Key result
HW-0168 potently activates hERG channels, increasing current amplitude ~2.5-fold and shortening action potential duration.
Why the study?
Reduction of hERG activity causes type 2 long QT syndrome and ventricular arrhythmia, making pharmacological activation of hERG a potential therapeutic strategy for cardiac arrhythmias.
Answers are grounded in this paper and cite their sources.
HW-0168 is a novel hERG channel activator that increases current amplitude and shortens action potential duration, highlighting its potential for studying hERG physiology and treating long QT syndrome.
The human ether-a-go-go-related gene (hERG) encodes the K+ channel that carries the rapid component of the delayed rectifier current in the human heart. Reduction of hERG activity induced by gene mutations or pharmacological inhibition is responsible for the type 2 form of long QT syndrome in patients which can develop into ventricular arrhythmia and sudden cardiac death. Therefore, pharmacological activation of hERG may lead to therapeutic potential for cardiac arrhythmias. In this study we characterized a small and novel compound, N-(2-(tert-butyl)phenyl)-6-(4-chlorophenyl)-4-(trifluoromethyl) nicotinamide, HW-0168, that exhibits potent activation of hERG channel with an EC50 of 0.41 ± 0.2 μM. Using whole-cell patch clamp recording of HEK293 cells stably expressed hERG channels, we found that HW-0168 dramatically increased current amplitude about 2.5 folds and slowed down current inactivation about 4 folds. HW-0168 shifted the voltage-dependent channel activation to hyperpolarizing direction about 3.7 mV and the voltage-dependent channel inactivation to depolarizing direction about 9.4 mV. In addition, recording of guinea-pig ventricular cells confirmed that HW-0168 shortened the action potential duration. In conclusion, we identified a novel hERG channel activator HW-0168 that can be used for studying the physiological role of hERG in cardiac myocytes and may be beneficial for treating long QT syndrome.
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Dong et al. (2019) studied Long QT syndrome. HW-0168 was evaluated on hERG channel current amplitude and inactivation. The novel small molecule HW-0168 potently activated hERG channels (EC50 0.41 μM), increasing current amplitude 2.5-fold and shortening action potential duration in guinea-pig ventricular cells.
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