Nitroglycerin-induced tolerance affects multiple sites in the organic nitrate bioconversion cascade

P. J. Henry, J. D. Horowitz, W. J. Louis

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62 Citations (Scopus)

Abstract

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 μM 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 < .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 < .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 < .05, n = 5). We conclude that, in this isolated coronary artery prepartion, 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. In addition to an organic nitrate-specific site of tolerance, a second site through which the non-nitrate vasodilators SNP and SIN-1 also act is markedly affected by NTG-induced tolerance.

Original languageEnglish
Pages (from-to)762-768
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume248
Issue number2
Publication statusPublished - 1 Jan 1989
Externally publishedYes

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