%0 Journal Article %A Yasuhito Arakida %A Keiko Ohga %A Kiyomi Suwa %A Masaki Yokota %A Keiji Miyata %A Toshimitsu Yamada %A Kazuo Honda %T Effects of Lipid Mediator Antagonists on Predominant Mediator-Controlled Asthmatic Reactions in Passively Sensitized Guinea Pigs %D 1999 %J Journal of Pharmacology and Experimental Therapeutics %P 1285-1291 %V 290 %N 3 %X The role of cysteinyl leukotrienes (cys-LTs) and thromboxane A2 (TXA2) 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, LTC4/D4/E4 and TXB2, in lungs of challenged guinea pigs. The predominant mediator in indomethacin-untreated asthma was TXA2, 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 TXA2 equally participated. Either LTD4 or TXA2 receptor antagonists given alone inhibited the asthmatic response in conditions where the corresponding mediator plays a predominant role. The combination of LTD4and TXA2 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 LTD4 and TXA2receptors, showed the same antiasthmatic effect as a combinated LTD4 receptor antagonist and a TXA2 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. The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/290/3/1285.full.pdf