Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes

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FONTE

The National Academy of Sciences of the USA

RESUMO

Our recent data show that in cardiac myocytes polyunsaturated fatty acids (PUFAs) are antiarrhythmic. They reduce INa, shorten the action potential, shift the threshold for excitation to more positive potentials, and prolong the relative refractory period. In this study we use patch-clamp techniques in whole-cell mode and confocal Ca2+ imaging to examine the effects of PUFAs on the voltage-gated L-type Ca2+ current (ICa,L), elementary sarcoplasmic reticulum Ca2+-release events (Ca2+-sparks), and [Ca2+]i transients in isolated rat ventricular myocytes. Extracellular application of eicosapentaenoic acid (EPA; C20:5 n − 3) produced a prompt and reversible concentration-dependent suppression of ICa,L. The concentration of EPA to produce 50% inhibition of ICa was 0.8 μM in neonatal rat heart cells and 2.1 μM in adult ventricular myocytes. While the EPA induced suppression of ICa,L, it did not significantly alter the shape of the current–voltage relation but did produce a small, but significant, negative shift of the steady-state inactivation curve. The inhibition of ICa,L was voltage- and time-dependent, but not use- or frequency-dependent. Other PUFAs, such as docosahexaenoic acid, arachidonic acid, linolenic acid, linoleic acid, conjugated linoleic acid, and eicosatetraynoic acid had similar effects on ICa,L as EPA. All-trans-retinoic acid, which had been shown to suppress induced arrhythmogenic activity in rat heart cells, also produced a significant inhibition of ICa,L. The saturated stearic acid and the monounsaturated oleic acid had no effect on ICa,L. Because both ICa,L and sarcoplasmic reticulum Ca2+-release underlie many cardiac arrhythmias, we examined the effects of EPA on ICa,L and Ca2+-sparks. While EPA suppressed both, it did not change the temporal or spatial character of the Ca2+-sparks, nor did it alter the ability of ICa,L to trigger Ca2+-sparks. We conclude that PUFAs may act as antiarrhythmic agents in vivo in normal and Ca2+-overloaded cells principally because they reduce Ca2+ entry by blocking ICa,L. Furthermore, PUFAs act directly to decrease INa and ICa,L, but indirectly to reduce the [Ca2+]i transients and [Ca2+]i-activated membrane current. Although a negative inotropic action is associated with application of PUFAs, it is clear that by reducing ICa,L, INa and Ca2+-sparks, PUFAs can reduce spontaneous extrasystoles in the heart. The mechanisms by which PUFAs act are discussed.

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