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

Abstract

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.

Pro- and antiarrhythmic properties of a diet rich in fish oil

“…Additionally, EPA decreased diastolic Ca 2+ concentrations and imaging of Ca 2+ waves showed that EPA also increased Ca 2+ wave amplitudes and propagation [55]. Increased Ca 2+ wave amplitudes by EPA correlated with enhanced sarcoplasmic reticulum load in rat ventricular myocytes [55][56][57]. It was concluded that ω3-PUFAs reduce sarcoplasmic reticulum Ca 2+ uptake and also inhibit Ca 2 + -release (ryanodine receptors (RyR).…”

“…Acute administration of ω3-PUFAs leads to a decrease in diastolic Ca 2+ concentration in rat ventricular myocytes and in ventricular myocytes isolated from rabbits with heart failure [28,55,57]. Furthermore, EPA reduces spontaneous waves of Ca 2+ -release from the sarcoplasmic reticulum that underlie DAD-related arrhythmias [28,12].…”

Acute Administration of Fish Oil Inhibits Triggered Activity in Isolated Myocytes From Rabbits and Patients With Heart Failure

“…10,13 Reductions in intracellular calcium by 3-PUFAs may be due to block of I Ca,L 10 and/or inhibition of the calcium release channels of the SR, the ryanodine receptors in the SR membrane. 12,13,29 Indeed, acute administration of 3-PUFAs reduced the open probability of the ryanodine receptors in the SR membrane in isolated SR vesicles. 29,30 In our study, similar mechanisms may account for the reduction in diastolic and systolic calcium levels induced by 3-PUFAs.…”

“…However, acute application of 3-PUFAs increased SR calcium content in healthy rat myocytes. 12,13 Further experiments are needed to establish the effect of fish oils on SR calcium content in HF.…”

“…8 -10 A shorter action potential prevents calcium overload and DADs 11 as a result of the longer diastolic interval and increased time for calcium removal. 4 Furthermore, acute application of 3-PUFAs to normal myocytes also decreases calcium transients, inhibits calcium sparks, and reduces spontaneous calcium release from the SR. 10,12,13 We hypothesized that fish oil 3-PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) inhibit DADinduced triggered activity in HF and normalize calcium handling. We used an established arrhythmogenic rabbit model of HF 6,14 to study the effect of acute administration of fish oil on the occurrence of triggered activity, DADs, and calcium aftertransients.…”