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 guin ea pigs, pretreatment with varying doses of indomethacin controlled the rat io of followed lipid mediators, LTC4/D-4/E-4 and TXB2, in lungs of challeng ed guinea pigs. The predominant mediator in indomethacin-untreated asthma w as TXA(2), and complete inhibition of cyclooxygenase by i.v. injection of 5 -mg/kg indomethacin-induced cys-LTs mainly mediated asthmatic response. Fur thermore, a 1-mg/kg indomethacin dose induced an asthmatic state where both cys-LTs and TXA(2) equally participated. Either LTD4 or TXA(2) receptor an tagonists given alone inhibited the asthmatic response in conditions where the corresponding mediator plays a predominant role. The combination of LTD , and TXA(2) receptor antagonists exhibited significant effects irrespectiv e of the condition used. Under conditions where both mediators equally part icipate, a combination of both receptor antagonists showed additive inhibit ion. YM158, a newly synthesized and orally active dual antagonist for LTD4 and TXA(2) receptors, showed the same antiasthmatic effect as a combinated LTD4 receptor antagonist and a TXA(2) receptor antagonist mixture. Therefor e, broad-acting compounds such as YM158 are expected to have antiasthmatic efficacies in a broader class of asthmatic patients than single-acting drug s.