Calcium overload and cardiac myocyte cell damage induced by arachidonate lipoxygenation.
The accumulation of arachidonic acid and lipoxygenase metabolites of arachidonate occurs in ischemic-reperfused myocardium. Although lipoxygenase inhibitors have been shown to attenuate myocardial infarct size after ischemia-reperfusion, the relationship between arachidonate lipoxygenation and myocardial injury remains unclear. To investigate the direct effect of arachidonate lipoxygenation on cardiac myocytes, isolated rat cardiac myocytes loaded with indo 1 were superfused with Tyrode solution containing arachidonic acid mixed with soybean lipoxygenase. Although neither arachidonic acid nor lipoxygenase alone had any effects, arachidonic acid plus lipoxygenase induced an increase in the twitch amplitude associated with an increased intracellular Ca2+ concentration ([Ca2+]i) and irreversible hypercontracture. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, blocked these effects. Linolenic acid, which is also a lipoxygenase substrate, caused the same effects as arachidonic acid in the presence of lipoxygenase, whereas oleic and stearic acid, which do not function as lipoxygenase substrates, did not. Both ascorbic acid and alpha-tocopherol attenuated an increase in [Ca2+]i and the cellular damage, whereas nicardipine and superoxide dismutase had no effects. These results suggest that lipoxygenase metabolites of arachidonic acid cause intracellular Ca2+ overload and cellular damage to cardiomyocytes, probably through augmentation of lipid peroxidation of the cell membranes by free radicals.
Oe
H
H
First Department of Medicine, Osaka University School of Medicine, Suita, Japan.
Kuzuya
T
T
Hoshida
S
S
Nishida
M
M
Hori
M
M
Kamada
T
T
Tada
M
M
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004558:Electric Stimulation; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006352:Heart Ventricles; D007211:Indoles; D015227:Lipid Peroxidation; D008084:Lipoxygenase / Q000378:metabolism / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013229:Stearic Acids / Q000378:metabolism / Q000494:pharmacology; D017962:alpha-Linolenic Acid / Q000378:metabolism / Q000494:pharmacology
D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D007211:Indoles; D009829:Oleic Acids; D013229:Stearic Acids; D017962:alpha-Linolenic Acid; C059587:Indo-1 pentaacetoxymethyl ester; D016718:Arachidonic Acid; D019301:Oleic Acid; C031183:stearic acid; D008084:Lipoxygenase; D002118:Calcium