The blockade of herg k+ channels expressedin xenopus oocytes by neuroleptic agents
V. N. Osipenko, V. E. Degtiar, V. G. Naidionov, Y. M. Shuba
A. A. Bogomoletz Institute of PhysiologyNational Academy of Sciences of Ukraine;International Center of Molecular PhysiologyNational Academy of Sciences of Ukraine, Kiev
Abstract
V. N. Osipenko, V. E. Degtiar, V. G. Naidionov, Y. M. Shuba
THE BLOCKADE OF HERG K+ CHANNELS EXPRESSED
IN XENOPUS OOCYTES BY NEUROLEPTIC AGENTS
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 dalayed 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 ?N50 values for the haloperidol-,
pimozide- and fluspirilen-induced blockade of fully activated IKr were 1.36, 1.74 and
2.34 mnM 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.
A. A. Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine;
International Center of Molecular Physiology
National Academy of Sciences of Ukraine, Kiev
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