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Effects of lipid mediator antagonists on predominant mediator-controlled asthmatic reactions in passively sensitized guinea pigs.
J Pharmacol Exp Ther 1999; 290(3):1285-91JP

Abstract

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.

Authors+Show Affiliations

Inflammation Research Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Miyukigaoka, Tsukuba-shi, Ibaraki, Japan. arakida.yasuhito@yamanouchi.co.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10454505

Citation

Arakida, Y, et al. "Effects of Lipid Mediator Antagonists On Predominant Mediator-controlled Asthmatic Reactions in Passively Sensitized Guinea Pigs." The Journal of Pharmacology and Experimental Therapeutics, vol. 290, no. 3, 1999, pp. 1285-91.
Arakida Y, Ohga K, Suwa K, et al. Effects of lipid mediator antagonists on predominant mediator-controlled asthmatic reactions in passively sensitized guinea pigs. J Pharmacol Exp Ther. 1999;290(3):1285-91.
Arakida, Y., Ohga, K., Suwa, K., Yokota, M., Miyata, K., Yamada, T., & Honda, K. (1999). Effects of lipid mediator antagonists on predominant mediator-controlled asthmatic reactions in passively sensitized guinea pigs. The Journal of Pharmacology and Experimental Therapeutics, 290(3), pp. 1285-91.
Arakida Y, et al. Effects of Lipid Mediator Antagonists On Predominant Mediator-controlled Asthmatic Reactions in Passively Sensitized Guinea Pigs. J Pharmacol Exp Ther. 1999;290(3):1285-91. PubMed PMID: 10454505.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effects of lipid mediator antagonists on predominant mediator-controlled asthmatic reactions in passively sensitized guinea pigs. AU - Arakida,Y, AU - Ohga,K, AU - Suwa,K, AU - Yokota,M, AU - Miyata,K, AU - Yamada,T, AU - Honda,K, PY - 1999/8/24/pubmed PY - 1999/8/24/medline PY - 1999/8/24/entrez SP - 1285 EP - 91 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 290 IS - 3 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/10454505/Effects_of_lipid_mediator_antagonists_on_predominant_mediator_controlled_asthmatic_reactions_in_passively_sensitized_guinea_pigs_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10454505 DB - PRIME DP - Unbound Medicine ER -