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Cardiovascular Research 2003 60(2):337-346; doi:10.1016/S0008-6363(03)00545-5
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

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

J.S Swana, K Dibbb, N Negrettic, S.C O'Neillb and R Sitsapesan*,a

aDepartment of Pharmacology, University of Bristol, Medical School, University Walk, Bristol BS8 1TD, UK
bDepartment of Medicine, University of Manchester, Manchester M13 9PT, UK
cUCV, Ap. Postal 50587, Caracas, Venezuela

*Corresponding author. Tel.: +44-117-928-8675; fax: +44-117-925-0168. Email address: r.sitsapesan{at}bris.ac.uk

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.

KEYWORDS Arrhythmias; Excitation–contraction coupling; Calcium (cellular); Ion channels

Time for primary review 27 days


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