Inhibitory effect of YM-244769, a novel Na/Ca exchanger inhibitor on Na/Ca exchange current in guinea pig cardiac ventricular myocytes

Recently, YM-244769 (N-(3-aminobenzyl)-6-{4-[(3-fluorobenzyl)oxy]phenoxy} nicotinamide) has been reported as a new potent and selective Na/Ca exchange (NCX) inhibitor by using various cells transfected with NCX using the Ca fluorescent technique. However, the electrophysiological study of YM-244769 on NCX had not been performed in the mammalian heart. We examined the effects of YM-244769 on NCX current (I) in single cardiac ventricular myocytes of guinea pigs by using the whole-cell voltage clamp technique. YM-244769 suppressed the bidirectional I in a concentration-dependent manner. The IC values of YM-244769 for the bidirectional outward and inward I were both about 0.1 μM. YM-244769 suppressed the unidirectional outward I (Ca entry mode) with an IC value of 0.05 μM. The effect on the unidirectional inward I (Ca exit mode) was less potent, with 10 μM of YM-244769 resulting in the inhibition of only about 50 %. At 5 mM intracellular Na concentration, YM-244769 suppressed I more potently than it did at 0 mM [Na]. Intracellular application of trypsin via the pipette solution did not change the blocking effect of YM-244769. In conclusion, YM-244769 inhibits the Ca entry mode of NCX more potently than the Ca exit mode, and inhibition by YM-244769 is [Na]-dependent and trypsin-insensitive. These characteristics are similar to those of other benzyloxyphenyl derivative NCX inhibitors such as KB-R7943, SEA0400, and SN-6. The potency of YM-244769 as an NCX1 inhibitor is higher than those of KB-R7943 and SN-6 and is similar to that of SEA0400.