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Vol. 281, Issue 1, 384-392, 1997
Department of Medicine (J.F., Z.W., G.-R.L., S.N.),
Montreal Heart
Institute and University of Montreal, and Department of Pharmacology
and Therapeutics (S.N.), McGill University, Montreal, Quebec, Canada
A variety of class III antiarrhythmic agents have been shown to block
the delayed rectifier current, but their effects on other
K+ currents, particularly in human tissues, are less clear.
We studied the concentration-dependent actions of the class III
compounds d-sotalol, E-4031 and ambasilide on the transient
outward current (Ito) and the ultra-rapid delayed rectifier
current (IKur) in human atrial myocytes.
d-Sotalol and E-4031 failed to alter Ito or
IKur at concentrations up to 500 and 50 µM, respectively.
In contrast, ambasilide produced a concentration-dependent inhibition of Ito and IKur, with statistically significant
effects at 10 µM and maximum effects at 100 µM. The 50% inhibitory
concentration of ambasilide averaged 23 ± 2 µM and 34 ± 3 µM for Ito and IKur respectively. Ambasilide
did not alter the voltage-dependence of activation or inactivation of
Ito, or the voltage-dependence of IKur, and it
did not affect Ito recovery from inactivation. On the other
hand, ambasilide accelerated Ito inactivation, by introducing a more rapid component that accelerated with increasing drug concentration. Furthermore, block of both Ito and
IKur developed over time after the onset of depolarization,
with time constants of 5.8 ± 0.8 msec and 2.5 ± 0.4 msec at
concentrations of 10 and 50 µM for Ito and 6.1 ± 0.8 msec and 2.1 ± 0.3 msec at 10 and 50 µM for
IKur. We conclude that neither d-sotalol nor
E-4031 affects Ito or IKur, whereas ambasilide
produces efficacious open-channel block of both currents, in human
atrial myocytes.
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