Relaxant Action of Diclofenac Sodium on Mouse Airway Smooth Muscle.

Chunfa Chen,Congli Cai,Jinhua Shen,Shunbo Shi,Qing-Hua Liu,Shuhui Han,Meng-Fei Yu,Yongle Yang

doi:10.3389/fphar.2019.00608

Abstract

Diclofenac sodium (DCF) is a nonsteroidal anti-inflammatory drug (NSAID) and is widely used as an analgesic and anti-inflammatory agent. Herein, we found that DCF could relax high K+ (80 mM K+)-/ACh-precontracted tracheal rings (TRs) in mice. This study aimed to elucidate the underlying mechanisms of DCF-induced relaxations. The effects of DCF on airway smooth muscle (ASM) cells were explored using multiple biophysiological techniques, such as isometric tension measurement and patch-clamping experiments. Both high K+- and ACh-evoked contraction of TRs in mice were relaxed by DCF in a dose-dependent manner. The results of isometric tension and patch-clamping experiments demonstrated that DCF-induced relaxation in ASM cells was mediated by cytosolic free Ca2+, which was decreased via inhibition of voltage-dependent L-type Ca2+ channels (VDLCCs), nonselective cation channels (NSCCs), and Na+/Ca2+ exchange. Meanwhile, DCF also enhanced large conductance Ca2+ activated K+ (BK) channels, which led to the relaxation of ASMs. Our data demonstrated that DCF relaxed ASMs by decreasing the intracellular Ca2+ concentration via inhibition of Ca2+ influx and Na+/Ca2+ exchange. Meanwhile, the enhanced BK channels also played a role in DCF-induced relaxation in ASMs. These results suggest that DCF is a potential candidate for antibronchospasmic drugs used in treating respiratory diseases such as asthma and chronic obstructive pulmonary disease.

Highlights

300 million individuals suffer from asthma worldwide (World Health Organization, 2001)
The enhanced BK channels played a role in Diclofenac sodium (DCF)-induced relaxation in airway smooth muscle (ASM). These results suggest that DCF is a potential candidate for antibronchospasmic drugs used in treating respiratory diseases such as asthma and chronic obstructive pulmonary disease
Our results demonstrate that DCF effectively relaxed ACh/high K+-precontracted tracheal rings (TRs) by inhibiting voltage-dependent L-type Ca2+ channels (VDLCCs)-mediated extracellular Ca2+ influx and enhancing the activity of BK channels

Summary

Introduction

300 million individuals suffer from asthma worldwide (World Health Organization, 2001). Asthma is characterized by variable and recurring episodes, such as wheezing, shortness of breath, chest tightness, and coughing (Asher et al, 2006; Lotvall et al, 2011). Asthma can be controlled using traditional drugs, including corticosteroids (Adams and Jones, 2006; Kowalski et al, 2016), long/short-acting beta-agonists (Black et al, 2009; Morales, 2013), leukotriene receptor antagonists (Stoloff, 2000), and Chinese medicine herbs (Yang et al, 2017). Exacerbations still occur and may require emergency room visits, hospitalization, and intensive treatments. This is becoming a large economic, social, and healthcare burden. It is urgent to develop new effective drugs to treat asthma

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