Modulation of dihydropyridine-sensitive calcium channels in heart cells by fish oil fatty acids.
The highly unsaturated n-3 fatty acids from fish oils, eicosapentaenoic acid [EPA; C20:5 (n-3)] and docosahexanoic acid [DHA; C22:6 (n-3)], prevent the toxicity of high concentrations of the cardiac glycoside ouabain to isolated neonatal rat cardiac myocytes. Arachidonic acid [C20:4 (n-6)] lacks such protective action. The protective effect of the n-3 fatty acids is associated with their ability to prevent high levels of cytosolic free calcium from occurring in response to the ouabain. This in turn results, at least in part, from a 30% reduction in calcium influx rate induced by the n-3 fatty acids. This protective effect is simulated by nitrendipine, a dihydropyridine inhibitor of the L-type calcium channels in cardiac myocytes. Nitrendipine (0.1 mM) alone, however, inhibits myocyte contractility, as do verapamil (10 microM) and diltiazem (1.0 microM). EPA or DHA (5 microM) blocks the inhibitory effects of nitrendipine but not those of verapamil or diltiazem. Bay K8644, a known dihydropyridine agonist of L-type calcium channels, produces a ouabain-like effect that is also prevented by EPA or DHA. Specific binding of [3H]nitrendipine to intact myocytes is noncompetitively inhibited by EPA or DHA in a manner that reduces the number of high- and low-affinity binding sites (Bmax) and increases their affinities. The fish oil fatty acids prevent calcium overload from ouabain and Bay K8644. They also prevent a calcium-depleted state in the myocytes caused by the L-type calcium channel blocker nitrendipine. The protective effects of the n-3 fatty acids appear to result from their modulatory effects on nitrendipine-sensitive L-type calcium channels.
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Department of Medicine, Massachusetts General Hospital, Boston 02114.
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D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005395:Fish Oils / Q000494:pharmacology*; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects; D009568:Nitrendipine / Q000378:metabolism / Q000494:pharmacology; D010042:Ouabain / Q000633:toxicity; D051381:Rats; D014700:Verapamil / Q000494:pharmacology
D015220:Calcium Channels; D004095:Dihydropyridines; D005231:Fatty Acids, Unsaturated; D005395:Fish Oils; D010042:Ouabain; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009568:Nitrendipine; D014700:Verapamil; D002118:Calcium