Cholinergic pathways in the lungs and anticholinergic therapy for chronic obstructive pulmonary disease.
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 beta2 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.
Belmonte
Kristen E
KE
Respiratory and Inflammation Centre of Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA, USA. kristen_belmonte@merck.com
D000280:Administration, Inhalation; D016535:Bronchial Hyperreactivity / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000627:therapeutic use; D018680:Cholinergic Antagonists / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006801:Humans; D008168:Lung / Q000294:innervation*; D010275:Parasympathetic Nervous System / Q000502:physiology / Q000503:physiopathology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000503:physiopathology*; D011976:Receptors, Muscarinic / Q000502:physiology*
D001993:Bronchodilator Agents; D018680:Cholinergic Antagonists; D011976:Receptors, Muscarinic