title: Lack of evidence for the involvement of cytochrome P-450 or other hemoproteins in metabolic activation of glyceryl trinitrate in rabbit aorta.
abstract: The present study was conducted to test the hypothesis that glyceryl trinitrate (GTN) metabolic activation in blood vessels is mediated by cytochrome P-450 or some other hemoprotein. The effects of cytochrome P-450 inhibitor [2-dimethylaminoethyl-2,2-diphenyl-n-pentanoate (SKF-525A) and metyrapone] on the response of rabbit aortic rings to GTN was determined by recording cumulative GTN dose-response curves in the presence of either or both inhibitors. The cytochrome P-450 inhibitors did not interfere with the ability of GTN to relax rabbit aortic rings. Treatment of rabbit aortic strips (RAS) with carbon monoxide (CO) was undertaken to elucidate a potential role of ferrous hemoproteins in mediating GTN-induced relaxation. CO did not significantly inhibit GTN-induced vasodilation of RAS. Biotransformation of GTN to glyceryl dinitrates by RAS exposed to CO for 5 min or nitric oxide (NO) for 10 min was determined by incubation of the tissues with 0.5 microM [3H]- or [14C]-GTN in the presence of CO or NO for 10 sec, 30 sec or 2 min. Neither CO nor NO exposure inhibited glyceryl-1,2- or -1,3-dinitrate formation by RAS after the 10-sec or 2-min incubation with RAS. For the 30-sec incubation, NO exposure did inhibit glyceryl dinitrate formation by RAS. This was deemed to be less important than the 10-sec data, the time just before the onset of relaxation. Therefore, emphasis is placed on lack of inhibition by NO at this earlier time point.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: J F
authors.initials: JF
authors.lastname: Brien
authors.forename: G S
authors.initials: GS
authors.lastname: Marks
authors.forename: B E
authors.initials: BE
authors.lastname: McLaughlin
authors.forename: K
authors.initials: K
authors.lastname: Nakatsu
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001711:Biotransformation; D002248:Carbon Monoxide / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D006420:Hemeproteins / Q000502:physiology*; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology; D005996:Nitroglycerin / Q000493:pharmacokinetics* / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects
chemical_list: D006420:Hemeproteins; D009569:Nitric Oxide; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D005996:Nitroglycerin; D008797:Metyrapone