Comparison of the effects of DC031050, a class III antiarrhythmic agent, on hERG channel and three neuronal potassium channels  

作　　者：Ping LI Hai-feng SUN Ping-zheng ZHOU Chao-ying MA Guo-yuan HU Hua-liang JIANG Min LI Hong LIU Zhao-bing GAO 

机构地区：[1]State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203,china [2]Life Science and Engineering College of Southwest Jiaotong University, Chengdu 610031, China

出　　处：《Acta Pharmacologica Sinica》2012年第6期728-736,共9页中国药理学报（英文版）

摘　　要：Aim： This study was conducted to test the selectivity of DC031050 on cardiac and neuronal potassium channels. Methods： Human ether-a-go-go related gene （hERG）, KCNQ and Kvl.2 channels were expressed in CHO cells. The delayed rectifier potassium current （IK） was recorded from dissociated hippocampal pyramidal neurons of neonatal rats. Whole-cell voltage patch clamp was used to record the voltage-activated potassium currents. Drug-containing solution was delivered using a RSC-IO0 Rapid Solution Changer. Results： Both DC031050 and dofetilide potently inhibited hERG currents with IC5o values of 2.3＋1.0 and 17.9±1.2 nmol/L, respectively DC031050 inhibited the IK current with an IC50 value of 2.7±1.5 pmol/L, which was 〉1000 times the concentration required to inhibit hERG current. DC031050 at 3 pmol/L did not significantly affect the voltage-dependence of the steady activation, steady inactivation of IK, or the rate of IK from inactivation. Intracellular application of DC031050 （5 pmol/L） was insufficient to inhibit IK. DC031050 up to 10 pmol/L had no effects on KCNQ2 and Kvl.2 channel currents. Conclusion： DC031050 is a highly selective hERG potassium channel blocker with a substantial safety margin of activity over neuronal potassium channels, thus holds significant potential for therapeutic application as a class III antiarrhythmic agent.Aim： This study was conducted to test the selectivity of DC031050 on cardiac and neuronal potassium channels. Methods： Human ether-a-go-go related gene （hERG）, KCNQ and Kvl.2 channels were expressed in CHO cells. The delayed rectifier potassium current （IK） was recorded from dissociated hippocampal pyramidal neurons of neonatal rats. Whole-cell voltage patch clamp was used to record the voltage-activated potassium currents. Drug-containing solution was delivered using a RSC-IO0 Rapid Solution Changer. Results： Both DC031050 and dofetilide potently inhibited hERG currents with IC5o values of 2.3＋1.0 and 17.9±1.2 nmol/L, respectively DC031050 inhibited the IK current with an IC50 value of 2.7±1.5 pmol/L, which was 〉1000 times the concentration required to inhibit hERG current. DC031050 at 3 pmol/L did not significantly affect the voltage-dependence of the steady activation, steady inactivation of IK, or the rate of IK from inactivation. Intracellular application of DC031050 （5 pmol/L） was insufficient to inhibit IK. DC031050 up to 10 pmol/L had no effects on KCNQ2 and Kvl.2 channel currents. Conclusion： DC031050 is a highly selective hERG potassium channel blocker with a substantial safety margin of activity over neuronal potassium channels, thus holds significant potential for therapeutic application as a class III antiarrhythmic agent.

关 键 词：DOFETILIDE DC031050 class III antiarrhythmic agent HERG KCNQ Kvl.2 delayed rectifier potassium current 

分 类 号：Q424[生物学—神经生物学] TQ463.4[生物学—生理学]