MITOCHONDRIAL HYPEROXIDATION SIGNALS RESIDUAL INTRACELLULAR DYSFUNCTION AFTER GLOBAL-ISCHEMIA IN RAT NEOCORTEX

Reperfusion after global ischemia (10-60 min in duration) in rat neoco rtex most commonly provoked transient hyperoxidation of mitochondrial electron carriers, tissue hyperoxygenation, and CBF hyperemia. These r esponses were normally accompanied by recovery of K+ homeostasis and E EG spike activity. Goals of this research were to understand putative relationships among these postreperfusion events with special emphasis on determining whether mitochondrial hyperoxidation results from intr acellular changes that may modulate residual damage. The amplitude of postischemic mitochondrial hyperoxidation (PIMHo) did not increase whe n CBF increased above an apparent threshold during reperfusion, and ti ssue hyperoxygenation was not required for PIMHo to occur or to contin ue. These findings suggest that PIMHo is not merely a response to incr eased CBF and tissue hyperoxygenation; rather, PIMHo is modulated, at least in part, by residual intracellular derangements that limit mitoc hondrial electron transport. This suggestion was supported by observat ions that NAD became hyper-oxidized after reoxygenation in anoxic hipp ocampal slices. Also, PIMHo occurred and subsequently resolved in many animals, but K-o(+) never was cleared fully to baseline and/or EEG sp ike activity never was evident. One suggestion is that PIMHo signals o r initiates residual intracellular derangements that in turn impair el ectrical and metabolic recovery of cerebral neurons after ischemia; an alternative suggestion is that PIMHo and tissue hyperoxygenation are not the sole factors modulating the immediate restoration of electrica l activity after ischemia. Present data also support the following: De creased oxygen consumption, despite adequate oxygen delivery, likely c ontributes to tissue hyperoxygenation after ischemia; and mitochondria l hyperoxidation is modulated by a limitation in the supply of electro ns to the mitochondrial respiratory chain.