The cardiac and hemodynamic effects of R80122, a new specific phosphodiesterase III inhibitor, were studied in a closed-chest canine model of acute global left ventricular ischemia complicated by heart failure. The results obtained were compared with those obtained with milrinone. Intravenous infusion of the compounds (0.005 mg/kg/min for both) was started when stable heart failure had developed and was continued for 50 min followed by a washout period of 60 min. Both R80122 and milrinone improved the function of the acutely failing heart, as indicated by the increase in the values of the variables related to left ventricular function, but differences existed. The most striking differences were the normalization of the left ventricular external mechanical efficiency with R80122, but not with milrinone, and the maintenance of aortic blood pressure during infusion of R80122, which decreased during infusion of milrinone. Milrinone tends to induce ventricular tachycardia more frequently than R80122. It can be concluded that R80122 and milrinone improve the function of the acutely failing heart, but that the changes induced by R80122 are better balanced, i.e., enhancement of external mechanical efficiency with maintenance of aortic blood pressure.