Effects of Phenytoin on Primary Glial Cell Cultures

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Abstract
The activity of enzymes involved in anion and cation transport, the concentration of intracellular K (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 [rat] glial cells was determined in the presence of an increasng K+ concentration (1-20 mM). Acutely, PHT had little effect on the K+ activation pattern of Na+,+K+-ATPase. 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 of 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. Apparently, glial cells acutely and chronically treated with therapeutic concentrations of PHT have an enhanced capacity to control elevated extracellular K levels. Return of the Em to control values at PHT concentrations > 10-5 M suggests that these cells are less able to regulate extracellular K. These data can partially explain the excitatory effects of PHT at high therapeutic concentrations.