The effect of arachidonic acid (AA) metabolism on histamine release and SRS (leukotrienes) production has been studied in guinea-pig lung using anaphylactic reaction and Ca2+ ionophore as the triggering agents in vitro. AA and L-cysteine enhanced SRS production without any appreciable effect on histamine release. Two nonsteroid anti-inflammatory agents, indomethacin and ketoprofen, which block prostaglandin production by the cyclooxygenase pathway, stimulated SRS production but had hardly any effect on histamine release, indicating that SRS synthesis is more sensitive to prostaglandin regulation. Enhancement of SRS production was more pronounced for antigen than for Ca2+ ionophore. This might be related to different cellular origin of SRS with the two triggering agents. Using rat peritoneal cells, both mast cells and the other cells were found to produce SRS in response to Ca2+ ionophore, the amount formed by the latter type of cells being higher. Inhibition of lipoxygenase by 5,8,11,14-eicosatetraynoic acid and nordihydroguaiaretic acid depressed SRS production, but had no effect on histamine release. SRS production triggered by Ca2+ ionophore was more sensitive, possibly because of different cellular origin of SRS in response to the two stimuli. The explanation for the discrepancy between the effect on SRS production and histamine release may also have to be sought in their different origins. SRS may mainly stem from cells, which are more sensitive to the inhibitors than the mast cell, which is the source of histamine.