Mechanism of endothelin-induced asthma

内皮素诱发哮喘的机制

• 批准号: 04670462
• 负责人: OKABE Tetsuro
• 金额: $ 0.38万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04670462/
• 关键词: endothelin; asthma; prostaglandin; pyrogen; receptor

Inhalation of aerosol of endothelin-1 induced dyspneal behavior in conscious guinea pigs pretreated with histamine or methacholine inhalation, while inhalation of endothelin-1 per se could not provoke dyspneal behavior in the animals. The dyspneal response was not affected either by nifedipine, a calcium channel blocker or by diphenhydramine, an antihistamine drug. Interestingly, the dyspneal response was potently inhibited by indomethasin, a cycolooxigenase inhibitor. In contrast, it has been shown that contraction of guinea pig tracheal strips induced by endothelin-1 was strongly inhibited by nifedipine in vitro. It has been also shown that both types of endothlein receptors (ETA and ETB) are present in lung tissues.Injection of endothelin-1, or 4-Ala-endothelin-1 (a ETB receptor specific agonist) caused elevation of body temperature in conscious rabbits. The pyrogenic action by endothelin-1 was also inhibited by indomethacin.Together with these observations the dyspneal response by endothelin appears to be induced by producing cyclooxigenase metabolites through selective stimuation of ETB receptor. We have clarified two novel roles of endothelin in vivo ; ie., dyspneal response and pyrogenic action, both of which are mediated by cyclooxigenase metabolites.

吸入内皮素-1气雾剂可引起经组胺或乙酰甲胆碱吸入预处理的清醒豚鼠呼吸困难行为，而吸入内皮素-1本身不能引起动物呼吸困难行为。钙通道阻滞剂硝苯地平或抗组胺药苯海拉明均不影响呼吸困难反应。有趣的是，呼吸困难反应被吲哚美辛（一种环氧化酶抑制剂）有效抑制。与此相反，它已被证明在体外强烈抑制内皮素-1引起的豚鼠气管条的收缩被硝苯地平。肺组织中同时存在两种内皮素受体（ETA和ETB），注射ET-1或4-Ala-ET-1（ETB受体特异性激动剂）可引起清醒家兔体温升高。内皮素-1的致热作用也可被吲哚美辛抑制。与这些观察结果一起，内皮素引起的呼吸困难反应似乎是通过选择性刺激ETB受体产生环氧化酶代谢产物而诱导的。我们已经阐明了内皮素在体内的两个新作用，即，呼吸困难反应和热原作用，两者均由环氧化酶代谢产物介导。

项目成果

Koshi,T.: "Inhibition of endothelin(ET)-1 and ET-2-Induced vasoconstriction by anti-ET-1 mono clonal antibody." Chem.Pharm.Bull. 39. 1295-1297 (1991)

Koshi,T.：“抗 ET-1 单克隆抗体抑制内皮素 (ET)-1 和 ET-2 诱导的血管收缩。”

Koshi,T et al: "Inhibition of Endothelin(ET)-1 and ET-2 induced vasocovstriction by anti-ET-1 monoclonal antibody" Chem Pharm Bull. 37. 1291-1297 (1991)

Koshi,T 等人：“抗 ET-1 单克隆抗体抑制内皮素 (ET)-1 和 ET-2 诱导的血管收缩”Chem Pharm Bull。

Arai,K et al: "Characterization of in human urine immunoreactive endothelin" Biochem.Biophys Res Commun. 182. 1506-1513 (1992)

Arai,K 等人：“人尿免疫反应性内皮素的表征”Biochem.Biophys Res Commun。

Edano et al: "Digestion of endothelin-1 on cultured vascular smooth muscle cells" Chem Pharm Bull. in press. (1994)

Edano 等人：“培养的血管平滑肌细胞上内皮素 1 的消化”Chem Pharm Bull。

Arai, K., Koshi, T., Edano, T., Ohkuchi, M., Hirata, M., and Okabe, T.: "Characterization of immunoreactive endothelin in human urine." Biochem.Biophys.Res.Commun.182. 1506-1513 (1992)

Arai, K.、Koshi, T.、Edano, T.、Ohkuchi, M.、Hirata, M. 和 Okabe, T.：“人尿液中免疫反应性内皮素的表征。”