Early physiological events induced by hypoxia plus low D-glucose were investigated by intracellular recording in the rat hippocampal slice. A rapid intracellular depolarization corresponded to the extracellularly recorded anoxic depolarization. This intracellular depolarization consisted of two pharmacologically distinct components, an initial depolarization and a persistent depolarization. The persistent phase of depolarization was selectively blocked by lowering calcium and raising magnesium and by N-methyl-D-aspartate (NMDA) antagonists. This persistent depolarization can account for the long-term synaptic failure seen following experimental ischemia in vitro.