Background Supply of sulfhydryl groups with the administration of N-acetylcysteine (NAC) has been reported to reverse tolerance to nitroglycerin but not to isosorbide dinitrate (ISDN). Lack of interaction between NAC and ISDN was suggested as an explanation for these findings. The present study was therefore designed to further evaluate this hypothesis. For this purpose, we compared the hemodynamic and hormonal effects of ISDN when given alone and in combination with NAC.Methods and Results We performed a randomized, crossover design evaluation of the hemodynamic and hormonal effects of ISDN and ISDN+NAC in 14 patients with chronic congestive heart failure due to left ventricular systolic dysfunction. The findings of this study demonstrated a substantial NAC-mediated potentiation of ISDN effect on mean right atrial pressure (-11+-21% versus -38+-27%, -17+-20% versus -34+-27%, and -7+-20% versus -25+-26% at 2, 3, and 4 hours, respectively; all P<.05), mean pulmonary artery wedge pressure (-18+-16% versus -33+-14%, -15+-25% versus -33+-19%, -14+-22% versus -25+-22%, and -16+-16% versus -26+-16% at 2, 3, 4, and 5 hours, respectively; all P<.05), mean pulmonary artery pressure (-8+-11% versus -20+-15% at 3 hours, P<.05), and cardiac output (an increase of 2+-16% versus 25+-20% at 4 hours, P<.05). Although there were no significant changes in serum catecholamine levels and plasma renin concentration with both regimens, ISDN+NAC resulted in a greater fall in plasma levels of atrial natriuretic peptide (296+-251 pg/mL after ISDN versus 202+-118 pg/mL after ISDN+NAC, P<.05).Conclusions The results of this study provide strong evidence for the existence of an interaction between thiols and ISDN and further support the role of sulfhydryl groups in the activation and therapeutic action of organic nitrates. The discrepancy between the results of this study demonstrating NAC-induced potentiation of ISDN effects and a previous study showing failure to reverse ISDN tolerance with NAC may suggest that ISDN-NAC interaction requires normal intracellular levels of sulfhydryl groups and does not occur after intracellular sulfhydryl group depletion. (Circulation. 1994;89:2595-2600.)