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Cholinergic Pathways in the Lungs and Anticholinergic Therapy for Chronic Obstructive Pulmonary Disease

Respiratory and Inflammation Centre of Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, Pennsylvania

Correspondence and requests for reprints should be addressed to Kristen E. Belmonte, Ph.D., Neuroscience Drug Discovery, Merck Research Laboratories, WP26A-2000, 770 Sumneytown Pike, West Point, PA 19486. E-mail: kristen_belmonte{at}merck.com

Abundant data from animal models and humans support the hypothesis that changes at the level of parasympathetic neuronal control of airway smooth muscle result in increased bronchoconstriction in response to vagal stimulation, leading to airway hyperresponsiveness. Neuronal inhibitory M₂ muscarinic acetylcholine receptors on parasympathetic nerves are responsible for limiting acetylcholine release from these nerves. In humans with asthma, and after pulmonary inflammatory events in experimental animals, these receptors are dysfunctional, which results in airway hyperresponsiveness. Although it is unknown what mechanisms underlie airway hyperresponsiveness in chronic obstructive pulmonary disease, loss of parasympathetic control of airway smooth muscle is thought to be a contributing mechanism. As such, anticholinergic therapy is used extensively and with a high degree of success in the treatment of this condition. The future for inhaled anticholinergic compounds for the treatment of chronic obstructive pulmonary disease appears to rest in their combination with other agents, such as ß₂ agonists and phosphodiesterase-4 inhibitors. Nonselective anticholinergic agents might be the best choice, because M₂ muscarinic receptors on airway smooth muscle inhibit the generation and accumulation of cyclic adenosine monophosphate. Adequate concurrent blockade of M₃ muscarinic receptors would be expected to counteract the enhanced acetylcholine release that would result from blockade of neuronal inhibitory M₂ muscarinic receptors.

Key Words: airway hyperresponsiveness • bronchodilator therapy • muscarinic receptors • parasympathetic nerves

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