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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受体属于B_2受体，参与豚鼠气道微血管渗漏和支气管收缩。非肽类缓激肽B_2受体激动剂FR 190997与BK在气道反应中的生物活性有显著差异。FR 190997在豚鼠静脉注射后几乎没有显示气道开放压（Pao）增加，尽管观察到其肿胀反应。这种不能引起支气管收缩的现象可以部分地由以下体外实验的结果来解释。在离体气管环条和肺实质切片中，FR 190997显示出非常弱的收缩活性，表明体内支气管收缩较少。此外，观察到的FR 190997缺乏作用不太可能是由于使用的动物种属不同，因为在大鼠和豚鼠中均未观察到这些组织制备物的显著收缩，并且<-1>即使在大鼠种属中也观察到30 nmol kg-1剂量的FR 190997的Pao增加较少。B_1受体似乎不参与此过程，因为desArg^9-缓激肽对Pao无明显增强作用，而B_1受体拮抗剂desArg^9[Leu^8]-缓激肽对Pao的增强作用无明显拮抗作用。因此，在气管或肺组织中可能存在一种不同于B_1和B_2的BK受体，它可能参与缓激肽引起的支气管收缩。通过分子克隆鉴定编码呼吸道BK受体的新基因还需要进一步的研究。假设FR 190997和FR 173657都能特异性地与B_2受体结合，那么，配体激活BK受体的另一种机制或构象状态也是相当重要的，这将是这些组织中特异性的。