Referenced in: none

Automatically associated channels: Nav1.5 , Nav1.8 , Slo1

Title: The effects of A-803467 on cardiac Nav1.5 channels.

Authors: Zhonglin Han, Yu Jiang, Feng Xiao, Kejiang Cao, Dao W Wang

Journal, date & volume: Eur. J. Pharmacol., 2015 May 5 , 754, 52-60

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25701724

Abstract
A-803467 is a selective Nav1.8 blocker, but its mechanism of action at cardiac sodium channels is uncertain. Thus, we investigated the mechanistic effects of A-803467 on cardiac sodium channels in isolated mouse ventricular myocytes and in human embryonic kidney 293 (HEK293) cell lines that transiently expressed Nav1.5/SCN5A, the predominant cardiac sodium channel. At 0.3μM and greater, A-803467 blocked cardiac sodium currents in a dose-dependent manner in both ventricular myocytes and in SCN5A-expressing HEK293 cell lines. In both models, the drug caused significant depolarizing shifts at the conductance voltage relationship midpoint, hyperpolarizing shifts in voltage-dependent channel inactivation, and slower recovery from inactivation. Also, the drug reduced sodium current amplitude in a frequency-dependent manner, and blocked late sodium currents, accelerated inactivation, and enhanced the intermediate inactivation state. Our results provide strong evidence that A-803467 affects multiple biophysical characteristics of the canonical cardiac Nav1.5 channel and our data can be used to study potential applications of A-803467 as an antiarrhythmic drug.