We have studied the effects of aminophylline on diaphragmatic contractility in 12 anesthetized dogs. The phrenic nerves were stimulated supramaximally (20 Hz, 0.1 ms) with electrodes placed around the fifth roots, and the transdiaphragmatic pressure (Pdi) generated at functional residual capacity (FRC) was measured with balloon catheters. Constancy of FRC was monitored by measuring the end-expiratory transpulmonary pressure, the dogs being occluded at FRC before the stimulations. The electrical activity of the diaphragm (Edi) during the stimulations was recorded with electrodes inserted in both hemidiaphragms. Phrenic stimulations during an infusion of aminophylline (10 mg/kg in 5 min) increased Pdi by 25 +/- 8% of control values, whereas the Edi remained unchanged. This potentiating effect of aminophylline was abolished when an identical dose was injected during a continuous infusion of a calcium blocker (verapamil, 0.1 mg X kg-1 X min-1). Infusion of another methylxanthine compound, caffeine (10 mg/kg), also increased Pdi for an identical electrical phrenic nerve stimulation by 21 +/- 6% compared with control values. However, the potentiating effect of caffeine was not abolished by verapamil. We conclude that aminophylline in vivo increases diaphragmatic contractility and that extracellular calcium is necessary for this action, a mechanism not shared by another methylxanthine compound, caffeine.