Chronic exposure to a β₂-adrenoceptor agonist increases the airway response to methacholine

Scheduled chronic administration of β₂-adrenoceptor agonist bronchodilators in patients with asthma recently has been reported to be associated with a worsening of symptoms and an increase in bronchial responsiveness. We wanted to determine whether a 28-day in vivo exposure to albuterol (β₂-adrenoceptor agonist) altered the response of rabbit airways to the cholinergic agonist methacholine. We found, using in vitro tissue bath techniques, that in mainstem bronchi from rabbits given a 28-day exposure to albuterol, maximum contraction to methacholine was increased in the albuterol-treated group (control group = 1.10 ± 0.11 g vs. treated group = 1.50 ± 0.13 g, P < 0.05). The potency (EC₇₅) was also increased in the albuterol-treated group. The potency for the control group was 5.6 μM (95% confidence limit: 2.3-13 μM) and was 1.7 μM (95% confidence limit: 1.1-2.8 μM, P < 0.05) for the albuterol-treated group. In a subgroup of animals, maximum contraction to KCl, a receptor-independent contractile stimulus, was not significantly different between the groups (control group = 0.79 ± 0.23 g vs. treated group = 0.82 ± 0.20 g). The potency (EC₅₀) for KCl-induced contractions was also not significantly different between the groups: control = 12 mM (95% confidence limit: 3.3-44 mM) vs. treated 19 mM (95% confidence limit: 18-20 mM). These data demonstrate that chronic in vivo exposure to a β₂-adrenoceptor agonist can alter the in vitro tissue bath response of airway smooth muscle to methacholine. Therefore, cholinergic mechanisms in the airway smooth muscle appear to be altered by chronic β₂-adrenoceptor agonist exposure. This change in the airway smooth muscle response to methacholine may play a role in the increase of bronchial responsiveness associated with regular β₂-adrenoceptor agonist use.