Protein kinase A is activated by the n–3 polyunsaturated fatty acid eicosapentaenoic acid in rat ventricular muscle

• Published in: The Journal of physiology 2007-07, Vol.582 (1), p.349-358
• Main Authors: Szentandrássy, Norbert, Pérez‐Bido, M. R., Alonzo, E., Negretti, N., O'Neill, Stephen C.
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - metabolism; Action Potentials; Animals; Anti-Arrhythmia Agents - metabolism; Anti-Arrhythmia Agents - pharmacology; Calcium Channels, L-Type - metabolism; Calcium Signaling - drug effects; Calcium-Binding Proteins - metabolism; Cardiovascular; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; Cyclic AMP-Dependent Protein Kinases - metabolism; Depression, Chemical; Dose-Response Relationship, Drug; Eicosapentaenoic Acid - metabolism; Eicosapentaenoic Acid - pharmacology; Enzyme Activation; Heart - drug effects; Heart Ventricles - cytology; Heart Ventricles - metabolism; In Vitro Techniques; Isoquinolines - pharmacology; Male; Myocardial Contraction - drug effects; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - enzymology; Myocytes, Cardiac - metabolism; Patch-Clamp Techniques; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Rats; Rats, Wistar; Sulfonamides - pharmacology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2007.132753

During cardiac ischaemia antiarrhythmic n–3 polyunsaturated fatty acids (PUFAs) are released following activation of phospholipase A2, if they are in the diet prior to ischaemia. Here we show a positive lusitropic effect of one such PUFA, eicosapentaenoic acid (EPA) in the antiarrhythmic concentration range in Langendorff hearts and isolated rat ventricular myocytes due to activation of protein kinase A (PKA). Several different approaches indicated activation of PKA by EPA (5–10 μmol l−1): the time constant of decay of the systolic Ca2+ transient decreased to 65.3 ± 5.0% of control, Western blot analysis showed a fourfold increase in phospholamban phosphorylation, and PKA activity increased by 21.0 ± 7.3%. In addition myofilament Ca2+ sensitivity was reduced in EPA; this too may have resulted from PKA activation. We also found that EPA inhibited L‐type Ca2+ current by 38.7 ± 3.9% but this increased to 63.3 ± 3.4% in 10 μmol l−1 H89 (to inhibit PKA), providing further evidence of activation of PKA by EPA. PKA inhibition also prevented the lusitropic effect of EPA on the systolic Ca2+ transient and contraction. Our measurements show, however, PKA activation in EPA cannot be explained by increased cAMP levels and alternative mechanisms for PKA activation are discussed. The combined lusitropic effect and inhibition of contraction by EPA may, respectively, combat diastolic dysfunction in ischaemic cardiac muscle and promote cell survival by preserving ATP. This is a further level of protection for the heart in addition to the well‐documented antiarrhythmic qualities of these fatty acids.