The isolated rat lung was used to study both the effect of leukotriene C4 on pulmonary perfusion pressure and the synthesis and release of cyclooxygenase products in the pulmonary circulation. A cell-free perfusate was passed only once through the pulmonary circulation or was recirculated. During single transit, leukotriene C4 produced dose-dependent increases in pulmonary perfusion pressure that were abolished by FPL-55712, a leukotriene receptor antagonist, but were not altered significantly by indomethacin. The duration of the pulmonary pressor response to leukotriene C4 was markedly prolonged during recirculation compared to single transit. Leukotriene C4 also induced dose-dependent increases in effluent levels of 6-keto-prostaglandin F1 alpha and thromboxane B2 that were attenuated by indomethacin or FPL-55712 pretreatment. We conclude that leukotriene C4 directly constricts the pulmonary vasculature independent of cyclooxygenase products, is not rapidly degraded by the pulmonary circulation and stimulates the release of cyclooxygenase products in the pulmonary circulation that can be attenuated by pretreatment with indomethacin or FPL-55712.