Effects of eicosapentaenoic acid on cardiac SR Ca(2+)-release and ryanodine receptor function.
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 Ca(2+)-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 beta-adrenergic stimulation. We have investigated whether the inhibitory effect of PUFAs on the Ca(2+)-release mechanism is caused by direct inhibition of the SR Ca(2+)-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 Ca(2+)-release while increasing SR Ca(2+) content even when PKA activity is inhibited with H-89. This suggests that the EPA-induced inhibition of SR Ca(2+)-release is not dependent on activation of PKA. Consistent with this, single-channel studies demonstrate that EPA (10-100 microM), 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.
Swan
J S
JS
Department of Pharmacology, University of Bristol, Medical School, University Walk, Bristol BS8 1TD, UK.
Dibb
K
K
Negretti
N
N
O'Neill
S C
SC
Sitsapesan
R
R
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003864:Depression, Chemical; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D011919:Rats, Inbred Strains; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D012756:Sheep; D013449:Sulfonamides
D000889:Anti-Arrhythmia Agents; D007546:Isoquinolines; D019837:Ryanodine Receptor Calcium Release Channel; D013449:Sulfonamides; D015118:Eicosapentaenoic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium