NS8593 inhibits Ca2+ permeant channels reversing mouse airway smooth muscle contraction.
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.
['Liu|Bei-Bei|BB|', 'Peng|Yong-Bo|YB|', 'Zhang|Wen-Jing|WJ|', 'Zhao|Xiao-Xue|XX|', 'Chen|Li-Ping|LP|', 'Liu|Meng-Su|MS|', 'Wang|Ge-Ge|GG|', 'Liu|Ya-Jing|YJ|', 'Shen|Jinhua|J|', 'Zhao|Ping|P|', 'Xue|Lu|L|', 'Yu|Meng-Fei|MF|', 'Chen|Weiwei|W|', 'Ma|Li-Qun|LQ|', 'Qin|Gangjian|G|', 'Dai|Jiapei|J|', 'Liu|Qing-Hua|QH|']
D015057:1-Naphthylamine D000818:Animals D018926:Anti-Allergic Agents D001249:Asthma D002118:Calcium D020746:Calcium Channels, L-Type D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D009119:Muscle Contraction D009126:Muscle Relaxation D009130:Muscle, Smooth D010047:Ovalbumin
NS8593 Airway smooth muscle L-type voltage-dependent Ca(2+) channel Store-operated Ca(2+) entry Transient receptor potential channel