Role of Na+/Ca2+ exchanger in preventing Na+ overload and hepatocyte injury: opposite effects of extracellular and intracellular Ca2+ chelation

Biochem Biophys Res Commun. 1997 Mar 6;232(1):107-10. doi: 10.1006/bbrc.1997.6227.


We have previously shown that an increase of intracellular Na+ occurs in isolated rat hepatocytes undergoing ATP depletion and that Na+ accumulation is associated with an uncontrolled influx of Ca2+ through the activation in reverse mode of the Na+/Ca2+ exchanger. In the present study we have investigated the relationship between alterations of Na+ and Ca2+ homeostasis and hepatocyte killing using treatments which differentially chelate extracellular or intracellular Ca2+. Chelation of extracellular Ca2+ by ethylene glycol bis-(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) potentiated Na+ overload and cell killing induced in isolated rat hepatocytes by hypoxia or menadione. Similar effects were also observed when Na+ accumulation was induced by the combined addition of Na+ ionophore monensin and the inhibition of plasma membrane Na+/K+ ATPase by ouabain. Conversely, the use of the intracellular Ca2+ chelator EGTA acetoxymethyl ester (EGTA/AM) reduced Na+ overload and hepatocyte death induced by hypoxia or cell treatment with menadione or monensin plus ouabain. The effects of EGTA/AM were reverted in the presence of bepridil, an inhibitor of Na+/Ca2+ exchanger. Altogether these results indicated that differential chelation of intracellular or extracellular Ca2+ influences in opposite ways hepatocyte killing due to ATP depletion by modulating intracellular Na+ levels through the reversed activity of the Na+/Ca2+ exchanger.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Carrier Proteins / metabolism*
  • Chelating Agents
  • Extracellular Space
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Rats
  • Rats, Wistar
  • Sodium / metabolism*
  • Sodium-Calcium Exchanger


  • Carrier Proteins
  • Chelating Agents
  • Sodium-Calcium Exchanger
  • Sodium
  • Calcium