Abnormal activity of the cardiac Na+/Ca2+ exchanger (NCX1) can affect intracellular Ca2+ homeostasis and cause arrhythmias. The n-3 polyunsaturated fatty acids (PUFAs), however, may prevent arrhythmias. To test the effect of PUFAs on the cardiac NCX1 current (I-NCX1), the canine NCX1 cDNA was expressed in human embryonic kidney (HEK293t) cells. The average density Of I-NCX1 I was 10.9 +/- 2.6 pA/pF (n=44) in NCX1-transfected cells and eicosapentaenoic acid (EPA, C20:5n-3) significantly inhibited I-NCX1. The suppression of I-NCX1 by EPA was concentration-dependent with an IC50 of 0.82 +/- 0.27 muM. EPA had a similar effect on outward or inward I-NCX1. Docosahexaenoic acid (DHA, C22:6n-3) and arachidonic acid (AA, C20:4n-6) also significantly inhibited I-NCX1, whereas the saturated fatty acid, stearic acid (SA, C 18:0), did not. Our data demonstrate that the n-3 PUFAs significantly suppress cardiac I-NCX1, which is probably one of their protective effects against lethal arrhythmias. (C) 2004 Elsevier Inc. All rights reserved.