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

• Published in: Pflügers Archiv Vol. 467; no. 6; pp. 1227 - 1236
• Main Authors: Chen, Kui-Hao, Liu, Hui, Yang, Lei, Jin, Man-Wen, Li, Gui-Rong
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2015; Springer Nature B.V
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Calcium Channel Blockers - pharmacology; Cell Biology; Cells, Cultured; Heart Ventricles - cytology; HEK293 Cells; Human Physiology; Humans; Imidazoles - pharmacology; Inhibitory Concentration 50; Ion Channels; Molecular Medicine; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Neurosciences; Pyrazoles - pharmacology; Rats; Receptors; Receptors and Transporters; Sodium Channel Blockers - pharmacology; Voltage-Gated Sodium Channels - metabolism; SKF-96365; Pyr3; Cardiac myocytes; Voltage-gated sodium current
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-014-1565-4

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 IC 50 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.