Electrophysiological properties of YM‐244769, a new and selective NCX blocker, in heart

Abstract

A selective Na+/Ca2+ exchange (NCX) inhibitor would be very useful for studying both the physiological roles of NCX and a new drug therapy for cardiovascular diseases. In the present study, we examined electrophysiological properties of YM‐244769, a novel benzyloxyphenyl NCX inhibitor, in mammalian heart. NCX currents (INCX) were measured in single cardiac ventricular myocytes of guinea pig by using the whole‐cell voltage‐clamp technique. YM‐244769 suppressed the bi‐directional INCX in a concentration‐dependent manner (0.01–3uM). The IC50 values of YM‐244769 for the bi‐directional outward and inward INCX were both about 0.1uM. YM‐244769 suppressed the uni‐directional outward INCX (Ca2+ entry mode) with the IC50 value of 0.05 uM. In contrast, 10 uM YM‐244769 inhibited it only by about 50%. At 5 mM intracellular Na+ concentration, YM‐244769 suppressed INCX more potentially than it did at 0 mM [Na+]i. Intracellular application of trypsin via the pipette solution did not change the blocking effect of YM‐244769. On the other hand, YM‐244769 (1–10uM) did not affect the other membrane currents; INa, ICa, IK1, ISS, Ito and IOAG. YM‐244769 (0.3–3uM) suppressed hypoxia/reoxygeneration‐induced Ca2+ overload.YM‐244769 inhibits the Ca2+ entry mode of NCX more potently than the Ca2+ exit mode in cardiac myocytes. YM‐244769 is a representative NCX inhibitor against the Ca2+ entry mode.