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Direct and indirect modulation of rat cardiac sarcoplasmic reticulum function by n–3 polyunsaturated fatty acids

Measurements were made of trans‐sarcolemmal Ca2+ fluxes and intracellular [Ca2+]i in rat ventricular myocytes loaded with Indo‐1 to determine how the n‐3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) suppresses spontaneous waves of Ca2+ release. We report that in 10 μm EPA, the Ca2+ efflux generated by individual waves increased by 11.3 ± 4.9 % over control levels. However, wave‐generated efflux per unit time fell overall by 19 ± 5.3 %. On removal of EPA, wave frequency increased transiently such that Ca2+ efflux was greater than normal and the cell lost 28.0 ± 10.6 μmol l−1 Ca2+. This probably represents the loss of extra Ca2+ accumulated by the sarcoplasmic reticulum (SR), while Ca2+ release was inhibited. These results are evidence of inhibition of the SR Ca2+‐release mechanism and reduced availability of Ca2+ to the SR From the relationship between average intracellular Ca2+ and the frequency of spontaneous waves, we have calculated the relative contributions of these different mechanisms to the lower frequency of waves. In EPA, the frequency of spontaneous waves fell by 37.5 ± 8.1 %, the majority of this (29.2 ± 8.8 %) is due to inhibition of the Ca2+‐release mechanism. In EPA, the rate of fall of Ca2+ in the caffeine response (an indicator of surface membrane Ca2+ efflux pathway activity) was not altered. We conclude, therefore, that the lower resting level of Ca2+ observed in EPA is due to a lower influx of Ca2+ across the surface membrane rather than increased activation of efflux pathways. How these effects might contribute to the anti‐arrhythmic actions of EPA is discussed.