IKr specific blockers commonly exhibit reverse frequency-dependent prolongation of the action potential duration (APD). APD prolongation induced by IKr specific blockers varies according to the species of animal. The APD of animals with few KCNE1 genes (e.g., humans, rabbits and cats) is only slightly prolonged by IKr specific blockers. On the other hand, the APD of animals with more KCNE1 genes (e.g., guinea pigs) is markedly prolonged by IKr specific blockers, and the APD prolongation exhibits strong reverse frequency-dependency. However, the mechanism of the difference in APD prolongation is not clearly understood. In this study, we analyzed the relation of APD prolongation induced by an IKr specific blocker and the KCNE1 expression level with simulations using cardiac membrane action potential models that differ in the KCNE1 expression level based on electrophysiological experiments. In the experiments, KCNE1 of 0.2 ng, 1 ng and 5 ng was coinjected with KCNQ1 of 5 ng in Xenopus Oocytes. Expressed currents were recorded 1-2 days after injection by the double-microelectrode voltage clamp method at 35°C. Maximum IKs conductance and relations between time constants, maximum activation parameter and membrane action potential were obtained from fitting functions describing IKs channel properties in the Luo-Rudy model to experimental results with the Nelder-Mead simplex method. In simulations, we stimulated three models differing in KCNE1 expression level at six frequencies. From the simulation results, it was confirmed that an increase in KCNE1 expression level strengthened APD prolongation and the reverse frequency-dependency induced by the IKr specific blocker. In time histories of IKs, IKs increased as the result of high-frequency stimulation in the case of more KCNE1 genes. An increase in IKs induced by time constant prolongation with an increase in the KCNE1 expression level led to a relative decrease in IKr contribution ratio to outward ion currents. This is the mechanism of the difference in APD prolongation and reverse frequency-dependency induced by an IKr specific blocker according to animal species.
