Biological characterization of bradykinin receptor involved in functional control of airway

众所周知，缓激肽在体内是一种强有力的支气管收缩因子，并能引起离体气管的收缩。BK受体是参与豚鼠呼吸道微血管渗漏和支气管收缩的B_2受体。非肽类缓激肽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。豚鼠静脉注射FR190997后，虽然出现了降压反应，但几乎没有引起气道开放压(PAO)升高。这种没有引起支气管收缩的失败可以由以下体外实验结果部分解释。在离体气管环条和肺实质切片中，FR190997表现出很弱的收缩活动，表明体内的支气管收缩较小。此外，FR190997的效果不太可能是由于所使用的动物种类不同所致，因为这些组织制剂在大鼠和豚鼠中都没有明显的收缩，即使在大鼠物种中，FR190997在30nmol kg~(-1)~(-1)的剂量下也观察到较少的PAO增加。B_1受体不参与PAO的表达和增加，而B_1受体拮抗剂desArg^9[Leu^8]-Bradykinin不能明显拮抗缓激肽引起的PAO增加。由此可见，气管或肺组织中可能含有一种新的BK受体，而不是B_1和B_2，该受体可能参与了缓激肽引起的支气管收缩。进一步的研究将需要通过分子克隆来鉴定编码新的BK受体的cDNAs。假设FR190997和FR173657都与B_2受体特异结合，那么配体激活BK受体的另一种机制或构象状态也将是值得考虑的，这将是这些组织中特有的。

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.