title: Biotransformation of glyceryl trinitrate occurs concurrently with relaxation of rabbit aorta.
abstract: This study was conducted to test the hypothesis that biotransformation of glyceryl trinitrate (GTN) is involved in GTN-induced relaxation of vascular smooth muscle. Isolated rabbit aortic strips (RAS) were contracted submaximally with phenylephrine (PE) and then were incubated with 0.5 microM [14C]GTN in a time course study. GTN-induced relaxation (inhibition of PE-induced tone) of RAS was monitored and tissue GTN and glyceryl-1,2- and 1,3-dinitrate (GDN) concentrations were measured by thin-layer chromatography and liquid scintillation spectrometry at 0.5, 1, 2 and 20 min after incubation. Biotransformation of GTN to GDN occurred during GTN-induced relaxation of RAS. The tissue GDN concentration was dependent on the time duration of incubation with GTN and was related to the magnitude of GTN-induced tissue relaxation. At the 20-min interval, the GDN concentration in the incubation medium indicated appreciable efflux of GDN metabolites from the RAS. In the biotransformation of GTN by RAS, there was about 4-fold preferential formation of 1,2-GDN compared with 1,3-GDN. RAS were made tolerant to GTN in vitro by incubation with 500 microM GTN for 1 hr. After washing, GTN-tolerant and nontolerant (incubation with vehicle for 1 hr) RAS were contracted submaximally with PE, and then were incubated with 0.5 microM [14C]GTN for 2 min. GTN-induced relaxation of RAS and tissue GDN concentration were significantly less for GTN-tolerant tissue compared with nontolerant tissue. Tissue GTN concentration was similar for both GTN-tolerant and nontolerant RAS, which indicated that the tissue uptake of GTN was similar and that GTN biotransformation was diminished in tolerant tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D001711:Biotransformation; D002250:Carbon Radioisotopes; D004361:Drug Tolerance; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D005996:Nitroglycerin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D002250:Carbon Radioisotopes; D009573:Nitrites; C014509:dinitroglycerol; D009569:Nitric Oxide; D005996:Nitroglycerin