beta2-Adrenoceptor agonist modulates endothelin-1 receptors in human isolated bronchi.
Chronic exposure of human isolated bronchi to beta(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 microM fenoterol (15 h, 21 degrees 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.
Faisy
Christophe
C
UPRES EA220, UFR Biomédicale des Saints-Pères, 45 rue des Saints-Pères, 75006 Paris, France. christophe.faisy@wanadoo.fr
Pinto
Francisco
F
Danel
Claire
C
Naline
Emmanuel
E
Risse
Paul-Andre
PA
Leroy
Ingrid
I
Israel-Biet
Dominique
D
Fagon
Jean-Yves
JY
Candenas
Maria-Luz
ML
Advenier
Charles
C
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D019332:Endothelin-1 / Q000494:pharmacology; D005280:Fenoterol / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D012333:RNA, Messenger / Q000096:biosynthesis; D044022:Receptor, Endothelin A / Q000096:biosynthesis*; D044023:Receptor, Endothelin B / Q000096:biosynthesis*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000318:Adrenergic beta-Agonists; D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D005280:Fenoterol