© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Cardiac ischemia causes inhibition of the Na/K ATPase by a labile cytosolic compound whose production is linked to oxidant stress
Cardiac Physiology, Centre for Cardiovascular Biology and Medicine, King's College London, The Rayne Institute, St. Thomas’ Hospital, London SE1 7EH, UK
* Corresponding author. Tel.: +44-20-7928-9292x3376; fax: +44-20-7928-0658. michael.shattock{at}kcl.ac.uk
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.
KEYWORDS HRP, horseradish peroxidase; MPG, mercaptopropionylglycine; PAGE, polyacrylamide gel electrophoresis; PMSF, phenylmethylsulfonyl fluoride; SDS, sodium dodecylsulfate; SLP, sarcolemma/particulate fraction
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