Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Inhibitory Effect of Nicardipine on hERG Channel

  • Chung, Eun-Yong (Korea Food and Drug Administration) ;
  • Cho, Hea-Young (Korea Food and Drug Administration) ;
  • Cha, Ji-Hun (National Institute of Food and Drug Safety Evaluation) ;
  • Kwon, Kyoung-Jin (National Institute of Food and Drug Safety Evaluation) ;
  • Jeon, Seol-Hee (National Institute of Food and Drug Safety Evaluation) ;
  • Jo, Su-Hyun (Department of Physiology and Institute of Bioscience and Biotechnology, School of Medicine, Kangwon National University) ;
  • Kim, Eun-Jung (National Institute of Food and Drug Safety Evaluation) ;
  • Kim, Hye-Soo (Korea Food and Drug Administration) ;
  • Chung, Hye-Ju (Korea Food and Drug Administration)
  • Received : 2010.07.27
  • Accepted : 2010.09.14
  • Published : 2010.10.31
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Abstract

Drug-induced long QT syndrome is known to be associated with the onset of torsades de pointes (TdP), resulting in a fatal ventricular arrhythmia. QT interval prolongation can result from blocking the human ether-a-go-go-related gene (hERG) channel, which is important for the repolarization of cardiac action potential. Nicardipine, a Ca-channel blocker and antihypertensive agent, has been reported to increase the risk of occasional serious ventricular arrhythmias. We studied the effects of nicardipine on hERG $K^+$ channels expressed in HEK293 cells and Xenopus oocytes. The cardiac electrophysiological effect of nicardipine was also investigated in this study. Our results revealed that nicardipine dose-dependently decreased the tail current of the hERG channel expressed in HEK293 cells with an $IC_{50}$ of 0.43 ${\mu}M$. On the other hand, nicardipine did not affect hERG channel trafficking. Taken together, nicardipine inhibits the hERG channel by the mechanism of short-term channel blocking. Two S6 domain mutations, Y652A and F656A, partially attenuated (Y652A) or abolished (F656A) the hERG current blockade, suggesting that nicardipine blocks the hERG channel at the pore of the channel.

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References

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