Vol. 57, Issue 5, 857-864, May 2000

Up-Regulation of Airway Smooth Muscle Histamine H₁ Receptor mRNA, Protein, and Function by ₂-Adrenoceptor Activation

Judith C. W. Mak, Ad F. Roffel, Toshio Katsunuma,¹ Carolina R. S. Elzinga, Johan Zaagsma, and Peter J. Barnes

Department of Thoracic Medicine (J.C.W.M., T.K., P.J.B.), Imperial College School of Medicine, National Heart and Lung Institute, London, UK; and Department of Molecular Pharmacology (A.F.R., C.R.S.E., J.Z.), University of Groningen, AV Groningen, The Netherlands

Histamine, released from activated mast cells, causes bronchoconstriction mediated by H₁ receptors, whereas ₂-agonists are widely used for the relief of bronchoconstriction. In this study, we examined the effects of the ₂-adrenoceptor agonist, fenoterol, on the expression of H₁ receptors at the mRNA and protein levels, and functional responses. Incubation of bovine tracheal smooth muscle with fenoterol (10⁷ M) for 2 h increased H₁ receptor mRNA (maximum ~190%). The number of H₁ receptors was increased after 12 and 18 h without any change in binding affinity. In the contraction experiments, the concentration-response curves for histamine-induced contraction were shifted significantly to the left after 18-h exposure to fenoterol, consistent with the increase in receptor number. The fenoterol-induced increase in H₁ receptor mRNA was concentration-dependent and was abolished by propranolol and ICI 118551, but not by CGP 20712A, indicating that fenoterol acts via ₂-adrenoceptors. These effects were mimicked by other cAMP-elevating agents forskolin and prostaglandin E₂, and by the stable cAMP analog 8-bromo-cAMP. Cycloheximide alone produced superinduction of H₁ receptor mRNA and augmented the fenoterol-induced increase in H₁ receptor mRNA. Fenoterol increased both the stability and the transcription rate of H₁ receptor mRNA. Pretreatment with dexamethasone did not prevent fenoterol-induced up-regulation of H₁ receptor mRNA. Thus, fenoterol increases the expression of airway smooth muscle H₁ receptors via activation of the cAMP system through increased gene transcription and mRNA stability. This mechanism may be involved in the adverse responses encountered with the clinical use of short-acting ₂-agonists.