Paracetamol Relaxing Airway Smooth Muscle

Objective:To re-develop paracetamol tablets,exploring whether they can treat asthma and the mechanism.Methods:At the tissue level,we used force measuring system to explore the effect of paracetaol on high K⁺-and ACh-induced precontraction of tracheal rings,and lung slice technique to determine its effect on intrapulmonary trachea;at the cellular level,we used patch clamp and confocal microscope to determine the effect of paracetamol on channel currents and intracellular Ca²⁺levels;at the molecular level,we utilized Western blot to define the effect of paracetamol on the phosphorylation of myosin phosphatase target subunit 1?MYPT1?of the Ca²⁺sensitization pathway;In addition,at the whole level,we explored the effects of paracetamol on the resistance of the respiratory system?Rrs?.Results:The results show that 5 mg/mL paracetamol completely inhibited the pre-contraction of treacheal rings induced by high K⁺and acetylcholine?ACh?,and it also inhibited the decreases of the airway areas caused by ACh in mouse lung slices.ACh-induced contraction was inhibited by nifedipine(inhibitor of L-type voltage-dependent Ca²⁺channel;LVDCC),YM-58483(inhibitor of store-operated Ca²⁺channel;SOCC)and Y-27632(inhibitor of ROCK,a linker of the pathway of Ca²⁺sensitization).We further demonstrated that paracetamol blocked LVDCC-and SOCC-mediated currents in single mouse airway smooth muscle?ASM?cells?ASMCs?and inhibited high K⁺-and ACh-induced Ca²⁺influx.Furthermore,paracetamol decreacsed the phosphorylation of MYPT1induced by ACh.Finally,paracetamol inhibited ACh-induced increases of the resistance of the mouse respirator system.Concusion:Paracetamol inhibits the precontraction of ASM through blocking LVDCCs,SOCCs,and Ca²⁺sensitization.Therefore,paracetamol could be a new drug to treat asthma.