Mechanism of the increase in intracellular sodium during metabolic inhibition: Direct evidence against mediation by voltage-dependent sodium channels

Rafael Mejía-Alvarez, Eduardo Marban

Research output: Contribution to journalArticle

Abstract

During ischemia or metabolic inhibition, intracellular Na+ concentration ([Na+]i) increases considerably. Elevation of [Na+]i figures critically in the mechanism of cellular injury by promoting Ca2+ influx via the Na+Ca2+ exchanger, but the exact mechanism of this intracellular Na+ accumulation remains unknown. To test directly the hypothesis that voltage-dependent Na+ channels are involved, we measured Na+ currents (INa) in isolated guinea-pig ventricular myocytes using the patch-clamp technique. The cell-attached configuration was used in order to avoid disturbing the intracellular milieu. Metabolic inhibition was induced by exposing the cells to either iodoacetate (IAA, 1 mm) to inhibit glycolysis or 2,4-dinitrophenol (DNP, 0.2 mm) to uncouple oxidative phosphorylation. The amplitude of INa was measured in multichannel patches before and during exposure to IAA or DNP, by depolarizing the cell to different membrane potentials from a holding potential of -135 mV. Analysis of current-voltage relations before and during metabolic inhibition revealed a modest but significant reduction of peak INa at test potentials positive to -40 mV with DNP; no change was observed with IAA. The voltage dependence of steady-state parameters of inactivation was not altered by either intervention; specifically, no steady-state ("window") current was induced. Although we cannot exclude the possibility that other factors not explored here might lead to different conclusions during genuine ischemia, metabolic inhibition alone does not up-regulate the function of Na+ channels. Thus, we conclude that other mechanisms underlie the accumulation of intracellular Na+ observed during metabolic inhibition.

Original languageEnglish (US)
Pages (from-to)1307-1320
Number of pages14
JournalJournal of Molecular and Cellular Cardiology
Volume24
Issue number11
DOIs
StatePublished - 1992

Keywords

  • Glycolysis
  • Oxidative phosphorylation
  • Patch-clamp
  • Sodium current
  • Ventricular myocytes

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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