Different voltage dependence of ICaL blockade in nonselective IKr blockers causes their opposite effects on early afterdepolarization in drug-induced arrhythmia

Several false-positive results in the human ether-à-gogo-related gene test suggest that blockers of the rapid component of delayed rectifier K+ current (IKr) do not necessarily produce drug-induced arrhythmias. Specifically, the occurrence of early afterdepolarization (EAD) differs among IKr blockers, even if the prolonged action potential duration is in the same range. To predict EAD in drug-induced arrhythmias, we proposed a prediction method based on the mechanisms underlying the difference in frequency of EAD among nonselective IKr blockers. The mechanisms were elucidated by examining how different blockade kinetics of L-type Ca2+ current (ICaL) affect the frequency of EAD, using mathematical models of human ventricular myocytes. Addition of voltage-independent ICaL blockade resulted in the suppression of EAD. However, when voltage-dependent ICaL blockade kinetics of amiodarone, bepridil, and terfenadine were incorporated into ICaL in the model, bepridil and terfenadine induced EAD more than the voltage-independent ICaL blockade, while amiodarone suppressed EAD more effectively. Opposite effects were accounted for by the difference in ICaL blockade at negatively polarized potential. EAD occurrence was found to be associated with ICaL blockade measured at −20 mV. These results suggest that voltage dependence of ICaL blockade may be useful in predicting the different risks of nonselective IKr blockers.