SK-AND-F 88046 - A UNIQUE PHARMACOLOGIC ANTAGONIST OF BRONCHOCONSTRICTION INDUCED BY LEUKOTRIENE-D4, THROMBOXANE AND PROSTAGLANDIN-F2-ALPHA AND PROSTAGLANDIN-D2 INVITRO

  • 1 January 1984
    • journal article
    • research article
    • Vol. 228  (1) , 128-132
Abstract
SK&F 88046, an imidodisulfamide initially reported as an end organ leukotriene (LT)D4 antagonist on guinea-pig lung parenchyma 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 was antagonized by SK&F 88046 and FPL 556712 [7-[3-[-4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid monosodium salt]. 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. 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 KCl. FPL 55712 weakly antagonized the actions of carbocyclic TxA2, but not the contractions induced by the other agonists. SK&F 88046 is evidently an antagonist of the indirect, Tx-dependent component of LTD4 action in the guinea pig, presumably via antagonism of Tx on the end organ. LTD4 can evidently exert its bronchoconstrictive actions via 2 mechanisms, a direct pathway and an indirect, Tx-dependent pathway. [Relevance to anaphylaxis and allergic asthma is discussed.].