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 approximately 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.