SKF-96365 blocks human ether-à-go-go-related gene potassium channels stably expressed in HEK 293 cells
| Autor: | Gui-Rong Li, Lei Yang, Guo-Sheng Xiao, Yan Wang, Kui-Hao Chen, Man-Wen Jin, Hui Liu, Hai-Ying Sun |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Guinea Pigs hERG Pharmacology QT interval Electrocardiography 03 medical and health sciences Heart Rate Potassium Channel Blockers medicine Animals Humans Repolarization Myocytes Cardiac cardiovascular diseases TRPC biology Chemistry Imidazoles Heart Cardiac action potential Potassium channel blocker Ether-A-Go-Go Potassium Channels Potassium channel HEK293 Cells 030104 developmental biology cardiovascular system biology.protein medicine.drug |
| Zdroj: | Pharmacological Research. 104:61-69 |
| ISSN: | 1043-6618 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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