Pathophysiology of anoxic depolarization: new findings and a working hypothesis.

Anoxic depolarization has been linked to the generation of hypoxic irreversible damage. Treatments that postpone its occurrence during hypoxia protect against irreversible damage. This work investigates possible mechanisms leading to anoxic depolarization and ways to prevent or delay it. Exogenous creatine (a compound that delays ATP depletion during hypoxia by increasing the intracellular store of phosphocreatine) doubles the latency of anoxic depolarization. Ouabain (100 microM) reproduces in normoxic slices the depolarization of anoxic depolarization and the concurrent changes in [K+]0; thus, failure of (Na+, K+)ATPase (which is likely to occur during hypoxia due to ATP depletion) is sufficient to cause anoxic depolarization. Electrophysiological evidence, however, suggests that failure of this ATPase causes anoxic depolarization through some intermediate event, probably Na(+)-induced cell swelling. In accordance with this hypothesis, increasing extracellular osmolarity with mannitol (25 mM) increases anoxic depolarization latency by approximately 25%. Other possible mechanisms of anoxic depolarization are also discussed.