To obviate the myocardial depressant action of propranolol, the use of this drug in combination with a positive inotropic agent, mannitol, was studied in the ischemic heart of the dog. Mannitol (25%) administered prior to propranolol augmented myocardial contractility, as shown by an upward shift of the relationship between the pressure change with time and the mean left atrial pressure. Subsequent administration of propranolol did not offset the positive inotropic response to mannitol whereas it markedly reduced the heart rate from a control ischemic value of 127.8 +/- 3.4 to 109 +/- 4.0 beats/min. The myocardial oxygen requirement, as determined by the tension-time index per minute, decreased 26.3 +/- 1.2% below the control ischemic value. These findings suggest that hypertonic mannitol augments contractility in the ischemic failing heart while sustaining the desirable negative chronotropic action of propranolol. This procedure may potentiate the beneficial effects of propranolol on the myocardial oxygen balance and serve as an effective therapeutic modality in the control of acute irreversible ischemia.