The cardiac effects of 2,3-butanedione monoxime on electrical and mechanical function, rhythm, oxygen utilization, and coronary flow responsiveness, particularly during severe ischemia and reperfusion, have not been studied. After perfusing hearts at 55 mm Hg, coronary perfusion was interrupted for 30 minutes and was then reestablished at the control perfusion pressure for 40 minutes. Hearts were divided into four groups (n = 10 each) treated with 0, 3, 5, or 10 mmol/L of 2,3-butanedione monoxime added to the perfusate for 10 minutes before and during ischemia and for the first 10 minutes of reperfusion. An additional nonischemic group served as a time control. Variables monitored were heart rate, atrioventricular conduction time, cardiac rhythm, isovolumetric systolic and diastolic left ventricular pressure, maximum rate of left ventricular pressure change, coronary flow, myocardial oxygen consumption, and the ratio of oxygen delivery to myocardial oxygen consumption. Before ischemia, 2,3-butanedione monoxime significantly decreased isovolumetric left ventricular systolic pressure and increased the ratio of oxygen delivery to myocardial oxygen consumption in a dose-dependent manner, with only slight changes in heart rate and atrioventricular time with 10 mmol/L of 2,3-butanedione, monoxime. After 40 minutes of reperfusion, isovolumetric left ventricular systolic pressure recovered to 81 +/- 5% and 83 +/- 2% of the initial control values for the 5 and 10 mmol/L 2,3-butanedione monoxime groups. This was significantly greater than the recovery for the 0 and 3 mmol/L 2,3-butanedione monoxime groups, 59 +/- 3% and 63 +/- 4%, respectively. Similarly, the duration of ventricular fibrillation and of tachycardia was significantly lower, coronary flow reserve was better preserved, and myocardial oxygen consumption was greater with reperfusion in the 5 and 10 mmol/L 2,3-butanedione monoxime groups than in the 0 mmol/L 2,3-butanedione monoxime group. This study shows that relatively low concentrations of 2,3-butanedione monoxime, given before global ischemia and early during reperfusion of isolated hearts, can protect against dysrhythmias and improve return of myocardial and vascular function.