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Protective Effect of Eicosapentaenoic Acid on Ouabain Toxicity in Neonatal Rat Cardiac Myocytes

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Protective Effect of Eicosapentaenoic Acid on Ouabain Toxicity in Neonatal Rat Cardiac Myocytes Proc. Nati. Acad. Sci. USA Vol. 87, pp. 7834-7838, October 1990 Medical Sciences Protective effect of eicosapentaenoic acid on ouabain toxicity in neonatal rat cardiac myocytes (cardiac glycoside toxicity/w-3 fatty acid effect/cytosolic calcium overload/cardiac antiarrhythmic/Na,K-ATPase inhibition) HAIFA HALLAQ*t, ALOIS SELLMAYERt, THOMAS W. SMITH§, AND ALEXANDER LEAF* *Department of Preventive Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114; tInstitut fur Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Universitat Munchen, Pettenkofer Strasse 9, 8000 Munich 2, Federal Republic of Germany; and §Cardiovascular Division, Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02114 Contributed by Alexander Leaf, June 26, 1990 ABSTRACT Isolated neonatal cardiac myocytes have been sarcolemmal membranes of the heart cells. Furthermore, a utilized as a model for the study of cardiac arrhythmogenic prospective randomized clinical trial (7) showed that, among factors. The myocytes respond to the toxic effects of a potent men who had recently suffered a myocardial infarction, those cardiac glycoside, ouabain at 0.1 mM, by an increase in their that were advised to eat fish two or three times a week had spontaneous beating rate and a reduction in amplitude of a 29% reduction in fatal myocardial infarctions over a sub- contractions resulting within minutes in a lethal state of sequent 2-year period compared to those patients not given contracture. Incubating the isolated myocytes for 3-S5 days in such advice. There was, however, no significant difference in culture medium enriched with 5 ,IM arachidonic acid [20:4 cardiac events; those eating fish just did not die as frequently (n-6)] had no effect on the development of lethal contracture of their myocardial infarctions. This result suggests that after subsequent exposure to 0.1 mM ouabain. By contrast, eating fish stabilized the cardiac rhythm, preventing fatal incubating the myocytes for 3-5 days with 5 ,IM eicosapen- ventricular fibrillation from occurring with the ischemic taenoic acid [20:5 (n-3)] completely prevented the toxic effects episode. of ouabain at 0.1 mM. There were no measurable differences This stabilizing effect offish oils on the heart rhythm could in the degree to which ouabain inhibited Na,K-ATPase activity be the result of changes in neurogenic or circulating arrhyth- by comparing the control with the arachidonic acid- or the mogenic factors and their cardiac receptors induced by eicosapentaenoic acid-enriched myocytes. No differences in ischemia or of a direct stabilizing effect of enrichment of bumetanide-inhibitable 86Rb flux were observed between the cardiac cells with fish oil fatty acids that is independent of three preparations. However, measurements with fura-2 of extraneous factors. To distinguish between these possibili- cytosolic free calcium levels indicated that control and arachi- ties, we studied isolated cardiac myocytes from neonatal rats donic acid-enriched myocytes developed toxic cytosolic calcium in vitro, free from circulating agonists. These cells beat concentrations of 845 ± 29 and 757 ± 64 nM, respectively, on spontaneously with a regular rhythm and amplitude of con- exposure to 0.1 mM ouabain, whereas in eicosapentaenoic traction. They maintain their function for several days in acid-enriched myocytes, physiologic calcium levels (214 ± 29 culture medium, which allows time for incorporation of long nM) were preserved. Incubating the myocytes with eicosapen- chain polyunsaturated fatty acids into the phospholipids of taenoic acid (5 ,uM) for 3-5 days resulted in a small reduction their cell membranes. The effects of such membrane modi- of arachidonic acid and a small but significant increase of fications on the function and survival of these cells can be eicosapentaenoic acid in membrane phospholipids of the my- quantitatively assessed. ocytes. We have examined another aspect of stabilization of car- diac myocyte function by (n-3) fatty acids in this preparation, Epidemiologic evidence from the Greenland Eskimos (1, 2) namely, a preventive effect on toxicity from cardiac glyco- and the Japanese (3) has suggested that eating fish and other sides-another arrhythmogenic stress. These neonatal rat marine animals can prevent coronary heart disease. Ingestion cardiac myocytes are sensitive to the effects of the cardiac offish oil affects several humoral and cellular factors that are glycoside ouabain, and at 0.1 mM ouabain the cells go into involved in atherogenesis in a manner that may be expected tetany and die. We report here that incorporating EPA into to prevent atherosclerosis (for review, see ref. 4). The the cell membranes ofthe isolated cardiac myocytes protects evidence suggests that fish oils may exert this beneficial them from the fatal effects of0.1 mM ouabain, at least in part, effect by aborting the cellular pathology of