Direct protective effects of poly-unsaturated fatty acids, DHA and EPA, against activation of cardiac late sodium current: a mechanism for ischemia selectivity.
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 DeltaKPQ-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 I(Na), acute application of DHA and EPA blocked veratridine-induced late sodium current (late I(Na-Verat)) in a concentration--dependent manner with IC(50) values of 2.1 +/- 0.5 microM and 5.2 +/- 0.8 microM,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 I(Na-KPQ). In addition to their role as blocking agents of peak I(Na), DHA and EPA reduced human late I(Na). These results could explain the antiarrhythmic properties of DHA and EPA during ischemia or following ischemia-reperfusion.
Pignier
Christophe
C
Division des Maladies Cardiovasculaires II, Centre de Recherche Pierre Fabre, Castres cedex, France. christophe.pignier@pierre-fabre.com
Revenaz
Coralie
C
Rauly-Lestienne
Isabelle
I
Cussac
Didier
D
Delhon
André
A
Gardette
Jean
J
Le Grand
Bruno
B
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009124:Muscle Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017202:Myocardial Ischemia / Q000150:complications*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014701:Veratridine / Q000494:pharmacology
D002316:Cardiotonic Agents; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568322:Scn5a protein, rat; D015222:Sodium Channels; D004281:Docosahexaenoic Acids; D014701:Veratridine; D015118:Eicosapentaenoic Acid