INVOLVEMENT OF B-2 RECEPTORS IN THE BRADYKININ-INDUCED RELAXATION OF GUINEA-PIG ISOLATED TRACHEA

1 The aim of this study was to determine the receptor type and involve ment of arachidonic acid metabolites in bradykinin-induced relaxation of the guinea-pig isolated trachea. 2 In the resting tracheal preparat ion, bradykinin (0.1 nM-30 mu M induced a concentration-related contra ctile response pD(2) = 8.8 +/- 0.3). The maximal tension (1056 +/- 321 mg) was observed at 0.3 mu M bradykinin. In contrast, when tracheal p reparations were pre-contracted with histamine (30 mu M leading to a h alf-maximum response), a concentration-related relaxation was observed with bradykinin. At the highest concentration of bradykinin used (3 m u M), a reversal of 63 +/- 13% of the contractile response to histamin e was observed. Both effects of bradykinin were inhibited by the cyclo -oxygenase inhibitor, indomethacin (1 mu M). In concentration-response curves, melittin (10 nM-1 mu M), a direct activator of phospholipase A(2), mimicked both effects of bradykinin. The highest concentration o f melittin used (1 mu M), induced a tension of 813 +/- 120 mg and led to the reversal of 41 +/- 8% of the contractile response to histamine. The contractile effect of melittin was inhibited in the presence of b oth indomethacin (1 mu M) and AA861 (1 mu M), a 5-1ipoxygenase inhibit or. 3 [Des Arg(9)]-bradykinin (1 nM-3 mu M), a B-1-receptor agonist, w as unable to relax precontracted guinea-pig tracheal preparations. The relaxation induced by bradykinin was antagonized by the B-2 receptor antagonists, Hoe 140 (D-Arg(0)[Hyp(3),Thi(5),D-Tic(7),Oic(8)]bradykini n and NPC 17761 (D-Arg(0)[Hyp(3),D-HypE(trans-thiophenyl)(7), Oic(8)]b radykinin). Hoe 140 (0.1 mu M to 0.6 mu M) behaved as a non-competitiv e antagonist with an apparent pA(2) = 7.2 +/- 0.4, whereas NPC 17761 ( 0.3 to 1 mu M) competitively antagonized bradykinin-induced relaxation with a pK(B), = 7.3 +/- 0.2. The Schild regression slope did not diff er from unity, 0.96 +/- 0.20, P<0.05. 4 These data demonstrate that br adykinin-induced relaxation of guinea-pig trachea occurs via the activ ation of bradykinin B-2-receptors. The stimulation of B-2-bradykinin r eceptors induces the activation of the cyclo-oxygenase pathway, leadin g either to contraction or relaxation depending on the tone of the tra chea.