Antigen‐induced contraction of guinea‐pig isolated trachea: studies with novel inhibitors and antagonists of arachidonic acid metabolites

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Abstract
1 Responses of antigen-challenged isolated trachea from sensitized guinea-pigs were pharmacologically characterized by use of some novel inhibitors and antagonists of arachidonic acid metabolites. 2 The cyclo-oxygenase inhibitor, indomethacin, prolonged without altering the maximum response to antigen in the absence of the anti-muscarinic agent, atropine, and/or the H1receptor blocker, mepyramine. In the presence of mepyramine, indomethacin both prolonged and increased the magnitude of the response. The selective (SQ-29548) and non-selective (L-640, 035) thromboxane A2 (TXA2) antagonist and the TXA2 synthetase inhibitor, OKY-046, were essentially inactive. 3 Two novel inhibitors of 5-lipoxygenase product formation, AA-861 and L-651,896 produced complete inhibition of the response to antigen on tissues treated with atropine and mepyramine, with or without indomethacin. 4 Equimolar concentrations of the leukotriene D4 (LTD4) receptor antagonists LY-171883 > L-649,923 ≧ L-648,051 ≧ FPL-55712 blocked part of the response to antigen on tissues treated with atropine, mepyramine and indomethacin. All compounds tended to block a larger component of the response in the absence of indomethacin. A similar tendency was observed with the potent phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX) but not the less potent phosphodiesterase inhibitor theophylline. 5 These results are consistent with the hypothesis that 5-lipoxygenase products acting on LTD4 receptors play only a minor role in the mediation of the contraction of guinea-pig trachea to antigen challenge. The nature of the residual contractile mediator is unknown; however, it can be completely blocked by the 5-lipoxygenase inhibitors AA-861 and L-651,896 and non-selectively blocked by the phosphodiesterase inhibitor, IBMX and non-selective LTD4 receptor antagonists, such as LY-171883.

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