Evidence suggests that chronic stimulation of β₂-adrenergic receptors (β₂-ARs) induces receptor tolerance that limits the efficacy of β-agonists in the treatment of asthma. The precise mechanisms that induce β₂-AR tolerance remain unclear.

We sought to determine whether steroids modulate albuterol-induced β₂-AR tolerance in human small airways.

β₂-AR responsiveness to isoproterenol was characterized in human precision-cut lung slices (PCLSs) precontracted to carbachol after pretreatment with albuterol.

Incubation of PCLSs with albuterol for 3, 6, or 12 hours attenuated subsequent isoproterenol-induced relaxation in a dose- and time-dependent manner. A 40% decrease (P < .0001) in maximum relaxation and a 45% decrease (P = .0011) in airway sensitivity from control values occurred after the maximum time and concentration of albuterol incubation. Desensitization was not evident when airways were relaxed to forskolin. Dexamethasone pretreatment of PCLSs (1 hour) prevented albuterol-induced β₂-AR desensitization by increasing the maximum drug effect (P = .0023) and decreasing the log half-maximum effective concentration values (P < .0001) from that of albuterol alone. Albuterol (12-hour incubation) decreased the β₂-AR cell-surface number (P = .013), which was not significantly reversed by 1 hour of preincubation with dexamethasone.

These data suggest that β₂-AR desensitization occurs with prolonged treatment of human small airways with albuterol through mechanisms upstream of protein kinase A and that steroids prevent or reverse this desensitization. Clarifying the precise molecular mechanisms by which β₂-AR tolerance occurs might offer new therapeutic approaches to improve the efficacy of bronchodilators in asthma and chronic obstructive pulmonary disease.