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.
Arakida
Y
Y
Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Miyukigaoka, Tsukuba-shi, Ibaraki, Japan. arakida.yasuhito@yamanouchi.co.jp
Ohga
K
K
Suwa
K
K
Yokota
M
M
Miyata
K
K
Yamada
T
T
Honda
K
K
D000284:Administration, Oral; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D007116:Immunization, Passive; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D015289:Leukotrienes / Q000378:metabolism / Q000502:physiology; D008297:Male; D008565:Membrane Proteins; D010648:Phenylacetates / Q000494:pharmacology; D018077:Receptors, Leukotriene; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012710:Serum Albumin, Bovine / Q000276:immunology; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism / Q000502:physiology; D013929:Thromboxane B2 / Q000378:metabolism / Q000502:physiology
D002867:Chromones; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008565:Membrane Proteins; D010648:Phenylacetates; D018077:Receptors, Leukotriene; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013777:Tetrazoles; D013844:Thiazoles; C115704:YM 158; D012710:Serum Albumin, Bovine; D013929:Thromboxane B2; D013928:Thromboxane A2; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor; C051762:daltroban; C047681:pranlukast