心筋細胞活動電位数値計算モデルを用いた動物種によるI_<Kr>ブロッカーに対する感受性の違いに関する検証

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I_<Kr> specific blockers commonly exhibit reverse frequency-dependent prolongation of the action potential duration (APD). APD prolongation induced by I_<Kr> 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 I_<Kr> specific blockers. On the other hand, the APD of animals with more KCNE1 genes (e.g., guinea pigs) is markedly prolonged by I_<Kr> 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 I_<Kr> 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 0.2ng, 1ng and 5ng was coinjected with KCNQ1 of 5ng in Xenopus Oocytes. Expressed currents were recorded 1-2 days after injection by the double-microelectrode voltage clamp method at 35℃. Maximum I_<Ks> conductance and relations between time constants, maximum activation parameter and membrane action potential were obtained from fitting functions describing I_<Ks> 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 I_<Kr> specific blocker. In time histories of I_<Ks>, I_<Ks> increased as the result of high-frequency stimulation in the case of more KCNE1 genes. An increase in I_<Ks> induced by time constant prolongation with an increase in the KCNE1 expression level led to a relative decrease in I_<Kr> contribution ratio to outward ion currents. This is the mechanism of the difference in APD prolongation and reverse frequency-dependency induced by an I_<Kr> specific blocker according to animal species.
2005-12-10

心筋細胞活動電位数値計算モデルを用いた動物種によるI_<Kr>ブロッカーに対する感受性の違いに関する検証

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