Differential fall in ATP accounts for effects of temperature on hypoxic damage in rat hippocampal slices

Intracellular recordings, ATP and cytosolic calcium measurements from CA1 p yramidal cells in rat hippocampal slices were used to examine the mechanism s by which temperature alters hypoxic damage. Hypothermia (34 degrees C) pr eserved ATP (1.7 vs. 0.8 nM/mg) and improved electrophysiologic recovery of the CA1 neurons after hypoxia; 58% of the neurons subjected to 10 min of h ypoxia (34 degrees C) recovered their resting and action potentials, while none of the neurons at 37 degrees C recovered. Increasing the glucose conce ntration from 4 to 6 mM during normothermic hypoxia improved ATP (1.3 vs. 0 .8 nM/mg) and mimicked the effects of hypothermia; 67% of the neurons recov ered their resting and action potentials. Hypothermia attenuated the membra ne potential changes and the increase in intracellular Ca2+ (212 vs. 384 nM ) induced by hypoxia. Changing the glucose concentration in the artificial cerebrospinal fluid primarily affects ATP levels during hypoxia. Decreasing the glucose concentration from 4 to 2 mM during hypothermic hypoxia worsen ed ATP, cytosolic Ca2+, and electrophysiologic recovery. Ten percent of the neurons subjected to 4 min of hypoxia at 40 degrees C recovered their rest ing and action potentials; this compared with 60% of the neurons subjected to 4 min of normothermic hypoxia. None of the neurons subjected to 10 min o f hypoxia at 40 degrees C recovered their resting and action potentials. Hy perthermia (40 degrees C) worsens the electrophysiologic changes and induce d a greater increase in intracellular Ca2+ (538 vs. 384 nM) during hypoxia. Increasing the glucose concentration from 4 to 8 mM during 10 min of hyper thermic hypoxia improved ATP (1.4 vs. 0.6 nM/mg), Ca2+ (267 vs. 538 nM), an d electrophysiologic recovery (90 vs. 0%). Our results indicate that the ch anges in electrophysiologic recovery with temperature are primarily due to changes in ATP and that the changes in depolarization and Ca2+ are secondar y to these ATP changes. Both primary and secondary changes are important fo r explaining the improved electrophysiologic recovery with hypothermia.