| Budget Amount *help |
¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2002: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Research Abstract |
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.
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