Changes in microcirculation, the NAD/NADH redox state, and electrical activity during 2 hours of ischemia and 4 hours of reperfusion produced by middle cerebral artery occlusion and release were studied in cats. Twelve animals were classified into three groups of ischemia (mild, moderate, and severe) based on the severity of electrocorticographic (ECoG) depression at the end of the recovery period. Four animals were studied as controls. Occlusion of the middle cerebral artery (MCAO) resulted in a marked but similar degree of reduction in cerebral blood flow (CBF) in all three groups. After this initial change, CBF increased continuously during occlusion in the mild group. CBF in the moderate and severe groups remained at the same low level during the entire period of MCAO. Immediately after MCAO, NAD reduction was increased by approximately 50% in all groups. At the end of MCAO, while the NAD/NADH redox state returned to its pre-ischemic reference level in the severe group, it remained markedly reduced in the mild and moderate groups. Removal of the clip led to slight reactive hyperemia in the mild and severe groups but not in the moderate group. Immediately after recirculation, NAD/NADH redox was shifted toward oxidation in all groups. However, this reoxidation of NADH was only partial in the mild and moderate groups, and a pronounced hyperoxidation occurred in the severe group. In spite of the similar behavior of CBF in the recovery period, a marked secondary NAD reduction occurred in the moderate group during the recirculation period. It is suggested that this represents cessation of mitochondrial electron transport in the dying cells, accompanied by stimulated anaerobic glycolysis in other cells.(ABSTRACT TRUNCATED AT 250 WORDS)