Blockade of human HERG K+ channels by rosiglitazone, an antidiabetic drug

Seung Ho Lee, Min Ji Sung, Sang June Hahn, Jimok Kim, Gyesik Min, Su Hyun Jo, Han Choe, Bok Hee Choi

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

This study examined the effect of rosiglitazone, an oral antidiabetic drug, on human ether-a-gogo- related gene (HERG) channels expressed in human embryonic kidney (HEK293) cells. Using the whole-cell patch-clamp technique, interaction between rosiglitazone and HERG in HEK293 cells was studied. Rosiglitazone inhibited HERG channels in a concentration-dependent manner, with an IC50 value of 18.8 μM and a Hill coefficient of 1.0. These effects were reversible after wash-out of the drug. The rosiglitazone-induced inhibition of HERG channels was voltagedependent, with a steep increase in inhibition over the voltage range of channel opening. However, inhibition was voltage-independent over the voltage range in which channels are fully activated. Rosiglitazone did not change the steady-state activation or inactivation curves or the activation or deactivation kinetics, implying that rosiglitazone blocks HERG channels predominantly in the open and inactivated state rather than in the closed state. The present study suggests that rosiglitazone blocks HERG channels by binding to activated and inactivated channels, and rosiglitazone use should thus be carefully monitored in patients with pre-existing QT prolongation.

Original languageEnglish (US)
Pages (from-to)1655-1664
Number of pages10
JournalArchives of Pharmacal Research
Volume35
Issue number9
DOIs
StatePublished - Sep 1 2012

Keywords

  • Antidiabetic drug
  • Cardiotoxicity
  • HERG
  • Long QT syndrome
  • Rosiglitazone

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Organic Chemistry

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