Beta2-Adrenoceptor Agonist Modulates Endothelin-1 Receptors in Human Isolated Bronchi

Abstract

Chronic exposure of human isolated bronchi to Beta2-adrenergic agonists, especially fenoterol, potentiates smooth muscle contraction in response to endothelin-1 (ET-1), a peptide implicated in chronic inflammatory airway diseases. Our objective was to determine whether ET-1 receptors ETA and ETB are involved in fenoterol enhancement. Twenty-two human bronchi were sensitized to ET-1 by prolonged incubation with 0.1 µM fenoterol (15 h, 21°C). Removing the epithelium after fenoterol incubation limited the maximal contraction (0.10 ± 0.36 g without epithelium versus 1.18 ± 0.22 with, n = 8, P = 0.04). After 15 h incubation, 14 and 8 paired rings were fixed, respectively, for immunolabeling of bronchial ETA and ETB receptors, and to determine the mRNA expression levels using real-time quantitative reverse transcription polymerase chain reaction. ETA and ETB receptor mRNA expressions were 1.27- ± 0.14-fold (not significant) and 2.24- ± 0.28-fold (P < 0.01) higher, respectively, in fenoterol-treated bronchi than in paired controls. Fenoterol incubation significantly increased epithelial ETA and ETB receptor labeling intensity scores (P = 0.001 and P = 0.002, respectively, versus controls), and enhanced the diffuse localization of ETA receptors on the epithelial cells (P = 0.002 versus controls), but did not change the ETB-receptor immunolabeling intensity on airway smooth muscle. We conclude that fenoterol-induced sensitization of human isolated bronchi involves epithelial ETA and ETB receptors, which suggests perturbation of the epithelial regulation of airway smooth muscle contraction in response to ET-1.