Relaxant Effect Of NS8593 Of TRPM7 Channel Inhibitor On Airway Smooth Muscle

NS8593??R?-N-?benzimidazol-2-yl?-1,2,3,4-tetrahydro-1-naphthylamine?is a selective blocker of TRPM7?Transient Receptor Potential Melastatin 7,TRPM7?channels,which inhibits contraction of vascular smooth muscle cells?VSMCs?.However,whether it affects the contraction of airway smooth muscle?ASM?is still unclear.The purpose of this paper was to investigate the relaxant effect of NS8593 on ASM and the underlying mechanism,finding a new drug for asthma and other ventilatory restrictive diseases.On isolated mouse tracheal rings,NS8593 inhibited acetylcholine?ACH?-andhighK⁺?80mMK⁺?-inducedASMcontractionsina concentration-dependent manner.Meanwhile,ACH-induced intrapulmonary ASM contractions were also inhibited by NS8593.ACH-induced contractions of ASMs were inhibited upon the addition of nifedipine?inhibitor of L-type voltage-dependent calcium channels?LVDCCs??and YM-58483?inhibitor of store-operated calcium channels?SOCs??.Therefore,we hypothesized that NS8593 inhibits LVDCCs and SOCs,resulting in relaxation.This was further confirmed by the results that NS8593 blocked LVDCC and SOC currents measured using patch clamp techniques.As these channels mediate Ca²⁺influx,therefore,the effect of NS8593 on intracellular Ca²⁺levels([Ca²⁺]_i)was studied using calcium imaging technique,and we found that NS8593 inhibited high K⁺-and ACH-induced[Ca²⁺]_i elevations and associated cell shortening.In addition,NS8593 reduced the increases of mouse respiratory resistance caused by ACH.Based on the above results,we conclude that NS8593 inhibits LVDCCs and SOCs,Ca²⁺influx end,[Ca²⁺]_i reductions,eventually resulting in relaxation of ASMs.These results suggest that NS8593 could be developed as a new bronchodilator.