Related Experiment Videos
In vivo induction and reversal of nitroglycerin tolerance in human coronary arteries
Abstract:
The mechanism by which tolerance to the clinical effects of organic nitrates develops has not been elucidated. This study was done to determine whether an intravenous infusion of nitroglycerin induces tolerance in the coronary vascular bed and whether such tolerance is reversed by the sulfhydryl-group donor N-acetylcysteine. We studied 19 subjects--17 with coronary artery disease and 2 without it--who had a mean age (+/- SD) of 54 +/- 9 years. Coronary sinus blood flow, which approximates blood flow to the left ventricle, was measured before and during intracoronary injections of nitroglycerin (10, 25, 50, and 100 micrograms). The patients then received a 24-hour intravenous infusion of saline (n = 7) or of nitroglycerin, 45 +/- 13 micrograms per minute (n = 12), after which the responses of coronary sinus flow to the same doses of intracoronary nitroglycerin used earlier were measured. In the seven patients given saline, the four doses of intracoronary nitroglycerin caused similar percentage increases in coronary sinus flow before and after the saline infusion. In the 12 patients given intravenous nitroglycerin, the four intracoronary doses caused percentage increases in coronary flow before the infusion of 30 +/- 9, 35 +/- 14, 41 +/- 12, and 52 +/- 15, respectively. After the infusion, the same doses of nitroglycerin caused smaller (P less than 0.05) percentage increases (16 +/- 6, 21 +/- 11, 23 +/- 12, and 27 +/- 11, respectively), indicating the development of partial tolerance. Subsequently, 7 of the 12 patients received N-acetylcysteine, after which intracoronary nitroglycerin caused percentage increases in coronary sinus flow similar to the values measured before the intravenous nitroglycerin was given (34 +/- 13, 32 +/- 8, 38 +/- 11, and 44 +/- 16, respectively). We conclude that the coronary vasodilator effect of nitroglycerin is attenuated by an intravenous infusion of nitroglycerin (that is, partial tolerance develops) and that tolerance to the agent can be reversed by administration of the sulfhydryl-group donor N-acetylcysteine. The mechanism by which N-acetylcysteine reverses tolerance will require further investigation.
Insights
Intravenous nitroglycerin infusion causes partial tolerance to its coronary vasodilator effects. This tolerance can be reversed by N-acetylcysteine, a sulfhydryl-group donor, suggesting a role for thiol groups in nitrate tolerance.
Area of Science:
- Cardiovascular Pharmacology
- Nitrate Vasodilators
- Drug Tolerance Mechanisms
Background:
- Organic nitrates are crucial for managing angina, but tolerance limits their efficacy.
- The precise mechanisms underlying nitrate tolerance remain incompletely understood.
- Investigating tolerance development and reversal is key to optimizing nitrate therapy.
Purpose of the Study:
- To determine if intravenous nitroglycerin induces tolerance in the coronary vascular bed.
- To assess whether N-acetylcysteine can reverse nitroglycerin-induced tolerance.
- To elucidate the role of sulfhydryl groups in nitrate tolerance.
Main Methods:
- Coronary sinus blood flow was measured in subjects with and without coronary artery disease.
- Tolerance was induced via a 24-hour intravenous nitroglycerin infusion.
- The effect of N-acetylcysteine on coronary blood flow response to nitroglycerin was evaluated.
Main Results:
- Intravenous nitroglycerin infusion led to partial tolerance, significantly reducing coronary vasodilator response.
- N-acetylcysteine administration reversed this tolerance, restoring responsiveness to nitroglycerin.
- Control saline infusion did not induce tolerance.
Conclusions:
- Continuous intravenous nitroglycerin causes partial tolerance in the coronary vasculature.
- N-acetylcysteine, a sulfhydryl donor, effectively reverses nitroglycerin tolerance.
- Thiol availability may be critical in the development and reversal of nitrate tolerance.