The role of nitric oxide formation in organic nitrate-induced vasodilation and organic nitrate tolerance.
Isolated rabbit aortic strips (RAS) were contracted submaximally with phenylephrine (PE) and then were incubated with 6.2 x 10(-7) M [3H] glyceryl trinitrate (GTN) (9.98 Ci/mmol) in a 30-s time-course study. GTN-induced relaxation of RAS was monitored and tissue GTN and GDN concentrations were determined by thin-layer chromatography and liquid scintillation spectrometry. There was time-dependent biotransformation of GTN to glyceryl dinitrate (GDN) by the RAS and a time-dependent increase in cyclic GMP content in the RAS. Statistically significant (P less than 0.05) biotransformation of GTN and elevation of cyclic GMP content in the tissue were found at 10 s in RAS, whereas the onset of relaxation occurred at 12 s. During the tissue biotransformation of GTN, there was preferential formation of 1,2-GDN compared with 1,3-GDN, suggesting that it is during the process of conversion of GTN to 1,2-GDN that elevation of cyclic GMP content occurs. The results of this study are consistent with the hypothesis that GTN is a prodrug, such that biotransformation to the active metabolite, nitric oxide (NO), is involved in GTN-induced relaxation of vascular smooth muscle. The data also indicate that the mechanism of GTN biotransformation and GTN-induced activation of guanylate cyclase may be related intimately. Isolated RAS were made tolerant to organic nitrates in vitro by incubation with 5 x 10(-4) M GTN for 1 h. After washout and submaximal contraction with PE, the tissues were incubated with 5 x 10(-7) M [14C]GTN for 2 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Marks
G S
GS
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Nakatsu
K
K
McLaughlin
B
B
Kawamoto
J
J
Slack
C
C
Brien
J F
JF
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001711:Biotransformation; D006152:Cyclic GMP / Q000378:metabolism; D004361:Drug Tolerance; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects*
D011355:Prodrugs; C014509:dinitroglycerol; D009569:Nitric Oxide; D005996:Nitroglycerin; D006152:Cyclic GMP