Because the pulmonary endothelium is sensitive to O2-induced damage, we studied in vivo angiotensin-converting enzyme (ACE) activity in the lungs of 14 catheterized unanesthetized dogs exposed either to air or continuous 100% O2 at 1 ATA. For 5 days, or until the dog died, we measured physiological variables and lung ACE activity. The metabolic data were analyzed with a model that accounted for the effect of changes in cardiac output. Nine dogs breathing O2 lived 88 +/- 21.8 (SD) h and except for blood O2 tensions were indistinguishible from controls until development of a terminal response lasting only a few hours. Hemodynamic instability preceded a precipitous terminal change in blood gas tensions which resulted in impairment of arterial oxygenation, hypercapnia, and acidosis. Plasma renin activity increased. The metabolic capacity of the pulmonary endothelium of O2-exposed animals decreased with time so that after 96 h it was 50% of the control. That of five control animals did not change with time. Thus changes in lung ACE activity preceded alterations in hemodynamics or gas exchange, and the contributions of each are discussed.