Mechanisms of airway smooth muscle response to isoproterenol and theophylline.

Airway smooth muscle preparations from various sites and species exhibit a range of sensitivities to the same beta-adrenergic agonist. This variability has been attributed to beta-receptor function but the exact mechanism determining the response has not been identified. After first inducing contraction with acetylcholine, we measured isoproterenol and theophylline relaxation responses in five separate airway smooth muscle preparations in vitro. The order of sensitivity was identical for both drugs: guinea pig trachea greater than dog lung strip greater than dog bronchiole greater than rat trachea greater than dog trachea. Because of evidence that both drugs act by increasing adenosine 3',5'-cyclic monophosphate (cAMP) concentrations, we utilized a kinetic model of cAMP metabolism to investigate the possibility that the identical order of sensitivity to both drugs could be explained by a common mechanism. Relaxation responses to both drugs are in accord with known kinetic data. Small differences in the velocity constants of enzymes affecting cAMP metabolism or differences in the relaxation response to the same concentrations of cAMP can fully explain the variable muscle responses to both drugs.