INVOLVEMENT OF BRADYKININ B-1 AND B-2 RECEPTORS IN RELAXATION OF MOUSE ISOLATED TRACHEA

The aim of the present study was to investigate the effects of bradyki nin and [des-Arg(9)]-bradykinin and their relaxant mechanisms in the m ouse isolated trachea. 2 In the resting tracheal preparations with int act epithelium, bradykinin and [des-Arg(9)] -bradykinin (each drug, 0. 01-10 mu M) induced neither contraction nor relaxation. In contrast, b radykinin (0.01-10 mu M) induced concentration-dependent relaxation wh en the tracheal preparations were precontracted with methacholine (1 m u M). The relaxation induced by bradykinin was inhibited by the B-2 re ceptor antagonist, -Arg(0)-[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-bradykinin (Hoe 140, 0.01-1 mu M) in a concentration-dependent manner whereas the B-1 receptor antagonist, [des-Arg(9),Leu(8)]-bradykinin (0.01-1 mu M) , had no inhibitory effect on bradykinin-induced relaxation. [des-Arg( 9)]-bradykinin (0.01-10 mu M) also caused concentration-dependent rela xation after precontraction with methacholine. The relaxation induced by [des-Arg(9)]-bradykinin was concentration-dependently inhibited by the B-1 receptor antagonist, [desArg(9),Leu(8)]-bradykinin (0.01-1 mu M), whereas the B-2 receptor antagonist, Hoe 140 (0.01-1 mu M) was wit hout effect. 3 In the presence of the cyclo-oxygenase inhibitor, indom ethacin (0.01-1 mu M), the relaxations induced by bradykinin and [des- Arg(9)] -bradykinin were inhibited concentration-dependently. 4 Two ni tric oxide (NO) biosynthesis inhibitors N-G-nitro-L-arginine methyl es ter (L-NAME, 100 mu M) and N-G-nitro-L-arginine (L-NOARG, 100 mu M) ha d no inhibitory effects on the relaxations induced by bradykinin and [ des-Arg(9)]-bradykinin. Neither did the selective inhibitor of the sol uble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (O DQ, 10 mu M) inhibit the relaxations induced by bradykinin and [des-Ar g(9)]-bradykinin. 5 Prostaglandin E-2 (PGE(2), 0.01-33 mu M) caused co ncentration-dependent relaxation of the tracheal preparations precontr acted with methacholine. Indomethacin (1 mu M) and ODQ (10 mu M) exert ed no inhibitory effects on the relaxation induced by PGE(2). 6 The NO -donor, sodium nitroprusside (SNP; 0.01-100 mu M) also caused concentr ation-dependent relaxation of the tracheal preparations precontracted with methacholine. ODQ (0.1-1 mu M) concentration-dependently inhibite d the relaxation induced by SNP. 7 These data demonstrate that bradyki nin and [des-Arg(9)]-bradykinin relax the mouse trachea precontracted with methacholine by the activation of bradykinin B-2-receptors and B- 1-receptors, respectively. The stimulation of bradykinin receptors ind uces activation of the cyclo-oxygenase pathway, leading to the product ion of relaxing prostaglandins. The NO pathway is not involved in the bradykinin-induced relaxation. The relaxation caused by NO-donors in t he mouse trachea is likely to be mediated via activation of soluble gu anylate cyclase.