P450 expression and nitrate tolerance following continuous infusion of organic nitrates in rats. The hypotensive effect of an nitroglycerin (NTG) bolus injection was abolished in rats that had been previously provided a continuous 48 h infusion of NTG. This effect was accompanied by a gradual but marked decrease in plasma and urinary nitrate levels following a peak at 18-24 h. Nitrate tolerance was reversible; the decline in the hypotensive effect and P450 levels observed after 2 d of continuous infusion was followed by restoration to control levels 2 d after cessation of the infusion. Similarly, the hypotensive action disappeared in P450-depleted, and -inhibited rats. At 48 h after infusion, NTG-induced NO generation of the vessels increased in acetone (a P450 inducer) -pretreated rats. The appearance and disappearance of P450 paralleled the conversion of organic nitrates to NO. Our observations indicate that nitrate tolerance is in large part the result of decreased P450 expression and activity. Interventions that maintain or increase P450 activity may be a strategy to provide relief from ischemic conditions in humans.
authors.affiliation: Department of Biochemistry and Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan. yukiko@med.osaka-cu.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Minamiyama
authors.forename: S
authors.initials: S
authors.lastname: Imaoka
authors.forename: S
authors.initials: S
authors.lastname: Takemura
authors.forename: S
authors.initials: S
authors.lastname: Okada
authors.forename: M
authors.initials: M
authors.lastname: Inoue
authors.forename: Y
authors.initials: Y
authors.lastname: Funae
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D003374:Coumarins / Q000494:pharmacology; D019388:Cytochrome P-450 CYP1A2 / Q000032:analysis / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004361:Drug Tolerance; D004790:Enzyme Induction; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006834:Hydrazines / Q000494:pharmacology; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000201:enzymology; D009566:Nitrates / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D005996:Nitroglycerin / Q000378:metabolism / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: C115239:3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamine; D003374:Coumarins; D006834:Hydrazines; D007375:Interleukin-1; D007527:Isoenzymes; D009566:Nitrates; D020030:Nitric Oxide Donors; D009573:Nitrites; D009599:Nitroprusside; C017299:7-ethoxycoumarin; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D019388:Cytochrome P-450 CYP1A2; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate