Mechanisms underlying the relaxation response induced by bradykinin in the epithelium‐intact guinea‐pig trachea in vitro

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Abstract
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+E). BK induced time‐ and concentration‐dependent relaxation of GPT+E. Similar responses were observed for prostaglandin E2 (PGE2) or the combination of subthreshold concentrations of BK plus PGE2. 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. The tyrosine kinase inhibitors herbimycin A and AG 490 also abolished BK‐induced relaxation in GPT+E. The nonselective nitric oxide synthase (NOS) inhibitor 7‐NINA concentration‐dependently inhibited BK effects. BK‐induced relaxation was prevented by the selective antagonists for EP3 (L 826266), but not by EP1 (SC 19221), EP1/EP2 (AH 6809) or EP4 (L 161982) receptor antagonists. Otherwise, the selective inhibitors of protein kinases A, G and C, mitogen‐activated protein kinases, phospholipases C and A2, nuclear factor‐κB or potassium channels all failed to significantly interfere with BK‐mediated relaxation. BK caused a marked increase in PGE2 levels, an effect that was prevented by NS 398, HOE 140 or AG 490. 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. Our results indicate that BK‐induced relaxation in GPT+E depends on prostanoids (probably PGE2 acting via EP3 receptors) and NO release and seems to involve complex interactions between kinin B2 receptors, COX‐2, nNOS, eNOS and tyrosine kinases. British Journal of Pharmacology (2005) 145, 740–750. doi:10.1038/sj.bjp.0706222

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