Antagonism by ETYA of the effects of leukotrienes on ileum and lung parenchymal strips independent of effects on arachidonic acid metabolism.

5,8,11,14-Eicosatetraynoic acid (ETYA), a compound which inhibits both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism, antagonized the contraction of segments of guinea-pig ileal longitudinal muscle produced by SRS-A (IC50 = 2.73 microM). This activity was unaffected by pretreatment of the tissues with 10 microM indomethacin. Phenidone, another mixed cyclooxygenase-lipoxygenase inhibitor, was inactive. FPL-55712, an SRS-A antagonist, was a very potent inhibitor (IC50 = 0.011 microM). BW755C and NDGA nonselectively inhibited the contractions of the guinea-pig ileal longitudinal muscle induced by SRS-A or histamine. ETYA antagonized the contraction of the guinea-pig ileal strip produced by 6 nM synthetic LTC4 (IC50 = 9.3 microM). FPL-55712 demonstrated an IC50 of 0.3 microM in a similar series of experiments. ETYA, 1, 3 or 10 microM did not inhibit the contractions elicited by 0.5 microM of histamine. This was not a tissue-selective effect since 100 microM ETYA antagonized the LTC4-induced contraction of the guinea-pig lung parenchymal strip preparation. These data demonstrate that ETYA antagonized the contractile effect of the leukotrienes on tissues from the gastrointestinal tract and lung. Furthermore, the inability of indomethacin or phenidone to inhibit the contractile response suggests that antagonism by ETYA may occur by a mechanism independent of cyclooxygenase and lipoxygenase enzymes.