Direct protective effects of poly-unsaturated fatty acids, DHA and EPA, against activation of cardiac late sodium current: A mechanism for ischemia selectivity

Abstract

Polyunsaturated fatty acids (PUFAs) such as docosahexaenoic and eicosapentaenoic acids (DHA, EPA) exert ischemic anti-arrhythmic effects. However, their mechanism of action remains unknown. The present study was designed to investigate their potential effect on the regulation of the late sodium current as the basis for their ischemic anti-arrhythmic activity. Human isoforms of wild-type SCN5A and ΔKPQ-mutated cardiac sodium channels were stably transfected in HEK 293 cells and, the resulting currents were recorded using the patch clamp technique in whole cell configuration. In addition to their effect to inhibit peak INa, acute application of DHA and EPA blocked veratridine-induced late sodium current (late INa-Verat) in a concentration - dependent manner with IC50 values of 2.1 ± 0.5 μM and 5.2 ± 0.8 μM,for DHA and EPA, respectively.Channels availability was reduced, resulting in a significant leftward shift of the steadystate inactivation curve by -10.0 ± 2.1 mV and -8.5 ± 0.2 mV for DHA and EPA, respectively. Similar inhibitory effects of DHA and EPA were also observed on late INa-KPQ. In addition to their role as blocking agents of peak INa, DHA and EPA reduced human late INa. These results could explain the antiarrhythmic properties of DHA and EPA during ischemia or following ischemia-reperfusion. © Steinkopff-Verlag 2007.