Intracellular Na+ inhibits volume-regulated anion channel in rat cortical astrocytes

Accumulating evidence indicates that increased intracellular Na+ concentration ([Na+]i) in astroglial cells is associated with the development of brain edema under ischemic conditions, but the underlying mechanisms are still elusive. Here, we report that in primary cultured rat cortical astrocytes, elevations of [Na+]i reflecting those achieved during ischemia cause a marked decrease in hypotonicity-evoked current mediated by volume-regulated anion channel (VRAC). Pharmacological manipulations revealed that VRAC inhibition was not due to the reverse mode of the plasma membrane sodium/calcium exchanger. The negative modulation of VRAC was also observed in an astrocytic cell line lacking the predominant astrocyte water channel aquaporin 4, indicating that [Na+]i effect was not mediated by the regulation of aquaporin 4 activity. The inward rectifier Cl- current, which is also expressed by cultured astrocytes, was not affected by [Na+]i increase. VRAC depression by high [Na+]i was confirmed in adult astrocytes, suggesting that it was not developmentally regulated. Altogether, these results provide the first evidence that intracellular Na+ dynamics can modulate astrocytic membrane conductance that controls functional processes linked to cell volume regulation and add further support to the concept that limiting astrocyte intracellular Na+ accumulation might be a favorable strategy to counteract the development of brain edema.