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SKF-96365 strongly inhibits voltage-gated sodium current in rat ventricular myocytes

  • Ion channels, receptors and transporters
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Abstract

SKF-96365 (1-(beta-[3-(4-methoxy-phenyl) propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride) is a general TRPC channel antagonist commonly used to characterize the potential functions of TRPC channels in cardiovascular system. Recent reports showed that SKF-96365 induced a reduction in cardiac conduction. The present study investigates whether the reduced cardiac conduction caused by SKF-96365 is related to the blockade of voltage-gated sodium current (I Na) in rat ventricular myocytes using the whole-cell patch voltage-clamp technique. It was found that SKF-96365 inhibited I Na in rat ventricular myocytes in a concentration-dependent manner. The compound (1 μM) negatively shifted the potential of I Na availability by 9.5 mV, increased the closed-state inactivation of I Na, and slowed the recovery of I Na from inactivation. The inhibition of cardiac I Na by SKF-96365 was use-dependent and frequency-dependent, and the IC50 was decreased from 1.36 μM at 0.5 Hz to 1.03, 0.81, 0.61, 0.56 μM at 1, 2, 5, 10 Hz, respectively. However, the selective TRPC3 antagonist Pyr3 decreased cardiac I Na by 8.5 % at 10 μM with a weak use and frequency dependence. These results demonstrate that the TRPC channel antagonist SKF-96365 strongly blocks cardiac I Na in use-dependent and frequency-dependent manners. Caution should be taken for interpreting the alteration of cardiac electrical activity when SKF-96365 is used in native cells as a TRPC antagonist.

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Acknowledgements

This work was supported in part by a General Research Fund (771712 M) from Research Grant Council of Hong Kong, and a grant from National Natural Science Foundation of China (No. 81273563).

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The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Physiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong, China

    Kui-Hao Chen, Hui Liu, Lei Yang & Gui-Rong Li

  2. Department of Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong, China

    Kui-Hao Chen, Hui Liu & Gui-Rong Li

  3. Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Kui-Hao Chen, Hui Liu & Man-Wen Jin

  4. Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Lei Yang

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  1. Kui-Hao Chen
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Correspondence to Man-Wen Jin or Gui-Rong Li.

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Chen, KH., Liu, H., Yang, L. et al. SKF-96365 strongly inhibits voltage-gated sodium current in rat ventricular myocytes. Pflugers Arch - Eur J Physiol 467, 1227–1236 (2015). https://doi.org/10.1007/s00424-014-1565-4

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