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.

众所周知，松曲蛋白在体内是有效的支气管收缩剂，并引起分离的气管收缩。豚鼠中涉及气道微血管泄漏和支气管收缩的BK受体被归类为B_2受体。在气道反应中发现了非肽Bradykinin B_2受体激动剂FR190997和BK之间生物学活性的显着差异。 FR190997在豚鼠静脉注射后的气道开口压力（PAO）几乎没有增加，尽管观察到其降压反应。这种不引起支气管收缩的失败可以部分通过体外实验的以下结果来解释。在孤立的气管环和肺实质切片中，FR190997表现出非常弱的收缩活性，表明体内支气管收缩较少。此外，由于使用了不同的动物物种，因此不太可能在FR190997上观察到的作用，因为在大鼠和豚鼠中未观察到这些组织制剂的显着收缩，并且在30 nmol kg^<-1>的剂量中，PAO的增加也较少。 B_1受体似乎不涉及，因为Desarg^9-胸皮蛋白没有表现出来并增加了PAO，而B_1受体拮抗剂Desarg^9 [Leu^8] -Bradyinin并未显着拮抗胸肌诱导的增加。因此，可以得出结论，气道中的气管或肺组织可能包含除B_1和B_2以外的新型BK受体，这可能参与了Bradykinin诱导的支气管收缩。需要进行进一步的阐明研究，以鉴定通过分子克隆在气道中编码新型BK受体的cDNA。假设FR190997和FR173657都特异性结合了B_2受体，这是配体激活BK受体的另一种机制或构象状态，在这些组织中将是特定的，也将是相当大的。