SR 142801, a tachykinin NK3 receptor antagonist, prevents β2-adrenoceptor agonist-induced hyperresponsiveness to neurokinin A in guinea-pig isolated trachea

Abstract We investigated whether fenoterolwas able to enhance contractile responsiveness to neurokininA (NKA) on the guinea-pig isolated trachea. We then studied the effects of two inhibitors of nuclear factor kappa B (NFκB), gliotoxinand pyrrolidine dithiocarbamate, and of the tachykinin NK 1 , NK 2 and NK 3 receptor antagonists, SR 140333, SR 48968 and SR 142801 and determined whether tachykinin receptorgene expression was up-regulated in the trachea after exposure to fenoterol. Fenoterol(0.1 μM, 15 h, 21 °C) induced an increased contractile response to NKA (mean of difference in maximal tension between control and fenoterol± S.E.M; +0.47 ± 0.14 g, n = 26, P 1 receptor (NK 1 R), NK 2 receptor (NK 2 R) and NK 3 receptor (NK 3 R) geneexpression was analyzed by semiquantitative RT–PCR. Compared to control tissues, NK 1 R and NK 2 R mRNA expression was increased by about 1.6-fold and 1.4-fold, respectively, in tissues treated with fenoterol. We were unable to detect the presence of NK 3 R mRNA in the guinea-pig trachea. In conclusion, fenoterolinduces tracheal hyperresponsiveness to NKA and an up-regulation of NK 1 R and NK 2 R geneexpression. The hyperresponsiveness implicates the NFκB pathway and is abolished by tachykinin NK 1 (SR 140333) and NK 3 (SR 142801) receptor antagonists.