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Biological characterization of bradykinin receptor involved in functional control of airway

参与气道功能控制的缓激肽受体的生物学特征

基本信息

批准号：
12670094
负责人：
HAYASHI Izumi
金额：
$ 1.15万
依托单位：
KITASATO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Bradykinin is known to be a potent bronchoconstrictor in vivo and to cause contraction of isolated trachea. BK receptor involved in airway microvascular leak and bronchoconstriction in guinea-pig was classified as a B_2 receptor. A prominent difference of biological activity between a nonpeptide bradykinin B_2 receptor agonist FR190997 and BK was found in airway responses. FR190997 showed almost no increase in airway opening pressure (Pao) after the intravenous injection in guinea-pig, although its hypotensive response was observed. This failure to cause bronchoconstriction could be partly explained by the following results from in vitro experiments. In isolated trachea ring strips and lung parenchymal Sections, FR190997 displayed a very weak contractile activity, suggesting less bronchoconstriction in vivo. Furthermore, it is not likely that the lack of effect observed with FR190997 is due to the different animal species used, since a significant contractions of those tissue preparations were not observed in both rat and guinea-pig, and less increase in Pao at a dose of 30 nmol kg^<-1> of FR190997 was also seen even in rat species. The B_1 receptor is not seemed to be involved, based on the fact that desArg^9-bradykinin did not exhibited and increase in Pao and the B_1 receptor antagonist, desArg^9[Leu^8]-bradykinin did not significantly antagonize the increase induced by bradykinin. Thus, it could be concluded that trachea or pulmonary tissue in airway may contain a novel BK receptor other than B_1 and B_2, which may be involved in bradykinin-induced bronchoconstriction. Further studies for the elucidation will be required to identify a cDNA encoding a novel BK receptor in airway by molecular cloning. Assuming that both FR190997 and FR173657 specifically bind to the B_2 receptor, another mechanism or conformational state for the ligand to activate BK receptor, which will be specific in those tissues, would be also considerable.

缓激肽在体内是一种有效的支气管收缩剂，可引起离体气管收缩。BK受体参与豚鼠气道微血管渗漏和支气管收缩，属于B_2受体。非肽缓激肽B_2受体激动剂FR190997与BK在气道反应中的生物活性有显著差异。FR190997经豚鼠静脉注射后，气道开口压（Pao）几乎没有升高，但有降压反应。这种不能引起支气管收缩的现象可以用以下体外实验的结果部分解释。在离体气管环条和肺实质切片中，FR190997显示出非常弱的收缩活性，提示体内支气管收缩较小。此外，FR190997所观察到的效果不太可能是由于所使用的动物种类不同，因为在大鼠和豚鼠中都没有观察到这些组织制剂的显著收缩，并且在FR190997剂量为30 nmol kg^<-1>时，即使在大鼠物种中也观察到Pao增加较少。B_1受体似乎与此无关，因为B_1受体拮抗剂desArg^9[Leu^8]-bradykinin在Pao中没有表现和增加，而B_1受体拮抗剂desArg^9[Leu^8]-bradykinin并没有显著拮抗由bradykinin引起的增加。由此可见，气道内或气道内肺组织中可能存在一种新的BK受体，该受体可能参与了缓激肽诱导的支气管收缩。进一步的研究将需要通过分子克隆来鉴定一个编码气道中新的BK受体的cDNA。假设FR190997和FR173657都与B_2受体特异性结合，那么该配体激活BK受体的另一种机制或构象状态也将是相当可观的，并且在这些组织中具有特异性。