Effect of OKY-046, a new thromboxane A2 synthetase inhibitor, on experimental asthma in guinea pigs

Hiroichi Nagai , Ikuhisa Yakuo , Michinori Togawa , Akinori Arimura , Naosuke Matsuura , Akihide Koda , Shuichiro Hamano , Arao Ujiie , Masayuki Nakazawa
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引用次数: 18

Abstract

The effect of OKY-046, a newly synthetized thromboxane A2 (TxA2) synthetase inhibitor, on IgE mediated experimental asthma in guinea pigs was investigated. Indomethacin, a cyclooxygenase inhibitor, and tranilast (N-5′), a potent anti-allergic agent, were used as comparative drugs. OKY-046 clearly improved asthmatic respiratory disorders in guinea pigs. Whereas indomethacin had no effect on the changes of asthmatic respiration, tranilast significantly inhibited the changes. OKY-046 inhibited the in vitro antigen-induced contraction of sensitized guinea pig lung parenchyma. This antigen-induced contraction was also inhibited by tranilast, but not by indomethacin. OKY-046 inhibited the contractions of lung parenchyma caused by leukotriene C4, D4 and E4 (LTC4, LTD4 and LTE4), but not by histamine. Indomethacin showed a biphasic action on the contractile responses caused by histamine and LTD4 Consequently, contractions due to either agonist at low concentrations were inhibited by indomethacin, but those at high concentrations were enhanced. Tranilast inhibited the contraction of lung parenchyma induced by a low concentration of LTD4 but not that produced by histamine. Moreover, OKY-046 inhibited an elevation of concentration of thromboxane B2 (TxB2) in guinea pig lung perfusate after infusion of LTC4 but did not affect the elevation of 6-keto-PGF. OKY-046 had no effect on the antigen-induced release of histamine but it inhibited the release of the slow reacting substance of anaphylaxis (SRS-A) from sensitized chopped lung tissues. Indomethacin at a high concentration inhibited the release of histamine but did not affect the release of SRS-A. Tranilast clearly inhibited the release of both mediators. These results suggest that OKY-046 inhibits IgE mediated experimental asthma in guinea pigs and that its main mechanism is related to the inhibition of LT induced contraction of airway smooth muscle and the release of SRS-A from lung tissues.

新型血栓素A2合成酶抑制剂OKY-046对豚鼠实验性哮喘的影响
研究了新合成的血栓素A2 (TxA2)合成酶抑制剂OKY-046对IgE介导的豚鼠实验性哮喘的作用。用环加氧酶抑制剂吲哚美辛和强效抗过敏剂曲尼司特(N-5′)作为对照药物。OKY-046明显改善了豚鼠的哮喘呼吸系统疾病。吲哚美辛对哮喘呼吸变化无影响,曲尼司特对哮喘呼吸变化有明显抑制作用。OKY-046对致敏豚鼠肺实质的体外收缩有抑制作用。曲尼司特也能抑制这种抗原诱导的收缩,但吲哚美辛不能。OKY-046对白三烯C4、D4和E4 (LTC4、LTD4和LTE4)引起的肺实质收缩有抑制作用,对组胺无抑制作用。吲哚美辛对组胺和LTD4引起的收缩反应表现出双相作用,两种激动剂引起的收缩在低浓度时均被吲哚美辛抑制,而在高浓度时则增强。曲尼司特对低浓度LTD4诱导的肺实质收缩有抑制作用,对组胺诱导的肺实质收缩无抑制作用。此外,OKY-046抑制LTC4输注后豚鼠肺灌注液中血栓素B2 (TxB2)浓度的升高,但不影响6-酮- pgf1 α的升高。OKY-046对抗原诱导的组胺释放无影响,但能抑制过敏反应慢反应物质(SRS-A)从致敏的切碎肺组织中释放。高浓度吲哚美辛对组胺的释放有抑制作用,但对SRS-A的释放无影响。曲尼司特明显抑制两种介质的释放。上述结果提示,OKY-046对IgE介导的豚鼠实验性哮喘具有抑制作用,其主要机制与抑制LT诱导的气道平滑肌收缩和肺组织SRS-A的释放有关。
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