Hexachlorophene Is a Potent KCNQ1/KCNE1 Potassium Channel Activator Which Rescues LQTs Mutants

Zheng, Yueming; Zhu, Xuejing; Zhou, Pingzheng; Lan, Xi; Xu, Haiyan; Li, Min; Gao, Zhaobing

Because HCP potentiates the KCNQ1/KCNE1 complex, we tested its effects on IKs in acutely isolated guinea pig cardiomyocytes. We found after application of 1 mM HCP, the IKs was increased 1.3460.15 fold (n = 4) at +50 mV measured potential. The G-V curve was left shifted 27.1362.44 mV (n = 4) (Fig. 5A , B & C). The effects of HCP on action potential were further examined. The action potential was elicited on isolated guinea pig ventricular myocytes by current injection. Upon application of 1 mM HCP, the action potential duration (APD) was shortened by 10.2461.71%. Consistently, the APD 90 (action potential duration at 90% repolarization) and APD 50 (action potential duration at 50% repolarization) were shortened by 10.5861.88% and 18.8263.65%, respectively (n = 7) (Fig. 5E & F) . The inhibitory effects can not restore in five minutes after removal of the compound but can be reversed by Choromonal 293B, a blocker of IKs. Choromonal 293B at 10 mM alone prolonged the APD around 30.0463.15% (n = 4). After co-application of 10 mM Choromonal 293B, the action potential duration was restored (n = 4) (Fig. 5E) . Accordingly, the effects of 1 mM HCP on APD was reduced to 5.4361.54% (n = 4). HCP at 3 mM effects caused further reduction of action potential duration. The change of APD, APD 90 and APD 50 were 31.7167.3, 34.1168.09 and 37.6567.36, respectively (n = 9). R-L3, a reported IKs activator which shortens APD effectively, was tested as a positive control [14] . In our system, 1 mM and 3 mM R-L3 significantly deceased the APD 50 about 9.5961.29% (n = 3) and 25.3062.29% (n = 3) (Fig. 5D) , which were consistent with the previous study. Thus, these data are consistent with the notion that HCP acts on the native KCNQ channels.