THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Copyright © 1984 by The American Society for Pharmacology and Experimental Therapeutics Responses to Leukotriene C4 in the Perfused Rat Lung1

The isolated rat lung was used to study both the effect of leukotnene C4 on pulmonary perfusion pressure and the synthe-sis 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, leukotnene 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 leukotnene 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,. and thromboxane B2 that were attenuated by indomethacin or FPL-5571 2 pretreatment. We conclude that leukotnene C4 1) directly constricts the pulmonary vasculature independent of cyclooxygenase products, 2) is not rapidly de-graded by the pulmonary circulation and 3) stimulates the release of cyclooxygenase products in the pulmonary circulation that can be attenuated by pretreatment with indomethacin or FPL-55712. LTC4 is a 5-lipoxygenase product of arachidonic acid metab-olism (Samuelsson et at., 1980) that is released in immediate hypersensitivity reactions (Borgeat and Sirois, 1981). This LT constricts airway and vascular smooth muscle obtained from lungs of several animal species (Drazen et at., 1980; Hand e