Mechanism of Methacholine?
Question posted by Suha Suha Suha on 27 Oct 2023
Last updated on 27 October 2023 by masso
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Methacholine
Mechanism of action
Asthma is a complicated condition associated with airway remodeling, including the proliferation of airway smooth muscle (ASM) and altered extracellular matrix, aberrant pro-inflammatory immune responses, and excessive ASM contraction leading to decreased lung function.1,2 Excessive ASM contraction in response to contractile agonists, a phenomenon termed airway hyperresponsiveness (AHR), is a physical manifestation of the altered pulmonary physiology in asthma.2 Although numerous factors, such as increased ASM levels, pro-contractile molecules, pro-inflammatory cytokines, and growth factors, contribute to AHR, one of the key factors in determining ASM tone is regulated by vagal parasympathetic nerve innervation.1,2,3 The response to acetylcholine and other cholinergic agonists at these neuromuscular junctions is predominantly controlled by inhibitory Gi-coupled M2 and excitatory Gq-coupled M3 muscarinic acetylcholine receptors (mAChRs). Activation of M3 receptors results in ASM contraction and resulting bronchoconstriction through downstream calcium-dependent signalling pathways, while M2 activation inhibits neuronal acetylcholine release.2,3,4
Methacholine is a non-specific mAChR agonist, capable of acting on all mAChR subtypes.5,6,7 However, in the context of AHR, methacholine's ability to induce bronchoconstriction through M3 receptors is clinically relevant.2,4,8 In addition, M3 agonism may increase the release of pro-inflammatory cytokines, further contributing to AHR.9 The inhibitory effect of M2 agonism by methacholine is likely also important, as shown by animal studies using mice with impaired M2 function, and by observations that eosinophilic inflammation, such as occurs in asthma, negatively impacts M2 function.3 Hence, asthmatic patients are more sensitive to inhaled cholinergic agonists such as methacholine; this forms the basis for the methacholine challenge test, which diagnoses AHR through an increased methacholine-induced response
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