Effects of Tetrodotoxin and Ranolazine on the Late INa of Zebrafish Ventricular Myocytes

The inward Na+ current (INa), generated by the voltage-gated Na+ channels, can be divided into two components: the fast, transient peak current (INa,peak) and the late, non-inactivating current (INa,late). INa,late plays a significant role in pathophysiology of the human heart and is a putative target for cardiovascular drugs. Because zebrafish (Danio rerio) is proposed as a potential model organism for preclinical drug screening, we decided to investigate the presence of INa,late in zebrafish ventricular myocytes. Patch-clamp experiments at +28°C and in an external saline solution containing 60 mM Na+ showed that INa,late exists in zebrafish ventricular myocytes. The density of INa,late was –0.58 ± 0.061 pA pF–1, which was 1.1 ± 0.13 increased by 10 nM Anemonia sulcata toxin 2 (ATX-II), an INa,late inducer, by 131.3 ± 17.5 reduced zebrafish ventricular INa,late and INa,peak with IC50 values of 79 and 151 µM, respectively. INa,late and INa,peak were also inhibited by tetrodotoxin (TTX) with IC50 values of 43 and 9.8 nM, respectively. The density and voltage-dependence of INa,late in zebrafish ventricular myocytes are similar to those of mammalian cardiomyocytes. On the other hand, the INa,late of zebrafish ventricular myocytes is less sensitive to ranolazine than that of mammalian cardiomyocytes, and ranolazine is less selective between INa,peak and INa,late in zebrafish than mammalian cardiomyocytes.