Azithromycin inhibits muscarinic 2 receptor‐activated and voltage‐activated Ca²⁺ permeant ion channels and Ca²⁺ sensitization, relaxing airway smooth muscle contraction

Abstract

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

Effects of azithromycin on bronchial remodeling in the natural model of severe neutrophilic asthma in horses

“…This study was performed to investigate whether modulation of ASM biology by macrolides contribute to their clinical efficacy. Indeed, azithromycin induces autophagy in human bronchial ASM 15 and relaxes pre-contracted human bronchial muscle strips 17 . In vivo, macrolide administration decreases ASM mass in rodents with an induced asthma-like disease 18 – 21 and in healthy mice 51 .…”

“…However, the mechanisms underlying these positive outcomes are unclear as the spectrum of action of macrolides goes beyond antimicrobial and immunomodulatory effects 11 . The modulation of airway smooth muscle (ASM) biology in vitro 14 – 17 and the decrease of ASM mass in experimental models of asthma by macrolides 18 – 21 might explain their attenuation of bronchial hyperresponsiveness 22 , 23 . However, these results need confirmation in humans as treatment success obtained in rodent models frequently fails to translate to clinical therapy 24 .…”

Relaxant Action of Diclofenac Sodium on Mouse Airway Smooth Muscle

“…Muscle force of TRs was measured as we previously reported elsewhere (Wang et al, 2019). Briefly, mice were sacrificed following intraperitoneal injection of pentobarbital sodium (150 mg/kg).…”

Vandetanib as a prospective anti-inflammatory and anti-contractile agent in asthma

“…To detect airway hyperresponsiveness, mTRs were were obtained from the control, asthma, vandetanib and dexamethasone groups (Figures 2A-D). ACh, which is a receptor agonist (Wang et al, 2019) was applied to induce airway contraction. The results showed that the 100 μM ACh-evoked contraction of mTRs in the asthma group (Figure 2B), was much higher than that in the control (Figure 2A), dexamethasone (Figure 2C) and To further investigate the relaxant feature of vandetanib in vivo, we detected Rrs using forced oscillation technique (Figure 2F).…”

“…Therefore, we sought to identify ion channels other than VDLCC involved in vandetanib-induced relaxation. NSCCs and VDLCCs were involved in ACh-induced smooth muscle contraction (Wang et al, 2019). Given that, ACh was employed to precontract mTRs.…”