Lack of evidence for the involvement of cytochrome P-450 or other hemoproteins in metabolic activation of glyceryl trinitrate in rabbit aorta.
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)
Liu
Z
Z
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Brien
J F
JF
Marks
G S
GS
McLaughlin
B E
BE
Nakatsu
K
K
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
D006420:Hemeproteins; D009569:Nitric Oxide; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D005996:Nitroglycerin; D008797:Metyrapone