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Nitroglycerin-induced tolerance affects multiple sites in the organic nitrate bioconversion cascade
P J Henry1, J D Horowitz, W J Louis
1Department of Medicine, University of Melbourne, Victoria, Australia.
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 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)
Insights
Nitroglycerin tolerance reduces the effectiveness of several vasodilators, including organic nitrates and nitric oxide donors. This suggests tolerance impacts multiple steps in the vasodilation pathway, not just a single site.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
Background:
- Nitroglycerin (NTG) tolerance is a clinical issue affecting vasodilator efficacy.
- Understanding the mechanisms of NTG tolerance is crucial for optimizing cardiovascular treatments.
Purpose of the Study:
- To investigate the impact of NTG-induced tolerance on the spasmolytic effects of various vasodilators.
- To identify potential sites of tolerance within the vasodilation signaling cascade.
Main Methods:
- Bovine isolated coronary artery rings were used to assess vasodilator responses.
- Rings were pre-exposed to NTG to induce tolerance or used as controls.
- Concentration-effect curves were generated for NTG, isosorbide dinitrate, sodium nitroprusside (SNP), 3-morpholinosydonimine (SIN-1), and others.
Main Results:
- NTG-tolerant rings showed significantly reduced responsiveness to NTG, isosorbide dinitrate, SNP, and SIN-1.
- Responses to S-nitroso-N-acetylpenicillamine and nitric oxide were only marginally affected.
- No significant difference in relaxation was observed for endothelium-dependent (A23187) or guanylate cyclase-independent (theophylline) vasodilators.
- Cross-tolerance studies indicated distinct tolerance mechanisms for organic nitrates versus non-nitrate vasodilators.
Conclusions:
- NTG-induced tolerance in coronary arteries affects multiple sites in the signaling pathway leading to vasodilation.
- Tolerance mechanisms differ between organic nitrates and other vasodilators like SNP and SIN-1.