BLOCKING EFFECTS OF POLYUNSATURATED FATTY-ACIDS ON NA+ CHANNELS OF NEONATAL RAT VENTRICULAR MYOCYTES

Recent evidence indicates that polyunsaturated long-chain fatty acids (PUFAs) prevent lethal ischemia-induced cardiac arrhythmias in animals and probably in humans, To increase understanding of the mechanism(s) of this phenomenon, the effects of PUFAs on Na+ currents were assessed by the whole-cell patch-clamp technique in cultured neonatal rat ventricular myocytes, Extracellular application of the free 5,8,11,14,17-eicosapentaenoic acid (EPA) produced a concentration-dependent suppression of ventricular, voltage-activated Na+ currents (I-Na) After cardiac myocytes were treated with 5 or 10 mu M EPA, the peak Is, (elicited by a single-step voltage change with pulses from -80 to -30 mV) was decreased by 51% +/- 8% (P < 0.01; n = 10) and 64% +/- 5% (P < 0.001; n = 21), respectively, within 2 min, Likewise, the same concentrations of 4,7,10,16,19-docosahexaenoic acid produced the same inhibition of I-Na. By contrast, 5 and 10 mu M arachidonic acid (AA) caused less inhibition of I-Na, but both n-6 and n-3 PUFAs inhibited I-Na significantly, A monounsaturated fatty acid and a saturated fatty acid did not, After washing out EPA I-Na, returned to the control level. Raising the concentration of EPA to 40 mu M completely blocked I-Na The IC50 of EPA was 4.8 mu M. The inhibition of this Na+ channel was found to be dose and time, but not use dependent. Also, the EPA-induced inhibition of I-Na was voltage dependent, since 10 mu M EPA produced 83% +/- 7% and 29% +/- 5% inhibition of I-Na elicited by pulses from -80 to -30 mV and from -150 to -30 mV, respectively, in single-step voltage changes, A concentration of 10 mu M EPA shifted the steady-state inactivation curve of I-Na by -19 +/- 3 mV (n = 7; P < 0.01), These effects of PUFAs on I-Na may be important for their antiarrhythmic effect in vivo.