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Effect of sibutramine HCl on cardiac hERG K+ channel

Ki-Suk Kim1, Eun-Joo Kim, Hyang-Ae Lee

  • 1Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Yuseong, Daejeon 305-343, South Korea.

Molecular and Cellular Biochemistry
|September 11, 2008
PubMed

Insights

Sibutramine hydrochloride inhibits the hERG potassium channel, prolonging cardiac action potential. This drug interaction, particularly at high concentrations, poses risks for patients susceptible to cardiac arrhythmias.

Area of Science:

  • Pharmacology
  • Cardiovascular Physiology
  • Molecular Biology

Background:

  • Clinically used drugs can block delayed rectifier K(+) channels, prolonging cardiac action potential duration and potentially causing long QT syndrome.
  • The hERG (human Ether-à-go-go-Related Gene) potassium channel is crucial for cardiac repolarization.

Purpose of the Study:

  • To investigate the mechanism by which sibutramine hydrochloride inhibits the hERG potassium channel.
  • To determine the specific residues involved in sibutramine's blockade of the hERG channel.

Main Methods:

  • HEK-293 cells expressing the hERG channel were used to study the effects of sibutramine hydrochloride on I(hERG) (hERG channel current).
  • Concentration-dependent inhibition, voltage-dependence, and time-dependence of I(hERG) blockade were assessed.
  • Mutagenesis studies were performed on key hERG channel residues (Y652A, F656A, T623A, S624A) to identify the binding site.

Main Results:

  • Sibutramine hydrochloride inhibited I(hERG) in a concentration-dependent manner with an IC(50) of 2.5 microM at -40 mV.
  • Inhibition showed weak voltage dependence but rapid time-dependence upon membrane depolarization.
  • Mutations at hERG residues Y652 and F656 significantly reduced sibutramine's blocking potency, while pore-region mutations T623A and S624A did not.

Conclusions:

  • Sibutramine hydrochloride preferentially inhibits the hERG potassium channel, primarily interacting with residues Y652 and F656.
  • Supratherapeutic concentrations of sibutramine hydrochloride should be avoided in patients with a high susceptibility to cardiac arrhythmia due to potential hERG channel blockade.

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