Abstract
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.
Footnotes
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Send reprint requests to: Yasuhito Arakida, Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd. 21, Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. E-mail:arakida.yasuhito{at}yamanouchi.co.jp
- Abbreviations:
- cys-LT
- cysteinyl leukotrienes (LTC4, LTD4, and LTE4)
- TX
- thromboxane
- YM158
- 3-[(4-tert-butylthiazol-2-yl)methoxy]-5′-[3-(4-chlorobenzenesulfonyl) propyl]-2′-(1H-tetrazol-5-ylmethoxy)benzanilide monosodium salt monohydrate
- Received January 28, 1999.
- Accepted May 25, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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