Vol. 290, Issue 3, 1285-1291, September 1999

Effects of Lipid Mediator Antagonists on Predominant Mediator-Controlled Asthmatic Reactions in Passively Sensitized Guinea Pigs

Yasuhito Arakida, Keiko Ohga, Kiyomi Suwa, Masaki Yokota, Keiji Miyata, Toshimitsu Yamada and Kazuo Honda

Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Miyukigaoka, Tsukuba-shi, Ibaraki, Japan

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 LTD₄ and 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 TXA₂ receptors, 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.