S-nitrosothiols are potent in vitro vasodilators, but little is known about their in vivo action. In this study, we compared the effects of S-nitroso N-acetyl penicillamine (SNAP) and nitroglycerin (NTG) on left ventricular (LV) hemodynamics in congestive heart failure rats. By using a twoday crossover design, stepwise i.v. infusions of SNAP or NTG at 3, 5 and 8 micrograms/min were administered for 30 min each, followed by a dose of 10 micrograms/min over the next 10 h. LV end-diastolic and peak-systolic pressures (LVEDP and LVPSP, respectively) were measured at selected intervals. SNAP and NTG produced maximal LVEDP reductions of 46 and 44%, respectively, at the highest infusion rate. However, at the lower doses, greater reductions of LVEDP were seen with SNAP. NTG had a smaller effect on LVPSP (maximum 6% reduction) than SNAP (maximum reduction of 15%). During the 10-h infusion of NTG, LVEDP gradually returned to base-line values, indicating the development of tolerance, despite relatively constant plasma levels of NTG over the infusion period. Tolerance in LVEDP effects was not observed during the 10-h infusion of SNAP. In the presence of NTG tolerance, rats were still responsive to SNAP (mean reduction of LVEDP 24%), suggesting the absence of cross-tolerance between these two nitrovasodilators. These results suggest that SNAP is a more potent in vivo vasodilator than NTG, has more arterial action than NTG and is less prone to produce LV hemodynamic tolerance.