Effects of phenytoin on primary glial cell cultures

The activity of enzymes involved in anion and cation transport, the concentration of intracellular potassium (K+i), and the transmembrane potential (Em) were determined following acute and chronic exposure of primary astroglial cultures to micromolar concentrations of phenytoin (PHT). Na+, K+-ATPase activity of homogenates of cultured glial cells was determined in the presence of an increasing K+ concentration (1-20 mM). Acutely, PHT had little effect on the K+ activation pattern of Na+, K+-ATPase. In contrast, the percentage of Na+, K+-ATPase activated by elevating the K+ concentration was dose dependently increased by chronic PHT treatment. This effect was accompanied by a marked increase in K+i and a significant membrane hyperpolarization. The acute effect of PHT on the Em was biphasic, characterized by membrane hyperpolarization at concentrations of 10(-6)-10(-5) M; at concentrations between 10(-5) and 10(-4) M, the Em progressively returned to control values. These results suggest that glial cells acutely and chronically treated with therapeutic concentrations of PHT have an enhanced capacity to control elevated extracellular potassium levels. Return of the Em to control values at PHT concentrations greater than 10(-5) M suggests that these cells are less able to regulate extracellular potassium. These data can partially explain the excitatory effects of PHT at high therapeutic concentrations.