Characterization of SN-6, a novel Na+/Ca2+ exchange inhibitor in guinea pig cardiac ventricular myocytes

We examined the effect of SN-6, a new benzyloxyphenyl Na+/Ca2+ exchange (NCX) inhibitor on the Na+/Ca2+ exchange current (INCX) and other membrane currents in isolated guinea pig ventricular myocytes using the whole-cell voltage-clamp technique. SN-6 suppressed INCX in a concentration-dependent manner. The IC50 values of SN-6 were 2.3 μM and 1.9 μM for the outward and inward components of the bi-directional INCX, respectively. On the other hand, SN-6 suppressed the outward uni-directional INCX more potently (IC50 value of 0.6 μM) than the inward uni-directional INCX. SN-6 at 10 μM inhibited the uni-directional inward INCX by only 22.4 ± 3.1%. SN-6 and KB-R7943 suppressed INCX more potently when intracellular Na+ concentration was higher. Thus, both drugs inhibit NCX in an intracellular Na+ concentration-dependent manner. Intracellular application of trypsin via a pipette solution did not change the blocking effect of SN-6 on INCX. Therefore, SN-6 is categorized as an intracellular-trypsin-insensitive NCX inhibitor. SN-6 at 10 μM inhibited INa, ICa, IK and IK1 by about 13%, 34%, 33% and 13%, respectively. SN-6 at 10 μM shortened the action potential duration at 50% repolarization (APD50) by about 34%, and that at 90% repolarization (APD90) by about 25%. These results indicate that SN-6 inhibits NCX in a similar manner to that of KB-R7943. However, SN-6 at 10 μM affected other membrane currents less potently than KB-R7943.