Nitrous oxide has a long clinical history, but its effects on the heart remain controversial. The direct effects of N2O on global myocardial function have not been reported. The authors' aim was to examine the inotropic, chronotropic, dromotropic, and vascular effects of N2O, compared with its N2control, on hearts isolated from the guinea pig. Hearts (N = 31) were isolated and perfused at 37° C with Krebs-Ringer solution at constant pressure. Isovolumetric left ventricular pressure (LVP) and its derivative (maximum rate of tension development [dP/dtmax) were measured by placing a saline-filled, latex balloon into the left ventricle. Bipolar electrodes were placed in the right atrium and right ventricle for measurement of heart rate (HR) and atrioventricular conduction time (AVCT). The venae cavae were ligated, and the right ventricle was cannulated through the pulmonic valve to collect coronary sinus effluent for measurement of coronary outflow O2tension, adenosine, and inosine. After stabilization and perfusion with 96% O2(plus 4% CO2), each heart was exposed for 10 min either to 48% N2O or to 48% N2with 48% O2. After repeated perfusion with 96% O2for 10 min, hearts were exposed in the reverse order to 48% N2O or 48% N2. In the postcontrol period, hearts were again exposed to 96% O2. Inflow Po2(in mmHg) was 506 ± 5 (standard error of the mean [SEM]) during 96% O2and 258 ± 5 during both 48% N2and 48% N2O. Effluent Po2was 155 ± 7 during 96% O2, 81 ± 5 during 48% N2and 83 ± 5 during 48% N2O. Adenosine increased coronary flow maximally 95 ± 5% in arrested and 50 ± 9% in paced hearts. Compared with in the O2controls, N2significantly increased coronary flow 26 ± 3%, reduced O2delivery 36 ± 2%, depressed LVP 20 ± 2% and +dP/dtmax15 ± 2%, and decreased myocardial O2consumption 36 ± 3%; effluent concentrations of adenosine and inosine increased 4.8 ± 0.8 and 2.7 ± 0.6 times. N2alone did not alter HR, AVCT, percentage O2extraction, or the O2supply-to-demand ratio. Substitution of 48% N2O for 48% N2, produced no additional change in these variables except for significant additional 5 ± 2% decreases in LVP and +dP/dtmax. N2O had no appreciable direct effects in addition to those of N2on coronary flow or O2consumption. Although the mild hypoxia caused by 48% N2or N2O decreased contractility and O2consumption and increased effluent release of adenosine and inosine, the increase in coronary flow was substantially less than maximal flow attained with adenosine. This suggests that reduced O2content, like reduced coronary flow, can itself potentially limit cardiac work. The findings also demonstrate that N2O adds little to the cardiac effects of reduced O2delivery except for a significant depression of contractility. The authors speculate that,in vivo, N2O may also be a mild direct cardiac depressant, especially in the presence of other cardiac depressant agents.