The exposure of isolated hepatocytes to the redox-cycling quinone menadione caused an early loss of mitochondrial membrane potential, adenosine triphosphate (ATP) depletion, and decreased intracellular pH. These alterations were followed by an increase in intracellular Na+ and, ultimately, cell death. If HCO3- was omitted from the incubation buffer, or the hepatocytes were incubated in an acidic medium (pH 6.5) the accumulation of Na+ was markedly reduced. Inhibition of the Na+/H+ exchanger and of the Na+/HC03- cotransporter by, respectively, amiloride and 4,4′-di-isothiocyano-2,2′-disulfonic acid stilbene (DIDS) suppressed the initial Na+ influx but did not prevent subsequent Na+ accumulation, because amiloride and DIDS inhibited the Na+/K+ pump. The omission of HCO3- from the extracellular medium or the incubation in acidic conditions also prevented menadione toxicity, without interfering with the loss of mitochondrial membrane potential and with ATP depletion. A similar protection was evident when hepatocytes were incubated with menadione in a medium without Na+. The preservation of adequate levels of ATP by supplementing hepatocytes with fructose allowed the initial Na+ load to be recovered and provided partial protection against menadione toxicity. These effects were suppressed if Na+/K+-ATPase was inhibited with ouabain. Taken together, these results indicated that the activation of the Na+/HCO3- cotransporter and of the Na+/K+ exchanger in response to the decrease of intracellular pH stimulated an enhanced influx of Na+. When the activity of the Na+/K+ pump was not able to control Na+ levels because of ATP depletion, such an uncontrolled Na+ influx precipitated irreversible injury and caused hepatocyte death. © 1995.

Carini, R., Bellomo, G., Benedetti, A., Fulceri, R., Gamberucci, A., Parola, M., et al. (1995). Alteration of Na+ homeostasis as a critical step in the development of irreversible hepatocyte injury after adenosine triphosphate depletion. HEPATOLOGY, 21(4), 1089-1098 [10.1016/0270-9139(95)90260-0].

Alteration of Na+ homeostasis as a critical step in the development of irreversible hepatocyte injury after adenosine triphosphate depletion

Benedetti, A.;Fulceri, R.;Gamberucci, A.;
1995-01-01

Abstract

The exposure of isolated hepatocytes to the redox-cycling quinone menadione caused an early loss of mitochondrial membrane potential, adenosine triphosphate (ATP) depletion, and decreased intracellular pH. These alterations were followed by an increase in intracellular Na+ and, ultimately, cell death. If HCO3- was omitted from the incubation buffer, or the hepatocytes were incubated in an acidic medium (pH 6.5) the accumulation of Na+ was markedly reduced. Inhibition of the Na+/H+ exchanger and of the Na+/HC03- cotransporter by, respectively, amiloride and 4,4′-di-isothiocyano-2,2′-disulfonic acid stilbene (DIDS) suppressed the initial Na+ influx but did not prevent subsequent Na+ accumulation, because amiloride and DIDS inhibited the Na+/K+ pump. The omission of HCO3- from the extracellular medium or the incubation in acidic conditions also prevented menadione toxicity, without interfering with the loss of mitochondrial membrane potential and with ATP depletion. A similar protection was evident when hepatocytes were incubated with menadione in a medium without Na+. The preservation of adequate levels of ATP by supplementing hepatocytes with fructose allowed the initial Na+ load to be recovered and provided partial protection against menadione toxicity. These effects were suppressed if Na+/K+-ATPase was inhibited with ouabain. Taken together, these results indicated that the activation of the Na+/HCO3- cotransporter and of the Na+/K+ exchanger in response to the decrease of intracellular pH stimulated an enhanced influx of Na+. When the activity of the Na+/K+ pump was not able to control Na+ levels because of ATP depletion, such an uncontrolled Na+ influx precipitated irreversible injury and caused hepatocyte death. © 1995.
Carini, R., Bellomo, G., Benedetti, A., Fulceri, R., Gamberucci, A., Parola, M., et al. (1995). Alteration of Na+ homeostasis as a critical step in the development of irreversible hepatocyte injury after adenosine triphosphate depletion. HEPATOLOGY, 21(4), 1089-1098 [10.1016/0270-9139(95)90260-0].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/28279
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