It is shown in a prospective study that the initial beneficial hemodynamic effect of nitroglycerine (NTG) significantly decreased after continuous 3-day infusion of this drug (10-50 micrograms/min) in acute myocardial infarction (AMI) patients associated with acute left heart failure. The effect of ameliorating anginapectoris and improving heart function with isosorbide dinitrate (ISDN) gradually decreased almost to pretreatment levels after oral administration of this drug (10-20mg, 4 times daily) for 3 weeks in anginapectoris patients associated with congestive heart failure (CHF) with accompanying increased level of plasma angiotensin II (AII) and body weight. However, when captopril (CPT, 12.5-25mg, 3 times daily) was combined with nitrates, the clinical effects were enhanced and maintained throughout the study, along with a decrease in the level of AII and body weight. In the hearts of rats perfused with CPT and NTG, the coronary flow (CF) significantly increased as compared with the flow when either drug was used alone. Enelapril (ENL, a non-sulfhydryl drug), however, did not show such effect. The above results indicate that repletion of sulfhydryl to vascular smooth muscle and antineurohumoral activation may be the potential mechanisms by which CPT reverses nitrate tolerance and enhances its clinical effects.