Azithromycin inhibits muscarinic 2 receptor‐activated and voltage‐activated Ca2+ permeant ion channels and Ca2+ sensitization, relaxing airway smooth muscle contraction. (6th February 2019)

• Record Type: Journal Article
• Authors: Wang, Qian; Yu, Meng‐Fei; Zhang, Wen‐Jing; Liu, Bei‐Bei; Zhao, Qing‐Yang; Luo, Xi; Xu, Hao; She, Yu‐Shan; Zang, Dun‐An; Qiu, Jun‐Ying; Shen, Jinhua; Peng, Yong‐Bo; Zhao, Ping; Xue, Lu; Chen, Weiwei; Ma, Li‐Qun; Nie, Xiaowei; Shen, Chenyou; Chen, Shu; Chen, Shanshan; Liu, Quan; Dai, Jiapei; Qin, Gangjian; Zheng, Yun‐min; Wang, Yong‐Xiao; ZhuGe, Ronghua; Chen, Jingyu; Liu, Qing‐Hua
• Is Part Of: Clinical and experimental pharmacology and physiology. Volume 46:Number 4(2019)
• Page Start: 329
• Page End: 336
• Publication Date: 2019-02-06
• Subjects: airway smooth muscle -- asthma -- azithromycin -- chronic obstructive pulmonary disease -- ion channels -- relaxation; Clinical pharmacology -- Periodicals; Pharmacology, Experimental -- Periodicals; Physiology, Experimental -- Periodicals; Physiology, Pathological -- Periodicals; 615.1
• DOI: 10.1111/1440-1681.13062
• Languages: English
• ISSNs: 0305-1870

Abstract

Summary: Azithromycin (AZM) has been used for the treatment of asthma and chronic obstructive pulmonary disease (COPD); however, the effects and underlying mechanisms of AZM remain largely unknown. The effects of AZM on airway smooth muscles (ASMs) and the underlying mechanisms were studied using isometric muscle force measurements, the examination of lung slices, imaging, and patch‐clamp techniques. AZM completely inhibited acetylcholine (ACH)‐induced precontraction of ASMs in animals (mice, guinea pigs, and rabbits) and humans. Two other macrolide antibiotics, roxithromycin and Klaricid, displayed a decreased inhibitory activity, and the aminoglycoside antibiotics penicillin and streptomycin did not have an inhibitory effect. Precontractions were partially inhibited by nifedipine (selective inhibitor of L‐type voltage‐dependent Ca 2+ channels (LVDCCs)), Pyr3 (selective inhibitor of TRPC3 and/or STIM/Orai channels, which are nonselective cation channels (NSCCs)), and Y‐27632 (selective inhibitor of Rho‐associated kinase (ROCK)). Moreover, LVDCC‐ and NSCC‐mediated currents were inhibited by AZM, and the latter were suppressed by the muscarinic (M) 2 receptor inhibitor methoctramine. AZM inhibited LVDCC Ca 2+ permeant ion channels, M2 receptors, and TRPC3 and/or STIM/Orai, which decreased cytosolic Ca 2+ concentrations and led to muscle relaxation. This relaxation was also enhanced by the inhibition of Ca 2+ sensitization. Therefore, AZM has potential as a novel and potent bronchodilator. The findings of this study improve the understanding of the effects of AZM on asthma and COPD.