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

Abstract

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.