Up-regulation of airway smooth muscle histamine H₁receptor mRNA, protein and function by ß₂-adrenoceptor activation

Histamine, released from activated mast cells, causes bronchoconstriction mediated by H-1 receptors, whereas beta(2)-agonists are widely used for the relief of bronchoconstriction. In this study, we examined the effects of the beta(2)-adrenoceptor agonist, fenoterol, on the expression of H-1 receptors at the mRNA and protein levels, and functional responses. Incubation of bovine tracheal smooth muscle with fenoterol (10(-7) M) for 2 h increased H-1 receptor mRNA (maximum similar to 190%). The number of H-1 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 H-1 receptor mRNA was concentration-dependent and was abolished by propranolol and ICI 118551, but not by CGP 20712A, indicating that fenoterol acts via beta(2)-adrenoceptors. These effects were mimicked by other cAMP-elevating agents forskolin and prostaglandin E-2, and by the stable cAMP analog 8-bromo-cAMP. Cycloheximide alone produced superinduction of H-1 receptor mRNA and augmented the fenoterol-induced increase in H-1 receptor mRNA. Fenoterol increased both the stability and the transcription rate of H-1 receptor mRNA. Pretreatment with dexamethasone did not prevent fenoterol-induced up-regulation of H-1 receptor mRNA. Thus, fenoterol increases the expression of airway smooth muscle H-1 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 beta(2)-agonists.