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Vol. 60, Issue 2, 244-253, August 2001
Department of Circulation, Research Institute of Environmental
Medicine, Nagoya University, Nagoya, Japan (K.K., K.Y., I.K.);
Department of Cell Physiology and Pharmacology, University of
Leicester, Leicester, United Kingdom (J.S.M.); and Department of
Internal Medicine, University of Utah, Salt Lake City, Utah (M.C.S.)
Vesnarinone, a cardiotonic agent, blocks IKr and, unlike
other IKr blockers, produces a frequency-dependent
prolongation of action potential duration (APD). To elucidate the
mechanisms, we studied the effects of vesnarinone on HERG, the
cloned human IKr channel, heterologously expressed in
Xenopus laevis oocytes. Vesnarinone caused a
concentration-dependent inhibition of HERG currents with an
IC50 value of 17.7 ± 2.5 µM at 0 mV
(n = 6). When HERG was coexpressed with the
-subunit MiRP1, a similar potency for block was measured
(IC50: 15.0 ± 3.0 µM at 0 mV, n = 5). Tonic block of the HERG channel current was minimal (<5% at 30 µM, n = 5). The rate of onset of block and the
steady-state value for block of current were not significantly
different for test potentials ranging from 
40 to +40 mV [time
constant (
) = 372 ± 76 ms at +40 mV,
n = 4]. Recovery from block at 60, 90, and
120 mV was not significantly different ( = 8.5 ± 1.5 s at 90 mV, n = 4). Vesnarinone produced
similar effects on inactivation-removed mutant (G628C/S631C) HERG
channels. The IC50 value was 10.7 ± 3.7 µM at 0 mV
(n = 5), and the onset and recovery from block of
current findings were similar to those of wild-type HERG. Amino acids
important for the binding of vesnarinone were identified using
alanine-scanning mutagenesis of residues believed to line the inner
cavity of the HERG channel. Six important residues were identified,
including G648, F656, and V659 located in the S6 domain and T623, S624,
and V625 located at the base of the pore helix. These residues are
similar but not identical to those determined previously for MK-499, an
antiarrhythmic drug. In conclusion, vesnarinone preferentially blocks
open HERG channels, with little effect on channels in the rested or
inactivated state. These actions may contribute to the favorable
frequency-dependent prolongation in APD.
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