Milrinone improves function in failing adult hearts. This study examined its effect on immature myocardium. Using an isolated working neonatal rabbit heart preparation, we measured myocardial function, high-energy compounds, and cyclic adenosine monophosphate. Hearts were subjected to 1 hour of normothermic ischemia, 10 minutes of reperfusion with Ringer's solution, and 30 minutes of reperfusion with either unaltered Ringer's, Ringer's with dobutamine (0.1 microgram/mL), or Ringer's with milrinone (1 microgram/mL). These hearts were compared with each other, with a control group continuously perfused for 70 minutes, and with a group of hearts that were made ischemic and reperfused for only 10 minutes. There was a progressive decline in adenosine triphosphate levels measured in hearts from the groups receiving 10 and 40 minutes of reperfusion with unaltered perfusate, and cardiac output fell to 82% +/- 4% of preischemic control in the latter group. When either dobutamine or milrinone was added to the reperfusion solution, postischemic myocardial function was restored completely, and the loss of adenosine triphosphate with reperfusion was halted. Cyclic adenosine monophosphate level was highest in ischemic/40-minute reperfused hearts, and there was no measurable increase in cyclic adenosine monophosphate level in the group of hearts receiving milrinone. The mechanism of preservation of high-energy stores with inotropic agents is not known but may involve potentiation of mitochondrial oxidative phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)