Interactions Among Three Classes Of Mediators Explain Antigen-Induced Bronchoconstriction In The Isolated Perfused And Ventilated Guinea Pig Lung

Intravascular challenge of isolated perfused and ventilated guinea pig lung (IPL) from actively sensitized guinea pigs, with cumulatively increasing ( 10 - 10,000 mug) doses of ovalbumin ( OVA), resulted in dose-dependent and reproducible reductions in lung conductance. The antihistamines mepyramine ( 1 muM) and metiamide ( 1 muM), the leukotriene antagonist zafirlukast ( 0.1 muM), or the cyclooxygenase enzyme ( COX) inhibitor diclofenac ( 10 muM) each caused a parallel and rightward shift in the dose-response relation for OVA, providing evidence for contributions of histamine, cysteinyl-leukotrienes, and COX products to the OVA-induced bronchoconstriction in the IPL. Moreover, when all three drugs were combined there was a complete abolishment of the response to OVA. When two antagonists or inhibitors were combined, the results, however, were more complex. The 5-lipoxygenase inhibitor BAY x1005 ( 30 muM) and the thromboxane TP) receptor antagonist BAY u3405 ( 1 muM) given as single treatment did not inhibit the response to OVA. However, combinations of different antagonists/inhibitors, including BAY x1005 and BAYu3405, caused pronounced inhibitions of the antigen responses, suggesting synergism in action. On the basis of these data it was concluded that although histamine and cysteinyl-leukotrienes mediate the major part of the bronchoconstriction, one or several prostanoids other than thromboxane contribute to the bronchoconstriction evoked by OVA. Moreover, the effect of diclofenac involved a dual action because it also made the IPL less sensitive to histamine and LTD4. The findings resemble and extend recent observations in clinical studies of patients with asthma and support the usefulness of this particular model in airway pharmacology.