Cardiac ischemia causes inhibition of the Na/K ATPase by a labile cytosolic compound whose production is linked to oxidant stress

William Fuller, Vina Parmar, Philip Eaton, James R. Bell, Michael J. Shattock

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    75 Citations (Scopus)

    Abstract

    Objective: Intracellular Na rises rapidly during cardiac ischemia and this has been attributed to the combination of increased influx of Na via sodium–proton exchange and decreased activity of the Na/K ATPase. The aim of these studies was to investigate the effects of ischemia on Na/K ATPase function in Langendorff-perfused rat hearts. Methods: Na/K ATPase activity was determined by measuring ouabain-sensitive phosphate generation from ATP by cardiac homogenates. Results: Global ischemia (15 and 30 min) caused a substantial reduction in Na/K ATPase function despite high substrate availability in the assay. When sarcolemmal membranes were purified away from the cytosol a profound activation of the Na/K ATPase was revealed following ischemia, indicating that the inhibition was due to the cytosolic accumulation of an inhibitor of Na/K ATPase. The half-life of the inhibitor in cardiac homogenates was 10±3 min at room temperature. Perfusion with the antioxidant MPG (1 mmol/l) reduced the accumulation of this inhibitor, however MPG was without effect on Na/K ATPase function when added directly to the Na/K ATPase activity assay. While the inhibitor reduced the activity of cardiac and brain forms of the Na/K ATPase in bioassay experiments, no effect was observed on the renal and skeletal muscle forms of the enzyme. Conclusions: An unstable cardiac and brain-specific inhibitor of the Na/K ATPase whose production is linked to oxidant stress, accumulates intracellularly during ischemia. Intracellular Na is a primary determinant of electro-mechanical recovery on reperfusion, so inhibition of the Na/K ATPase by this compound may be crucial in determining recovery from ischemia.
    Original languageEnglish
    Pages (from-to)1044-1051
    Number of pages8
    JournalCardiovascular Research
    Volume57
    Issue number4
    DOIs
    Publication statusPublished - 2003

    Keywords

    • Ion pumps
    • Ion transport
    • Ischemia
    • Membrane transport
    • Na/K pump

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