2. Academic Validation
  3. SKF-96365 blocks human ether-à-go-go-related gene potassium channels stably expressed in HEK 293 cells

SKF-96365 blocks human ether-à-go-go-related gene potassium channels stably expressed in HEK 293 cells

  • Pharmacol Res. 2016 Feb;104:61-9. doi: 10.1016/j.phrs.2015.12.012.
Hui Liu 1,  Lei Yang 2,  Kui-Hao Chen 1,  Hai-Ying Sun 3,  Man-Wen Jin 4,  Guo-Sheng Xiao 5,  Yan Wang 6,  Gui-Rong Li 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Departments of Physiology and Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.
  • 2 Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Departments of Physiology and Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.
  • 3 Departments of Physiology and Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China.
  • 4 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 5 Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, China.
  • 6 Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, China. Electronic address: wy@medmail.com.cn.
  • 7 Departments of Physiology and Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, China; Xiamen Cardiovascular Hospital, Medical College of Xiamen University, Xiamen, China. Electronic address: grli8@outlook.com.
PMID: 26689773 DOI: 10.1016/j.phrs.2015.12.012
Abstract

SKF-96365 is a TRPC channel antagonist commonly used to characterize the potential functions of TRPC channels in different systems, which was recently reported to induce QTc prolongation on ECG by inhibiting TRPC channels. The present study investigates whether the blockade of cardiac repolarization currents would be involved in the increase of QTc interval. Cardiac repolarization currents were recorded in HEK 293 cells stably expressing human ether-à-go-go-related gene potassium (hERG or hKv11.1) channels, hKCNQ1/hKCNE1 channels (IKs) or hKir2.1 channels and cardiac action potentials were recorded in guinea pig ventricular myocytes using a whole-cell patch technique. The potential effect of SKF-96365 on QT interval was evaluated in ex vivo guinea pig hearts. It was found that SKF-96365 inhibited hERG current in a concentration-dependent manner (IC50, 3.4μM). The hERG mutants S631A in the pore helix and F656V of the S6 region reduced the inhibitory sensitivity with IC50s of 27.4μM and 11.0μM, suggesting a channel pore blocker. In addition, this compound inhibited IKs and hKir2.1currents with IC50s of 10.8 and 8.7μM. SKF-96365 (10μM) significantly prolonged ventricular APD90 in guinea pig ventricular myocytes and QTc interval in ex vivo guinea pig hearts. These results indicate that the TRPC channel antagonist SKF-96365 exerts blocking effects on hERG, IKs, and hKir2.1 channels. Prolongation of ventricular APD and QT interval is related to the inhibition of multiple repolarization potassium currents, especially hERG channels.

Keywords

Cardiac potassium channels; Dimethyl sulfoxide (PubChem CID: 679); G418 sulfate (PubChem CID: 86605443); Human ether-à-go-go-related gene potassium channels; Pentobarbital sodium (PubChem CID: 23676152); QT interval; SK-96365 (1-[2-(4-Methoxyphenyl)-2-[3-(4-methoxyphenyl) propoxy]ethyl]imidazole) (PubChem CID: 104956); hKCNQ1/hKCNE1 channels; hKir2.1 channels.

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