Effects of lipid mediator antagonists on predominant mediator-controlled asthmatic reactions in passively sensitized guinea pigs.

The role of cysteinyl leukotrienes (cys-LTs) and thromboxane A(2) (TXA(2)) in guinea pig models of aspects of bronchial asthma was investigated. In a novel antigen (BSA)-induced asthmatic model using passively sensitized guinea pigs, pretreatment with varying doses of indomethacin controlled the ratio of followed lipid mediators, LTC(4)/D(4)/E(4) and TXB(2), in lungs of challenged guinea pigs. The predominant mediator in indomethacin-untreated asthma was TXA(2), and complete inhibition of cyclooxygenase by i.v. injection of 5-mg/kg indomethacin-induced cys-LTs mainly mediated asthmatic response. Furthermore, a 1-mg/kg indomethacin dose induced an asthmatic state where both cys-LTs and TXA(2) equally participated. Either LTD(4) or TXA(2) receptor antagonists given alone inhibited the asthmatic response in conditions where the corresponding mediator plays a predominant role. The combination of LTD(4) and TXA(2) receptor antagonists exhibited significant effects irrespective of the condition used. Under conditions where both mediators equally participate, a combination of both receptor antagonists showed additive inhibition. YM158, a newly synthesized and orally active dual antagonist for LTD(4) and TXA(2) receptors, showed the same antiasthmatic effect as a combinated LTD(4) receptor antagonist and a TXA(2) receptor antagonist mixture. Therefore, broad-acting compounds such as YM158 are expected to have antiasthmatic efficacies in a broader class of asthmatic patients than single-acting drugs.