Nitroglycerin-induced tolerance affects multiple sites in the organic nitrate bioconversion cascade.
The effect of nitroglycerin (NTG)-induced tolerance on the spasmolytic effects of a series of vasodilators was determined to establish potential sites of tolerance. Concentration-effect curves to vasodilators were completed concurrently in U46619-contracted bovine isolated coronary artery rings pre-exposed to 100 microM NTG for 10 min (NTG-tolerant rings) and in control rings not pre-exposed to NTG. Compared to control rings, NTG-tolerant rings were markedly less responsive (P less than .01, n = 8-10) to the spasmolytic actions of NTG, isosorbide dinitrate, sodium nitroprusside (SNP) and 3-morpholinosydonimine (SIN-1), whereas the spasmolytic actions of S-nitroso-N-acetylpenicillamine and nitric oxide were only marginally attenuated in NTG-tolerant rings. On the other hand, no significant difference in the relaxant responses of NTG-tolerant and control coronary artery rings were observed to either the endothelium-dependent vasodilator, A23187 or the guanylate cyclase-independent vasodilator, theophylline. In additional cross-tolerance studies, relaxations to the organic nitrate vasodilator, NTG were significantly more attenuated (P less than .05, n = 5) by tolerance induced by NTG, than by either SNP or SIN-1, whereas the actions of the non-nitrate vasodilators, SNP and SIN-1 were attenuated more by SNP-and SIN-1-induced tolerance than by NTG-induced tolerance (P less than .05, n = 5). We conclude that, in this isolated coronary artery preparation, NTG-induced tolerance affects at least two major sites in the cascade of events between the initial site of NTG action and guanylate cyclase activation.(ABSTRACT TRUNCATED AT 250 WORDS)
Henry
P J
PJ
Department of Medicine, University of Melbourne, Victoria, Australia.
Horowitz
J D
JD
Louis
W J
WJ
D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004730:Endothelium, Vascular / Q000502:physiology; D006162:Guanylate Cyclase / Q000032:analysis; D066298:In Vitro Techniques; D007548:Isosorbide Dinitrate / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D010276:Parasympatholytics; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate