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₂-Adrenoceptor Agonist Modulates Endothelin-1 Receptors in Human Isolated Bronchi

UPRES EA220, Faculté de Médecine Paris-Ouest and UFR Biomédicale des Saints-Pères, and Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, Paris, France; and Centro de Investigaciones Cientificas Isla de la Cartuja, Instituto de Investigaciones Quimicas, Sevilla, Spain

Correspondence and requests for reprints should be addressed to Christophe Faisy, M.D., Ph.D., UPRES EA220, UFR Biomédicale des Saints-Pères, 45 rue des Saints-Pères, 75006 Paris, France. E-mail: christophe.faisy{at}wanadoo.fr

Chronic exposure of human isolated bronchi to ₂-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.

Key Words: airway hyperresponsiveness • asthma • ETA and ETB receptors • fenoterol

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