Modulation of bradykinin responses in airway smooth muscle by epithelial enzymes

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Abstract
We have studied the effect of epithelium removal on responses of guinea pig trachea to bradykinin (BK). BK (1 nM–10 μM) gave a concentration-dependent relaxation when epithelium was present (E+: EC50=10±3 nM). Epithelium removal resulted in a biphasic response to BK with relaxation at low concentrations (E−: EC50=3.0±1.0 nM) and a recontraction to baseline at higher concentrations (EC50=2.0±1 μM). Phosphoramidon (10 μM), an inhibitor of neutral endopeptidase (NEP), which cleaves BK into inactive peptides, potentiated relaxation (EC50=1.0±0.9 nM and 0.1±0.1 nM in E+ and E respectively) and contraction in trachea with intact epithelium (EC50=0.08±0.03 μM). Inhibition of cyclooxygenase by indomethacin (5 μM), inhibited relaxation to BK in E+ tracheal segments, resulting in a slight contraction (EC50=1.0 μM), whereas a potent contractile response was observed in E−segments (EC50 1.6 μM, maximal contraction >1 g). In the presence of both indomethacin and phosphoramidon BK caused contraction, even in the presence of epithelium (EC50=0.2±0.11 μM), and the response in the absence of epithelium was similar to the response observed in trachea with intact epithelium (EC50=0.25±0.1 μM). The contractile effect of BK on airway smooth muscle may be inhibited by a protective role of epithelium, due to release of relaxant prostanoids and by degradation by epithelial NEP. In asthma, bronchoconstrictor responses to BK may be partly explained by loss of airway epithelium.