In Vivo Induction and Reversal of Nitroglycerin Tolerance in Human Coronary Arteries

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 W-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 μg). The patients then received a 24-hour intravenous infusion of saline (n = 7) or of nitroglycerin, 45±13 μg 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<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. (N Engl J Med 1987; 317:805–9)., THE phenomenon of vascular tolerance to organic nitrates has been recognized for many years. In laboratory animals, the hypotensive effect of nitrates is rapidly attenuated during short periods of administration.^{1 2 3 4 5 6 7 8} However, the relevance of these observations to the use of nitrates by patients with heart disease has remained unsettled. Although several studies have failed to demonstrate a diminution in the antianginal efficacy of oral and topical nitroglycerin,^{9 10 11 12} others have documented the presence of clinically important nitrate tolerance in patients given long-acting nitrates for a week or longer.^{13 14 15 16} Furthermore, recent studies have shown that tolerance may appear as early as 18…