[Blockade of HERG K+ channels expressed in Xenopus oocytes by antipsychotic agents]

Fiziol Zh (1994). 2001;47(1):17-25.
[Article in Ukrainian]

Abstract

We have investigated the effects of neuroleptic agents, haloperidol, pimozide and fluspirilen, that are used in clinics to treat psychiatric disorders, but reportedly have proarrhythmic side effects, on HERG-encoded K+ channels responsible for the rapid component of cardiac delayed rectifier K+ current, IKr. All three agents blocked HERG-directed IKr in Xenopus oocytes in a voltage-dependent manner. The extent of the blockade increased with depolarization correlating with channels activation consistent with open-channel blocking mechanism. The IC50 values for the haloperidol-, pimozide- and fluspirilen-induced blockade of fully activated IKr were 1.36, 1.74 and 2.34 mcM respectively. Neuroleptics did not affect the HERG channels steady-state activation and inactivation properties. Thus, the blockade of HERG channels may underly proarrhythmic actions of neuroleptics resulting in a slowing down of the repolarization phase of cardiac action potential, and prolongation of the electrocardiographic QT interval.

Publication types

  • Comparative Study
  • English Abstract

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology*
  • Cation Transport Proteins*
  • Dose-Response Relationship, Drug
  • Ether-A-Go-Go Potassium Channels
  • Female
  • Fluspirilene / pharmacology
  • Haloperidol / pharmacology
  • In Vitro Techniques
  • Oocytes / drug effects
  • Oocytes / metabolism*
  • Pimozide / pharmacology
  • Potassium Channel Blockers / pharmacology*
  • Potassium Channels / drug effects*
  • Potassium Channels / metabolism
  • Potassium Channels / physiology
  • Potassium Channels, Voltage-Gated*
  • Xenopus laevis

Substances

  • Antipsychotic Agents
  • Cation Transport Proteins
  • Ether-A-Go-Go Potassium Channels
  • KCNH6 protein, human
  • Potassium Channel Blockers
  • Potassium Channels
  • Potassium Channels, Voltage-Gated
  • Pimozide
  • Fluspirilene
  • Haloperidol