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

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 mu M) 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 mu M at 0.5 Hz to 1.03, 0.81, 0.61, 0.56 mu M at 1, 2, 5, 10 Hz, respectively. However, the selective TRPC3 antagonist Pyr3 decreased cardiac I (Na) by 8.5 % at 10 mu M 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.