Stimulation of arachidonic acid metabolism and generation of thromboxane A2 by leukotrienes B4, C4 and D4 in guinea-pig lung in vitro.

1 Leukotriene C4 (LTC4), LTD4, slow-reacting substance of anaphylaxis (SRS-A) (from guinea-pig lung), bradykinin (Bk) and arachidonic acid (AA) release thromboxane A2 (TxA2) and prostaglandin-like materials from guinea-pig isolated perfused lungs. 2 Release of TxA2 induced by LTC4 and LTD4 is inhibited by a thromboxane synthetase inhibitor, imidazole (2.9 mM). 3 Mepacrine (200 microM), a phospholipase inhibitor, inhibits release of TxA2 and prostaglandin-like materials caused by SRS-A and Bk but not that due to exogenous AA 4 Leukotrienes B4, C4 and D4 are approximately equipotent in inducing dose-related contractions of guinea-pig parenchymal strips (GPPs). 5 Leukotriene-induced contractions of GPPs are greatly inhibited by imidazole (2.9 mM), carboxyheptylimidazole (24 microM) and mepacrine (400 microM). 6 FPL 55712 (1.9 microM), the SRS-A antagonist, blocks contractions of GPPs induced by LTC4 and LTD4 but not those due to LTB4 or Bk. 7 Tachyphylaxis to LTB4 occurs in GPPs but not to LTC4 or LTD4. 8 These results suggest that in guinea-pig lung in vitro, LTB4, LTC4 and LTD4 activate a phospholipase with subsequent generation of cyclo-oxygenase products of which TxA2 plays an important role.