Ipratropium decreases airway size in dogs by preferential M 2 muscarinic receptor blockade in vivo

Abstract

Background: Two major groups of drugs are available to prevent bronchoconstriction: beta-agonists and muscarinic blocking agents. Ipratropium is the most commonly used anticholinergic agent to treat chronic obstructive pulmonary disease. The authors studied anti-muscarinic agents to determine if they are as effective bronchodilators as beta-adrenergic agents and if not to identify the mechanism of their reduced effectiveness. Methods: Six anesthetized dogs were studied using high-resolution computed tomography to measure changes in the cross-sectional area of conducting airways induced by cumulative doses of ipratropium with and without gallamine, a selective M 2 muscarinic receptor blocker, and after metaproterenol. Results: Metaproterenol dilated the airways and ipratropium constricted the airways. Ipratropium in concentrations of 0.01 and 0.1 mg/ml constricted the airways to 22 ± 2% and 20 ± 3% of control, respectively (P < 0.01), whereas larger concentrations caused bronchodilation. After complete blockade of the M 2 receptors by pretreatment with intravenous gallamine, the bronchoconstrictor effect of ipratropium was abolished, and ipratropium dilated the airways by 16 ± 8% and 27 ± 10% of pre-gallamine baseline after doses of 0.01 and 0.1 mg/ml, respectively (P < 0.01). Conclusion: Low-dose ipratropium can decrease airway size by the initial, preferential blockade of neuronal M 2 muscarinic receptors, whereas a larger dose of ipratropium blocks M 3 muscarinic receptors on airway smooth muscle, resulting in bronchodilation.