We have studied the effects and mechanism of fenoterol (a beta 2-agonist) on contractility of the fatigued canine diaphragm. Transdiaphragmatic pressure (Pdi) was measured by a pair of balloons, and diaphragmatic contractility was assessed from changes in tetanic contraction, produced by supramaximal electrical stimulation of the phrenic nerves. Diaphragmatic fatigue was developed by applying an inspiratory resistive load to a spontaneously breathing dog for approximately 30 min. Fenoterol improved the Pdi of the fatigued canine diaphragm at all stimulation frequencies, and the increases in Pdi at low frequencies were greater. The potentiation of Pdi by fenoterol occurred in a dose-dependent manner with doses of 2.5 to 10 micrograms/kg and was equal to that of aminophylline. Dibutyryl cyclic AMP did not have significant effect on the Pdi at all stimulation frequencies. The augmentation of Pdi in the fatigued diaphragm by fenoterol was abolished by administration of a calcium antagonist, verapamil, and fenoterol did not change the diaphragmatic contractility in nonfatigued dogs. We thus have concluded that fenoterol improves contractility in the fatigued canine diaphragm and the effect might be brought about by an increased influx of calcium to the muscle cell.