BACKGROUND & AIMS Oxidative stress leads to a rapid initial loss of liver cell volume, but the adaptive mechanisms that serve to restore volume have not been defined. This study aimed to evaluate the functional interactions between oxidative stress, cell volume recovery, and membrane ion permeability. METHODS In HTC rat hepatoma cells, oxidative stress was produced by exposure to H(2)O(2) or D-alanine plus D-amino acid oxidase (40 U/mL). RESULTS Oxidative stress resulted in a rapid decrease in relative cell volume to 0.85 +/- 0.06. This was followed by an approximately 100-fold increase in membrane cation permeability and partial volume recovery to 0.97 +/- 0.05 of original values. The volume-sensitive conductance was permeable to Na(+) approximately K(+) >> Tris(+), and whole-cell current density at -80 mV increased from -1.2 pA/pF at 10(-5) mol/L H(2)O(2) to -95.1 pA/pF at 10(-2) mol/L H(2)O(2). The effects of H(2)O(2) were completely inhibited by dialysis of the cell interior with reduced glutathione, and were markedly enhanced by inhibition of glutathione synthase. CONCLUSIONS These findings support the presence of dynamic functional interactions between cell volume, oxidative stress, and membrane Na(+) permeability. Stress-induced Na(+) influx may represent a beneficial adaptive response that partially restores cell volume over short periods, but sustained cation influx could contribute to the increase in intracellular [Na(+)] and [Ca(2+)] associated with cell injury and necrosis.