Prevention and Reversal of Nitrate Tolerance in Patients with Congestive Heart Failure

To evaluate possible mechanisms underlying the development of nitrate tolerance, we treated 35 patients who had severe chronic heart failure with a prolonged (48-hour) intravenous infusion of nitroglycerin (6.4 μg per kilogram of body weight per minute) given either continuously or intermittently (12-hour infusions separated by intervals of 12 hours). Intravenous nitroglycerin produced immediate hemodynamic benefits in all patients, but the magnitude of this improvement was greatly diminished after 48 hours of continuous therapy with the drug. This attenuation was accompanied by cross-tolerance to oral isosorbide dinitrate and by an increase in heart rate, plasma renin activity, and body weight. In contrast, intermittent therapy with intravenous nitroglycerin was not associated with a loss of hemodynamic efficacy or cross-tolerance to oral nitrates and was not accompanied by changes in neurohormonal activity or body weight. In eight patients in whom nitrate tolerance developed during continuous intravenous therapy, the administration of the sulfhydryl-containing compound N-acetylcysteine (200 mg per kilogram orally) restored the hemodynamic state toward that observed at the start of the infusion of nitroglycerin (partial reversal of tolerance). In contrast, N-acetylcysteine had little hemodynamic effect in patients who were not receiving nitroglycerin. These data support the hypothesis that neurohormonal activation and depletion of sulfhydryl groups may interact to cause the loss of hemodynamic efficacy that occurs during prolonged treatment with intravenous nitroglycerin in patients with heart failure. Evaluation of the suggested role of sulfhydryl depletion in the development of tolerance will, however, require direct studies of vascular tissue. (N Engl J Med 1987; 317:799–804.) INTRAVENOUS nitroglycerin is widely used in the short-term management of unstable angina, severe hypertension, and congestive heart failure.^{1 2 3} Because the infusion of nitroglycerin produces immediate but transient hemodynamic benefits,² patients commonly receive prolonged intravenous therapy with the drug in an effort to sustain its favorable effects until clinical stability can be achieved. However, little is known about the efficacy of intravenous nitroglycerin when it is administered continuously for several days, and there is widespread concern that continuous exposure to the drug may rapidly induce a state of pharmacologic tolerance that can limit its usefulness.⁴ In patients with ischemic heart disease,.