title: SKF-96365 strongly inhibits voltage-gated sodium current in rat ventricular myocytes.
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.
authors.affiliation: Department of Physiology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Laboratory Block, 21 Sassoon Road, Pokfulam, Hong Kong, China.
authors.forename: Kui-Hao
authors.initials: KH
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.forename: Man-Wen
authors.initials: MW
authors.lastname: Jin
authors.forename: Gui-Rong
authors.initials: GR
authors.lastname: Li
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002478:Cells, Cultured; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000166:cytology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D007093:Imidazoles; D011720:Pyrazoles; D026941:Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; C559943:ethyl-1-(4-(2*3*3-trichloroacrylamide)phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole