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 (I-NCX) and other membrane currents in isolated guinea pig ventricular myocytes using the whole-cell voltage-clamp technique. SN-6 suppressed I-NCX in a concentration-dependent manner. The IC50 values of SN-6 were 2.3 mu M and 1.9 mu M for the outward and inward components of the bi-directional I-NCX, respectively. On the other hand, SN-6 suppressed the outward uni-directional I-NCX more potently (IC50 value of 0.6 mu M) than the inward uni-directional I-NCX. SN-6 at 10 mu M inhibited the uni-directional inward I-NCX by only 22.4 +/- 3.1%. SN-6 and KB-R7943 suppressed I-NCX 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 I-NCX. Therefore, SN-6 is categorized as an intracellular-trypsin-insensitive NCX inhibitor. SN-6 at 10 mu M inhibited I-Na, I-Ca, I-K and I-KI by about 13%, 34%, 33% and 13%, respectively. SN-6 at 10 mu M shortened the action potential duration at 50% repolarization (APD(50)) by about 34%, and that at 90% repolarization (APD(90)) 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 mu M affected other membrane currents less potently than KB-R7943. (c) 2007 Elsevier B.V. All rights reserved.