HERGチャネル阻害薬による催不整脈性のメカニズム:シミュレーションによる検討

抄録

(Backgrounds) Several papers reported that HERG channel block, namely blockade of rapid component of delayed rectifier K⁺ channel (IKr-blockade) occasionally brings on triggered action potentials (TA) in ventricular cells under pathological conditions. However, these mechanisms are not fully understood. In the present study, we analyzed the relationship between the IKr-blockade and TA using the comprehensive cardiac cell model, Kyoto Model. (Methods) A steady state condition of 1) Ca²⁺ overload and 2) low K⁺ conductance were established. Under each of two states, the effects of decreasing the conductance of IKr were examined. (Results) 1) Under Ca²⁺ overload, the Ca²⁺ influx via the L-type Ca²⁺ channel was increased, while the enhancement of Na⁺/K⁺ pump activity interferes with the Ca²⁺ overload via the Na⁺/Ca²⁺ exchanger. We found that TA was induced when [Ca²⁺] in sarcoplasmic reticulum is increased beyond a critical level. 2) Under low K⁺ conductance, the mean membrane potential per one cycle was gradually shifted to positive. When the open probability of L-type Ca²⁺ channel during diastole was increased beyond a critical level, another type of TA was induced. (Conclusions) These mechanisms of abnormal excitability are in good agreement with the view proposed by the previous experimental studies, and the Kyoto model can provide hypothetical quantitative mechanisms. [J Physiol Sci. 2007;57 Suppl:S197]