1 The effects of two nitric oxide (NO) biosynthesis-inhibitors N0-nitro-L-arginine (L-NOARG) and N0-monomethyl-L-arginine (L-NMMA) on the relaxation induced by bradykinin (BK, 100 nM), isoprenaline (Iso, 1 lAM) and sodium nitroprusside (SNP, 1 lgM) were investigated in epithelium-intact strips of guinea-pig isolated trachea. 2 Relaxations induced by BK (100 nM) in guinea-pig tracheal strips under spontaneous tone were inhibited in a concentration-related manner by L-NOARG and L-NMMA (1 to 100 lM), with ICs (and 95% confidence limits) of 9.1 (6.9-11.6) lM and 7.0 (4.2-12.3) gM, respectively. However, at the maximal concentration (100 tM) used, neither of these drugs inhibited completely BK-induced relaxation (maximal inhibition of 74± 7 and 67± 7%, respectively). On the other hand, D-NMMA, the Denantiomer of L-NMMA, up to 100 gM failed to inhibit BK-induced relaxation. The relaxation induced by Iso (1 lM) and SNP (1 lM) were not affected by either L-NOARG or L-NMMA (30 lM). 7 These findings indicate that BK-induced relaxation in guinea-pig trachea is mediated jointly by the release of NO or a NO-related substance and a prostanoid, probably prostaglandin E2.
1 In this study, we investigated some of the signalling pathways involved in bradykinin (BK)-induced relaxation in epithelium-intact strips of the guinea-pig trachea (GPT þ E). BK induced timeand concentration-dependent relaxation of GPT þ E. Similar responses were observed for prostaglandin E 2 (PGE 2 ) or the combination of subthreshold concentrations of BK plus PGE 2 . 2 The nonselective cyclooxygenase (COX) inhibitors indomethacin or pyroxicam, or the selective COX-2 inhibitors DFU, NS 398 or rofecoxib, but not the selective COX-1 inhibitor SC 560, all abolished BK-induced relaxation. 3 The tyrosine kinase inhibitors herbimycin A and AG 490 also abolished BK-induced relaxation in GPT þ E. 4 The nonselective nitric oxide synthase (NOS) inhibitor 7-NINA concentration-dependently inhibited BK effects. 5 BK-induced relaxation was prevented by the selective antagonists for EP 3 (L 826266), but not by EP 1 (SC 19221), EP 1 /EP 2 (AH 6809) or EP 4 (L 161982) receptor antagonists. 6 Otherwise, the selective inhibitors of protein kinases A, G and C, mitogen-activated protein kinases, phospholipases C and A 2 , nuclear factor-kB or potassium channels all failed to significantly interfere with BK-mediated relaxation. 7 BK caused a marked increase in PGE 2 levels, an effect that was prevented by NS 398, HOE 140 or AG 490. 8 COX-2 expression did not differ in preparations with or without epithelium, and it was not changed by BK stimulation. However, incubation with BK significantly increased the endothelial NOS (eNOS) and neuronal NOS (nNOS) expression, independent of the epithelium integrity. 9 Our results indicate that BK-induced relaxation in GPT þ E depends on prostanoids (probably PGE 2 acting via EP 3 receptors) and NO release and seems to involve complex interactions between kinin B 2 receptors, COX-2, nNOS, eNOS and tyrosine kinases.
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