Studies have shown that fish oils, containing n-3 fatty acids, have protective effects against ischemiainduced, fatal cardiac arrhythmias in animals and perhaps in humans. In this study we used the whole-cell voltage-clamp technique to assess the effects of dietary, free long-chain fatty acids on the Na ؉ current (I Na,␣ ) in human embryonic kidney (HEK293t) cells transfected with the ␣-subunit of the human cardiac Na ؉ channel (hH1 ␣ ). Extracellular application of 0.01 to 30 M eicosapentaenoic acid (EPA, C20:5n-3) significantly reduced I Na,␣ with an IC 50 of 0.51 ؎ 0.06 M. The EPAinduced suppression of I Na,␣ was concentration-and voltagedependent. EPA at 5 M significantly shifted the steady-state inactivation relationship by ؊27.8 ؎ 1.2 mV (n ‫؍‬ 6, P < 0.0001) at the V 1/2 point. In addition, EPA blocked I Na,␣ with a higher ''binding affinity'' to hH1 ␣ channels in the inactivated state than in the resting state. The transition from the resting state to the inactivated state was markedly accelerated in the presence of 5 M EPA. The time for 50% recovery from the inactivation state was significantly slower in the presence of 5 M EPA, from 2.1 ؎ 0.8 ms for control to 34.8 ؎ 2.1 ms (n ‫؍‬ 5, P < 0.001). The effects of EPA on I Na,␣ were reversible. Furthermore, docosahexaenoic acid (C22:6n-3), ␣-linolenic acid (C18:3n-3), conjugated linoleic acid (C18:2n-7), and oleic acid (C18:1n-9) at 5 M and all-trans-retinoic acid at 10 M had similar effects on I Na,␣ as EPA. Even 5 M of stearic acid (C18:0) or palmitic acid (C16:0) also significantly inhibited I Na,␣ . In contrast, 5 M EPA ethyl ester did not alter I Na,␣ (8 ؎ 4%, n ‫؍‬ 8, P > 0.05). The present data demonstrate that free fatty acids suppress I Na,␣ with high ''binding affinity'' to hH1 ␣ channels in the inactivated state and prolong the duration of recovery from inactivation.Dietary long chain polyunsaturated fatty acids (PUFAs) are able to prevent ischemia-induced fatal arrhythmias in animals (1-4) and probably in humans (5-7). Their antiarrhythmic actions have been demonstrated in cultured cardiac myocyte preparations in the absence of neuronal or humoral influences (8) and have been shown to result from a stabilizing effect of the PUFAs on the electrophysiology of each individual myocyte (9). The electrophysiologic effects of the PUFAs in turn are caused by their modulation of several ion currents through the plasma membrane of the cardiomyocytes (10-12). One of the ion currents affected by the PUFAs is the voltagedependent, fast sodium current, I Na (10), which is responsible for initiating the action potential in cells of excitable tissues. Thus the effects of the PUFAs on I Na must constitute an important factor in the ability of the PUFAs to prevent or terminate fatal cardiac arrhythmias.We have used whole-cell voltage-clamp studies on cultured neonatal rat cardiomyocytes to examine the effects of the PUFAs on I Na and have found that in their free fatty acid form they rapidly and strongly suppress I Na and prolong the duration of the inac...

Cocaine and lidocaine are local anesthetics (LAs) that block Na currents in excitable tissues. Cocaine is also a cardiotoxic agent and can induce cardiac arrhythmia and ventricular fibrillation. Lidocaine is commonly used as a postinfarction antiarrhythmic agent. These LAs exert clinically relevant effects at concentrations that do not obviously affect the normal function of either nerve or skeletal muscle. We compared the cocaine and lidocaine affinities of human cardiac (hH1) and rat skeletal (mu 1) muscle Na channels that were transiently expressed in HEK 293t cells. The affinities of resting mu 1 and hH1 channels were similar for cocaine (269 and 235 microM, respectively) and for lidocaine (491 and 440 microM, respectively). In addition, the affinities of inactivated mu 1 and hH1 channels were also similar for cocaine (12 and 10 microM, respectively) and for lidocaine (19 and 12 microM, respectively). In contrast to previous studies, our results indicate that the greater sensitivity of cardiac tissue to cocaine or lidocaine is not due to a higher affinity of the LA receptor in cardiac Na channels, but that at physiological resting potentials (-100 to -90 mV), a greater percentage of hH1 channels than mu 1 channels are in the inactivated (i.e., high-affinity) state.