We studied diaphragmatic muscle function during inspiratory flow resistive (IFR) loaded breathing in unanesthetized sheep. We measured the change in transdiaphragmatic pressure (dPdi) and arterial blood gas tensions and recorded diaphragmatic electromyogram (EMG) from electrodes implanted on the muscle. We found that, with IFR loads less than 150 cmH2O X l-1 X s, dPdi and the integrated EMG increased, reached a plateau, and were maintained at high levels. The centroid frequency (fc) of the EMG power spectrum did not consistently change. With IFR loads greater than 150 cmH2O X l-1 X s, O2 was administered to prevent hypoxia, cyanosis, and agitation. With these loads, dPdi increased severalfold above base line, reached a plateau, and then started to decrease. Arterial PCO2 increased sharply at the time when dPdi decreased. The integrated EMG (iEMG) and fc started to decrease gradually 10-20 min before dPdi started to decrease. We conclude that 1) the diaphragm is capable of generating large pressures for prolonged periods with no evidence of fatigue; 2) with very high IFR loads, mechanical failure of the diaphragm can occur in the unanesthetized awake sheep; 3) diaphragmatic fatigue is associated with acute hypercapnia and therefore failure of the entire respiratory pump; and 4) a decrease in iEMG and a concommitant shift in the power spectrum density towards lower frequencies precede the mechanical failure of the diaphragm.