Effect Of Mirtazapine On Airway Smooth Muscle Relaxation And Asthma Relief In Mice

Asthma,a chronic and heterogeneous respiratory disease,is characterized by airway inflammation,airway remodeling and airway hyperresponsivenesss.Airway smooth muscle is not only the target tissue of airway inflammation,but also the effector tissue of airway hyperresponsiveness and airway remodeling.And excessive airway smooth muscle contraction is also one of the main factors of asthma attack.Therefore,airway smooth muscle is a key target for exploring the pathological mechanism of asthma and the development of new asthma drugs.In recent years,"new use of old drugs"is a hot topic in drug development.We found that mirtazapine,an antidepressant,effectively relaxed precontracted mouse airway smooth muscle through literature review and preliminary screening of tension measurement experiments.Mirtazapine is an atypical antidepressant,which is mainly used to treat severe depression,obsessive-compulsive disorder,generalized anxiety disorder and sleep disorder.It is one of the most commonly used antidepressants in medical practice.Mirtazapine also has anti-inflammatory and anti-bladder smooth muscle contraction effects.Currently,whether mirtazapine can be used to relieve or treat asthma remains unknown.Therefore,in order to screen out new anti-asthma drugs,mirtazapine was used in this study.To this end,a series of experiments were designed to investigate this topic.Firstly,tension measurement experiments were designed to investigate the effect of mirtazapine on the precontracted main trachea.Secondly,patch-clamp experiments were used to investigate the effect of mirtazapine on relevant ion channel currents.Thirdly,MTT assay was conducted to investigate the toxicity of mirtazapine on16HBE cells.Then,pulmonary function instrument was used to investigate the effect of mirtazapine on respiratory system resistance in normal mice.Finally,the asthmatic mouse model was established.The effect of mirtazapine on airway hyperresponsiveness was reflected by comparing the respiratory system resistance elevated by ACh stimulation in the normal,asthma,dexamethasone and mirtazapine groups.The effects of mirtazapine on airway inflammation,airway remodeling and mucus secretion were reflected by HE staining,PAS staining,measurement of bronchial wall thickness and smooth muscle thickness,and detection of the expression of inflammatory factors and mucins such as IL-4,IL-13,TNF-α,IL-1β,Muc5ac and Muc5b at the transcription level.Our results showed that mirtazapine relaxed the contraction of airway smooth muscle induced by H-K⁺or ACh in a concentration dependent manner.Further experiment found that mirtazapine inhibited the contraction of airway smooth muscle by regulating the switching of L-voltage dependent calcium channels,Nonselective cation channels,Na⁺/Ca²⁺exchanger and Large conductance Ca²⁺-sensitive K⁺channels.Mirtazapine was safe and had no effect on the activity of tracheal tissue and16HBE cells.Mirtazapine reduced respiratory system resistance in both asthmatic and normal mice.Mirtazapine reduced airway hyperresponsiveness,airway inflammation and mucus secretion to some extent,but did not reduce airway remodeling in asthmatic mice,and there was a large gap in efficacy compared with the positive control drug dexamethasone.In conclusion,mirtazapine can inhibit the excessive contraction of airway smooth muscle and has some relief effect on some asthma symptoms,but it is not effective and is not an ideal drug for asthma treatment.This study provides a new data reference for the research of mirtazapine in asthma treatment.