BIOTRANSFORMATION OF GLYCERYL TRINITRATE OCCURS CONCURRENTLY WITH RELAXATION OF RABBIT AORTA

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  • 1 May 1986
    • journal article
    • research article
    • Vol. 237  (2) , 608-614
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 .mu.M [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-dintrate (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-GND. RAS were made tolerant to GTN in vitro by incubation with 500 .mu.M GTN for 1 hr. After washing, GTN-tolerant and nontolerant (incubation with vehicle for 1 hr) RAS were contracted submaxmimally with PE, and then were incubated with 0.5 .mu.M [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 inducated that the tissue uptake of GTN was similar and that GTN biotransformation was diminished in tolerant tissue. These results are consistent with the hypothesis that GTN biotransformation is involved in the mechanism of GTN-induced vasodilation.