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 micrograms 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.

Renal function was evaluated in 104 patients with severe chronic heart failure whom we treated with captopril or enalapril. Seventy patients showed no change or an improvement in renal function (group A), and 34 patients developed functional renal insufficiency (group B). Before converting-enzyme inhibition, group B patients received higher doses of furosemide (p less than 0.02) and had lower central venous pressures (p less than 0.05) than group A patients. After 1 to 3 months of converting-enzyme inhibition, an excessive reduction in left ventricular filling pressure (to less than 15 mm Hg) or mean arterial pressure (to less than 60 mm Hg) was noted in 28 of 34 (82%) patients in group B but in only 22 of 70 patients in group A (31%) (p less than 0.001). At the end of the study, drug-induced azotemia resolved after a reduction in the dosage of diuretics, despite unaltered treatment with captopril and enalapril. Hence, the deterioration of renal function after converting-enzyme inhibition in heart failure is not a toxic or immunologic reaction to therapy but results from specific hemodynamic events that can be ameliorated by sodium repletion.

To evaluate the concept that long duration of action is an advantageous property of angiotensin-converting enzyme inhibitors in the treatment of severe heart failure, we randomly assigned 42 patients to therapy with either a short-acting inhibitor (captopril, 150 mg daily) or a long-acting inhibitor (enalapril, 40 mg daily) for one to three months while concomitant therapy with digoxin and diuretics was kept constant. The treatment groups had similar hemodynamic and clinical characteristics at base-line evaluation and similar initial responses to converting-enzyme inhibition. During long-term therapy, captopril and enalapril produced similar decreases in systemic blood pressure, but the hypotensive effects of enalapril were more prolonged and persistent than those of captopril. Consequently, although the patients in both groups improved hemodynamically and clinically during the study, serious symptomatic hypotension (syncope and near syncope) was seen primarily among those treated with enalapril. Sustained hypotension also probably accounted for the decline in creatinine clearance (P less than 0.05) and the notable retention of potassium (P less than 0.05) observed in the patients treated with enalapril but not in those treated with captopril. We conclude that when large, fixed doses of converting-enzyme inhibitors are used in the treatment of patients with severe chronic heart failure, long-acting agents may produce prolonged hypotensive effects that may compromise cerebral and renal function, and thus they may have disadvantages in such cases, as compared with short-acting agents.