M2 Muscarinic Receptor-Dependent Contractions of Airway Smooth Muscle are Inhibited by Activation of β-Adrenoceptors.

Publisher: Oxford University Press Country of Publication: England NLM ID: 101770668 Publication Model: eCollection Cited Medium: Internet ISSN: 2633-8823 (Electronic) Linking ISSN: 26338823 NLM ISO Abbreviation: Function (Oxf)

Original Publication: [Oxford, UK] : Oxford University Press, [2020]-

Muscle Contraction* ; Receptors, Muscarinic*; Mice ; Animals ; Receptor, Muscarinic M2/genetics ; Muscarinic Antagonists/pharmacology ; Adrenergic beta-Agonists/pharmacology ; Muscle, Smooth ; Receptors, Adrenergic

Beta-adrenoceptor (β-AR) agonists inhibit cholinergic contractions of airway smooth muscle (ASM), but the underlying mechanisms are unclear. ASM cells express M3 and M2 muscarinic receptors, but the bronchoconstrictor effects of acetylcholine are believed to result from activation of M3Rs, while the role of the M2Rs is confined to offsetting β-AR-dependent relaxations. However, a profound M2R-mediated hypersensitization of M3R-dependent contractions of ASM was recently reported, indicating an important role for M2Rs in cholinergic contractions of ASM. Here, we investigated if M2R-dependent contractions of murine bronchial rings were inhibited by activation of β-ARs. M2R-dependent contractions were apparent at low frequency (2Hz) electric field stimulation (EFS) and short (10s) stimulus  intervals. The β1-AR agonist, denopamine inhibited EFS-evoked contractions of ASM induced by reduction in stimulus interval from 100 to 10 s and was more effective at inhibiting contractions evoked by EFS at 2 than 20 Hz. Denopamine also abolished carbachol-evoked contractions that were resistant to the M3R antagonist 4-DAMP, similar to the effects of the M2R antagonists, methoctramine and AFDX-116. The inhibitory effects of denopamine on EFS-evoked contractions of ASM were smaller in preparations taken from M2R ^-/- mice, compared to wild-type (WT) controls. In contrast, inhibitory effects of the β3-AR agonist, BRL37344, on EFS-evoked contractions of detrusor strips taken from M2R ^-/- mice were greater than WT controls. These data suggest that M2R-dependent contractions of ASM were inhibited by activation of β1-ARs and that genetic ablation of M2Rs decreased the efficacy of β-AR agonists on cholinergic contractions.
(© The Author(s) 2022. Published by Oxford University Press on behalf of American Physiological Society.)

Comment in: Function (Oxf). 2023 Feb 03;4(2):zqad006. doi: 10.1093/function/zqad006. (PMID: 36865063)

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Keywords: COPD; airways; bronchodilation; cholinergic; muscarinic; smooth muscle

V5F60UPD8P (denopamine)
0 (Receptors, Muscarinic)
0 (Receptor, Muscarinic M2)
0 (Muscarinic Antagonists)
0 (Adrenergic beta-Agonists)
0 (Receptors, Adrenergic)

Date Created: 20221103 Date Completed: 20230106 Latest Revision: 20230303

20250114

PMC9617473

10.1093/function/zqac050

36325515