The effect of exposure of rats to high concentrations of oxygen (90-95%, normobaric) on the activation of angiotensin I to angiotensin II and on the inactivation of bradykinin, prostaglandin E2 (PGE2) and 5-hydroxytryptamine (serotonin) in the pulmonary circulation of isolated perfused rat lungs was investigated. After 36 h exposure, PGE2 survival in the pulmonary circulation increased and reached 3 times the control value after 48 h exposure. A decrease in the conversion of angiotensin I to angiotensin II was seen after 48 h exposure. No decrease in the inactivation of 5-hydroxytryptamine was seen until after 60 h exposure. At this time bradykinin inactivation was also decreased. The decrease in metabolism of angiotensin I and PGE2 following 48 h exposure to oxygen was reversed by a subsequent exposure to room air for 12 h. In these experiments, therefore, the earliest sign of oxygen toxicity was a decrease in PGE2 metabolism, a reaction associated with cells other than endothelial cells.