A Comparative Study of the Rapid (I_Kr) and Slow (I_Ks) Delayed Rectifier Potassium Currents in Undiseased Human, Dog,...

To understand the large inter-species variations in drug effects on repolarization, the properties of the rapid (I_Kr) and the slow (I_Ks) components of the delayed rectifier potassium currents were compared in myocytes isolated from undiseased human donor (HM), dog (DM), rabbit (RM) and guinea pig (GM) ventricles by applying the patch clamp and conventional microelectrode techniques at 37 °C. The amplitude of the E-4031-sensitive I_Kr tail current measured at -40 mV after a 1 s long test pulse of 20 mV, which was very similar in HM and DM but significant larger in RM and GM. The L-735,821-sensitive I_Ks tail current was considerably larger in GM than in RM. In HM, the I_Ks tail was even smaller than in DM. At 30 mV, the I_Kr component was activated extremely rapidly and monoexponentially in each studied species. The deactivation of the I_Kr component in HM, DM, and RM measured at -40 mV. After a 30 mV pulse, it was slow and biexponential, while in GM, the I_Kr tail current was best fitted triexponentially. At 30 mV, the I_Ks component activated slowly and had an apparent monoxponential time course in HM, DM, and RM. In contrast, in GM, the activation was clearly biexponential. In HM, DM, and RM, I_Ks component deactivation measured at -40 mV was fast and monoexponential, while in GM, in addition to the fast component, another slower component was also revealed. These results suggest that the I_K in HM resembles that measured in DM and RM and considerably differs from that observed in GM. These findings suggest that the dog and rabbit are more appropriate species than the guinea pig for preclinical evaluation of new potential drugs expected to affect cardiac repolarization.