atherosclerosis in by preventing toxic levels of cytosolic calcium from devel- the arterial wall rather than by favorably affecting the plasma oping. lipid levels. The animal studies by McLennan and Charnock (5, 6) have indicated an additional important cardiovascular effect offish MATERIALS AND METHODS oils. They have demonstrated that diets high in saturated fat Tissue Culture. Myocardial cells were isolated from the content increased ventricular arrhythmias induced by tem- hearts of 1-day-old rats by serial trypsin treatment, as de- porary or permanent occlusion of the coronary arteries in scribed by Yagev et al. (8). Myocytes were enriched relative aged rats, whereas dietary vegetable oils diminished ventric- to fibroblasts by preplating. For the measurement of cyto- ular arrhythmias, and fish oil feeding essentially abolished solic free calcium ([Ca2+]1), cells were plated on rectangular fatal arrhythmias during ischemia and reflow. This antiar- glass cover slips. Cells plated on circular cover slips were rhythmic effect of fish oil fatty acids was associated with used for determinations. For measurements of increased amounts ofeicosapentaenoic acid [EPA; 20:5 (n-3)] contractility and especially of docosahexaenoic acid [22:6 (n-3)] in the Abbreviations: A4Ach, arachidonic acid; EPA, eicosapentaenoic acid; [Ca2']j, cytosolic free calcium. The publication costs of this article were defrayed in part by page charge tTo whom reprint requests should be addressed at: Cardiovascular payment. This article must therefore be hereby marked "advertisement" Health Center, Department of Preventive Medicine, Massachusetts in accordance with 18 U.S.C. §1734 solely to indicate this fact. General Hospital, Boston, MA 02114. 7834 Medical Sciences: Hallaq et al. Proc. Natl. Acad. Sci. USA 87 (1990) 7835 ion fluxes, cells were maintained in 35-mm Petri dishes. At radioactivity and for protein content. Bumetanide-sensitive the time of the experiments, the cells were in a confluent Rb+ influx was obtained in the presence of 10 ,uM bumetanide monolayer and exhibited synchronous regular spontaneous to inhibit the Na'-K+-2CI- channels and then by subtracting contractions. Cells were enriched with EPA or arachidonic both the ouabain- and the bumetanide-resistant influx from acid (A4Ach) by adding the free fatty acid at 5 gM to the the ouabain-resistant influx (15). Rb influx is expressed as incubating medium for 3-5 days at 37TC. The incubating nmol per mg of protein per min. medium was Ham's F10 with 20% (vol/vol) fetal horse Na,K-ATPase Activity. The activity of Na,K-ATPase was serum. assayed by the enzyme coupled NADH oxidation method Analysis of Lipids. After 3-5 days of incubation, cells from (16) on a microsomal fraction prepared from cardiac myo- the monolayer were washed three times with isotonic phos- cytes after 3-5 days of incubation in medium without added phate-buffered saline, scraped from the cover glass, and fatty acids or medium enriched with 5 ,uM EPA or 5 ,uM homogenized in 1 ml of ice-cold buffered saline (40C). Lipids A4Ach. Oxidation of NADH was continuously monitored were extracted according to Folch et al. (9) and separated by spectrophotometrically at 340 nm with and without 0.1 mM the method of Kates (10). The fatty acid methyl esters were or 1.0 mM ouabain present, as a measure of the ouabain- separated and quantified by gas chromatography (Hewlett- inhibitable ATP hydrolysis by the Na,K-ATPase. Packard) with a fused silica capillary Supelcowax 10 column Statistical Analyses. All data are expressed as mean + (Supelco). Fatty acids were identified by comparing their SEM. Statistical analysis of comparisons between different retention times on the column with that ofstandards (13:0 and treatment groups was done using Student's t test; P values 25:0 fatty acids) and quantified by using known amounts of <0.05 were considered significant. 23:0 fatty acids as an internal standard that were added at the Materials. 4Ach, EPA, boron trifluoride, methanol, lactic methylation step. dehydrogenase, pyruvate kinase, standard fatty acids, and Measurements of Contractility. Changes in the contractile the sodium salt of NADH, grade III, were purchased from state of individual cells in the monolayer were determined as Sigma. 45CaC12 and 86RbCl were obtained from New England the amplitude of the systolic motion of the cell. This was Nuclear. determined, as was the beating rate, using a phase-contrast microscope and video-motion detector as described (11). A RESULTS glass cover slip with attached cultured myocytes was con- Effects of Enrichment of Membrane Phospholipids with tinuously superfused during contractility measurements with Polyunsaturated Fatty Acids on Beating Rate and Contractil- a Hepes-buffered solution containing 5 mM Hepes, 1 mM ity. Many studies have shown that at concentrations in the CaC12, 5 mM KCI, 140 mM NaCl, 0.05 mM MgCl2, and 1% range of 0.1 mM, ouabain is a cardiac toxin that will induce fetal calf serum. The flow rate was 1 ml/min. After a 10-min arrhythmias and contracture with the heart stopping in sys- equilibration period ouabain was added to 0.1 mM to the tole.
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