NS8593 inhibits Ca 2+ permeant channels reversing mouse airway smooth muscle contraction

Bei-Bei Liu, Yong-Bo Peng, Wen-Jing Zhang, Xiao-Xue Zhao, Li-Ping Chen, Meng-Su Liu, Ge-Ge Wang, Ya-Jing Liu, Jinhua Shen, Ping Zhao, Lu Xue, Meng-Fei Yu, Weiwei Chen, Li-Qun Ma, Gangjian Qin, Jiapei Dai, etc.

Life Sci. 2019 Dec 1;238:116953.

PMID: 31626793

Abstract:

Aims:




This study focused on investigating whether NS8593 reverses airway smooth muscle (ASM) contraction and the underlying mechanism.













Main methods:




ASM contraction in mouse tracheal rings and lung slices was measured. Currents mediated by voltage dependent Ca2+ channels (VDCCs) and ACH-activated channels were measured using the whole-cell patch-clamp technique in single tracheal smooth muscle cells (TSMCs). Intracellular Ca2+ level and cell length were measured using an LSM 700 laser confocal microscope and a Zen 2010 software. Mouse respiratory system resistance (Rrs) was assessed using a FlexiVent FX system.













Key findings:




High K+ (80 mM K+) and ACH induced ASM contraction in mouse tracheal rings and lung slices, which was partially relaxed by nifedipine (blocker of L-type VDCCs, LVDCCs), YM-58483 (blocker of store-operated Ca2+ entry (SOCE), transient receptor potential C3 (TRPC3) and TRPC5 channels), respectively. However, the contraction was completely reversed by NS8593, whereas, slightly relaxed by formoterol. ACH activated inward currents, which displayed linear and reversed around 0 mV, indicating the currents were mediated by non-selective cation channels (NSCCs). Moreover, these currents were blocked by YM-58483. In addition, such currents were abolished by NS8593, implicating that NS8593 inhibits the same channels. Besides, NS8593 inhibited increases of intracellular Ca2+ and the associated cell shortening. Finally, NS8593 inhibited ACH-induced increases of mouse respirator system resistance (Rrs).













Significance:




Our results indicate that NS8593 inhibits LVDCCs and NSCCs, resulting in decreases of intracellular Ca2+ and then leading to ASM relaxation. These data suggest that NS8593 might be a new bronchodilator.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4249505	NS8593			Price