Effects of eicosapentaenoic acid on cardiac SR Ca2+-release and ryanodine receptor function

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Abstract

n-3 polyunsaturated fatty acids (PUFAs) can prevent life-threatening arrhythmias but the mechanisms responsible have not been established. There is strong evidence that part of the antiarrhythmic action of PUFAs is mediated through inhibition of the Ca2+-release mechanism of the sarcoplasmic reticulum (SR). It has also been shown that PUFAs activate protein kinase A (PKA) and produce effects in the cardiac cell similar to β-adrenergic stimulation. We have investigated whether the inhibitory effect of PUFAs on the Ca2+-release mechanism is caused by direct inhibition of the SR Ca2+-release channel/ryanodine receptor (RyR) or requires activation of PKA. Experiments in intact cells under voltage-clamp show that the n-3 PUFA eicosapentaenoic acid (EPA) is able to reduce the frequency of spontaneous waves of Ca2+-release while increasing SR Ca2+ content even when PKA activity is inhibited with H-89. This suggests that the EPA-induced inhibition of SR Ca2+-release is not dependent on activation of PKA. Consistent with this, single-channel studies demonstrate that EPA (10-100 μM), but not saturated fatty acids, reduce the open probability (Po) of the cardiac RyR incorporated into phospholipid bilayers. EPA also inhibited the binding of [3H]ryanodine to isolated heavy SR. Our results indicate that direct inhibition of RyR channel gating by PUFAs play an important role in the overall antiarrhythmic properties of these compounds. © 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

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Swan, J. S., Dibb, K., Negretti, N., O’Neill, S. C., & Sitsapesan, R. (2003). Effects of eicosapentaenoic acid on cardiac SR Ca2+-release and ryanodine receptor function. Cardiovascular Research, 60(2), 337–346. https://doi.org/10.1016/S0008-6363(03)00545-5

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