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Suppression of Voltage-Gated L-type Ca2+ Currents by Polyunsaturated Fatty Acids in Adult and Neonatal Rat Ventricular Myocytes

Abstract : Our recent data show that in cardiac myo-cytes polyunsaturated fatty acids (PUFAs) are antiarrhyth-mic. They reduce I Na , 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 Ca 2؉ imaging to examine the effects of PUFAs on the voltage-gated L-type Ca 2؉ current (I Ca,L), elementary sarcoplasmic reticu-lum Ca 2؉-release events (Ca 2؉-sparks), and [Ca 2؉ ] i tran-sients in isolated rat ventricular myocytes. Extracellular application of eicosapentaenoic acid (EPA; C20:5 n ؊ 3) produced a prompt and reversible concentration-dependent suppression of I Ca,L. The concentration of EPA to produce 50% inhibition of I Ca was 0.8 M in neonatal rat heart cells and 2.1 M in adult ventricular myocytes. While the EPA induced suppression of I Ca,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 I Ca,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 I Ca,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 I Ca,L. The saturated stearic acid and the monounsaturated oleic acid had no effect on I Ca,L. Because both I Ca,L and sarcoplasmic reticulum Ca 2؉-release underlie many cardiac arrhythmias, we examined the effects of EPA on I Ca,L and Ca 2؉-sparks. While EPA suppressed both, it did not change the temporal or spatial character of the Ca 2؉-sparks, nor did it alter the ability of I Ca,L to trigger Ca 2؉-sparks. We conclude that PUFAs may act as antiarrhythmic agents in vivo in normal and Ca 2؉-overloaded cells principally because they reduce Ca 2؉ entry by blocking I Ca,L. Furthermore, PUFAs act directly to decrease I Na and I Ca,L , but indirectly to reduce the [Ca 2؉ ] i transients and [Ca 2؉ ] i-activated membrane current. Although a negative inotropic action is associated with application of PUFAs, it is clear that by reducing I Ca,L , I Na and Ca 2؉-sparks, PUFAs can reduce spontaneous extrasystoles in the heart. The mechanisms by which PUFAs act are discussed.
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Xiao Yong-Fu, Ana Maria Gómez, James P Morgan, W. J Lederer, Alexander Leaf. Suppression of Voltage-Gated L-type Ca2+ Currents by Polyunsaturated Fatty Acids in Adult and Neonatal Rat Ventricular Myocytes. Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 1997, 94 (8), pp.4182 - 4187. ⟨10.1073/pnas.94.8.4182⟩. ⟨inserm-02477485⟩



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