Effects of diltiazem and propafenone on the inactivation and recovery kinetics of fKv1.4 channel currents expressed in Xenopus oocytes  

作　　者：Dong ZHANG Shi-min WANG Hui CHEN Xue-jun JIANG Sheng-ping CHAO 

机构地区：[1]Department of Cardiology, Renmin Hospital, Wuhan University, Wuhan 430073, China [2]Department of Cardiology, Zhongnan Hospital, Wuhan University, Wuhan 430071, China

出　　处：《Acta Pharmacologica Sinica》2011年第4期465-477,共13页中国药理学报（英文版）

摘　　要：Aim： To investigate the effects of diltiazem, an L-type calcium channel blocker, and propafenone, a sodium channel blocker, on the inactivation and recovery kinetics of fKvl.4, a potassium channel that generates the cardiac transient outward potassium current. Methods： The cRNA for fKvl.4hN, an N-terminal deleted mutant of the ferret Kvl.4 potassium channel, was injected into Xenopus oocytes to express the fKvl.4AN channel in these cells. Currents were recorded using a two electrode voltage clamp technique. Results： Diltiazem （10 to 1000 IJmol/L） inhibited the fKvl.4AN channel in a frequency-dependent, voltage-dependent, and concentration-dependent manner, suggesting an open channel block. The IC50 was 241.04±23.06 pmol/L for the fKvl.4hN channel （at ＋50 mV）, and propafenone （10 to 500 μmol/L） showed a similar effect （IC5o=103.68±10,13 pmol/L）. After application of diltiazem and propafenone, fKvl.4AN inactivation was hi-exponential, with a faster drug-induced inactivation and a slower C-type inactivation. Diltiazem increased the C-type inactivation rate and slowed recovery in fKvl.4hN channels. However, propafenone had no effect on either the slow inactivation time constant or the recovery. Conclusion： Diltiazem and propafenone accelerate the inactivation of the Kvl.4AN channel by binding to the open state of the channel Unlike propafenone, diltiazem slows the recovery of the Kvl.4AN channel.Aim： To investigate the effects of diltiazem, an L-type calcium channel blocker, and propafenone, a sodium channel blocker, on the inactivation and recovery kinetics of fKvl.4, a potassium channel that generates the cardiac transient outward potassium current. Methods： The cRNA for fKvl.4hN, an N-terminal deleted mutant of the ferret Kvl.4 potassium channel, was injected into Xenopus oocytes to express the fKvl.4AN channel in these cells. Currents were recorded using a two electrode voltage clamp technique. Results： Diltiazem （10 to 1000 IJmol/L） inhibited the fKvl.4AN channel in a frequency-dependent, voltage-dependent, and concentration-dependent manner, suggesting an open channel block. The IC50 was 241.04±23.06 pmol/L for the fKvl.4hN channel （at ＋50 mV）, and propafenone （10 to 500 μmol/L） showed a similar effect （IC5o=103.68±10,13 pmol/L）. After application of diltiazem and propafenone, fKvl.4AN inactivation was hi-exponential, with a faster drug-induced inactivation and a slower C-type inactivation. Diltiazem increased the C-type inactivation rate and slowed recovery in fKvl.4hN channels. However, propafenone had no effect on either the slow inactivation time constant or the recovery. Conclusion： Diltiazem and propafenone accelerate the inactivation of the Kvl.4AN channel by binding to the open state of the channel Unlike propafenone, diltiazem slows the recovery of the Kvl.4AN channel.

关 键 词：INACTIVATION RECOVERY Kv1.4 potassium channel DILTIAZEM PROPAFENONE two electrode voltage clamp technique 

分 类 号：Q424[生物学—神经生物学] TQ463[生物学—生理学]