Ipratropium Decreases Airway Size in Dogs by Preferential M2Muscarinic 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 M2 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 M2 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 M2 muscarinic receptors, whereas a larger dose of ipratropium blocks M3 muscarinic receptors on airway smooth muscle, resulting in bronchodilation.