SK&F 88046: a unique pharmacologic antagonist of bronchoconstriction induced by leukotriene D4, thromboxane and prostaglandins F2 alpha and D2 in vitro.

SK&F 88046, an imidodisulfamide initially reported as an end organ leukotriene (LT)D4 antagonist on guinea-pig lung parenchyma (Gleason et al., 1982), was studied further in order to elucidate its mechanism of action. The LTD4-induced contraction of the guinea-pig lung parenchyma, which occurs via both a direct action and an indirect, thromboxane (Tx)-dependent pathway (Weichman et al., 1982), was antagonized by SK&F 88046 and FPL 55712. SK&F 88046 was not acting on the lung parenchyma as a result of antagonism of cyclooxygenase or Tx synthetase, as SK&F 88046 did not block the LTD4-induced generation of TxB2 from the parenchyma. In contrast, the LTD4-induced contraction of the guinea-pig trachea, which is only directly mediated, was antagonized by FPL 55712 but not by SK&F 88046. However, SK&F 88046 did antagonize the contractions elicited by carbocyclic TxA2, a stable Tx analog, as well as those elicited by prostaglandins F2 alpha and D2, but not those elicited by histamine, carbachol or KCI. FPL 55712 weakly antagonized the actions of carbocyclic TxA2, but not the contractions induced by the other agonists. These results demonstrate that SK&F 88046 is an antagonist of the indirect, Tx-dependent component of LTD4 action in the guinea pig, presumably via antagonism of Tx on the end organ. These results provide additional evidence that LTD4 can exert its bronchoconstrictive actions via two mechanisms, a direct pathway and an indirect, Tx-dependent pathway.