We assessed the effects of negative intrathoracic pressure induced by inspiratory elastic loading on pulmonary, gas exchange with and without electrically induced hindlimb exercise in 8 normal, anesthetized dogs. Two elastic loads (EL) were used; one of 81 and one of 140 cmH2O/liter. These are equivalent to doubling and tripling the normal elastance of the dog's respiratory system, respectively. Elastic loading decreased ventilation and caused hypoxemia and hypercapnia, but it did not affect systemic arterial pressure or heart rate. During exercise, increase in ventilation was limited, whereas increase in cardiac output was not affected by elastic loading. Alveolar-arterial O2 tension difference (A-aDO2) was not changed significantly by exercise alone. However, elastic loading accompanied by exercise increased A-aDO2. Although comparable end-inspiratory pleural pressure was achieved with large EL (-29 +/- 2 cmH2O, mean +/- SE) and small EL with exercise (-30 +/- 2 cmH2O), the latter increased A-aDO2 whereas the former did not. Large negative intrapleural pressure combined with increased cardiac output may have caused transient interstitial edema.