Up-regulation of airway smooth muscle histamine H-1 receptor mRNA, protein, and function by beta(2)-adrenoceptor activation

Histamine, released from activated mast cells, causes bronchoconstriction m ediated by H-1 receptors, whereas beta(2)-agonists are widely used for the relief of bronchoconstriction. In this study, we examined the effects of th e beta(2)-adrenoceptor agonist, fenoterol, on the expression of H-1 recepto rs 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-i nduced contraction were shifted significantly to the left after 18-h exposu re to fenoterol, consistent with the increase in receptor number. The fenot erol-induced increase in H-1 receptor mRNA was concentration-dependent and was abolished by propranolol and ICI 118551, but not by CGP 20712A, indicat ing that fenoterol acts via beta(2)-adrenoceptors. These effects were mimic ked by other cAMP-elevating agents forskolin and prostaglandin E-2, and by the stable cAMP analog 8-bromo-cAMP. Cycloheximide alone produced superindu ction of H-1 receptor mRNA and augmented the fenoterol-induced increase in H-1 receptor mRNA. Fenoterol increased both the stability and the transcrip tion rate of H-1 receptor mRNA. Pretreatment with dexamethasone did not pre vent fenoterol-induced up-regulation of H-1 receptor mRNA. Thus, fenoterol increases the expression of airway smooth muscle H-1 receptors via activati on of the cAMP system through increased gene transcription and mRNA stabili ty. This mechanism may be involved in the adverse responses encountered wit h the clinical use of short-acting beta(2)-agonists.