Pathophysiology of ischemic cell death: I. Time of onset of irreversible damage; importance of the different components of the ischemic insult.

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Abstract
Rabbit retina was used as an example of organized central nervous tissue in in vitro experiments designed to characterize the onset of cell death from ischemia. Retinas were subjected to progressively longer periods of different types of ischemic insult and then given an opportunity to recover before being tested for irreversible damage, using failure to reinstitute protein synthesis as the principal criterion. Anoxia was more damaging than substrate deprivation, but they were synergistic in combination. Restricting the volume of extracellular fluid during the combined deprivation, to simulate complete circulatory arrest in vivo, caused irreversible damage to occur even sooner. The cells were able to recover from 20 min of the complete ischemia, but it took them more than 2 h to do so. After 30 min, there was extensive irreversible damage. Loss of viability was usually associated with failure to reinstitute energy metabolism, as assessed by 2-deoxyglucose uptake. Under some circumstances loss of viability may have been the consequence of the failed energy metabolism. Increasing medium Mg++, prior to ischemia, to levels that greatly reduce energy requirements caused a significant improvement in the recovery of 2-deoxyglucose uptake.