Abstract
In C6 glioma cells exposed to chemical hypoxia, an increase of extracellular lactate dehydrogenase (LDH) activity, cell death, and intracellular Ca2+ concentration ([Ca2+]i) occurred. Sodium nitroprusside (SNP), a nitric oxide donor and an iron-containing molecule, reduced chemical hypoxia-induced LDH release and cell death. These effects were counteracted by bepridil and by 5-(N-4-chlorobenzyl)-2',4'-dimethylbenzamil (CB-DMB), two specific inhibitors of the Na+-Ca2+ exchanger. SNP also increased the activity of the Na+-Ca2+ exchanger as a Na+ efflux pathway, stimulated by Na+-free conditions and evaluated by monitoring [Ca2+]i in single cells. In addition, SNP produced a further increase of chemical hypoxia-elicited [Ca2+]i elevation, and this effect was blocked by bepridil. Chemical hypoxia-evoked cell death and LDH release were counteracted by the ferricyanide moiety of the SNP molecule, K3Fe(CN)6, and by ferric chloride (FeCl3), and this effect was counteracted by CB-DMB. In addition, the iron ion chelator deferoxamine reversed the protective effect exerted by SNP on cell injury. Collectively, these findings suggest that the protective effect of SNP on C6 glioma cells exposed to chemical hypoxia is due to the activation of the Na+-Ca2+ exchanger operating as a Na+ efflux-Ca2+ influx pathway induced by iron present in the SNP molecule.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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8-Bromo Cyclic Adenosine Monophosphate / pharmacology
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Amiloride / analogs & derivatives
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Amiloride / pharmacology
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Animals
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Bepridil / pharmacology
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Calcium / metabolism
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Calcium Channel Blockers / pharmacology
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Cell Hypoxia / drug effects
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Cell Survival / drug effects
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Cell Survival / physiology
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Chelating Agents / pharmacology
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Chlorides
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Deferoxamine / pharmacology
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Enzyme Activation / drug effects
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Extracellular Space / metabolism
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Ferric Compounds / pharmacology
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Ferricyanides / pharmacology
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Fluoresceins
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Glioma
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L-Lactate Dehydrogenase / metabolism
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Molsidomine / analogs & derivatives
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Molsidomine / pharmacology
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Nitric Oxide / biosynthesis
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Nitroprusside / pharmacology*
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Sodium / pharmacology
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Sodium Channels / metabolism
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Sodium-Calcium Exchanger / metabolism*
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Staining and Labeling
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Tetrodotoxin / pharmacology
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Tumor Cells, Cultured / chemistry
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / enzymology
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Vasodilator Agents / pharmacology*
Substances
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Calcium Channel Blockers
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Chelating Agents
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Chlorides
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Ferric Compounds
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Ferricyanides
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Fluoresceins
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Sodium Channels
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Sodium-Calcium Exchanger
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Vasodilator Agents
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Nitroprusside
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2',4'-dimethylbenzamil
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8-Bromo Cyclic Adenosine Monophosphate
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Nitric Oxide
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Tetrodotoxin
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linsidomine
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Bepridil
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Amiloride
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Sodium
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Molsidomine
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L-Lactate Dehydrogenase
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Deferoxamine
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Calcium
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ferric chloride
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potassium ferricyanide
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diacetylfluorescein