Role of intracellular acidosis during incomplete cerebral ischemia

In vivo acid challenges were used to exacerbate the drop in intracellular pH (pH{dollar}sb{lcub}rm i{rcub}{dollar}) that ordinarily occurs during cerebral ischemia and to distinguish the roles of intracellular acidosis and decreased intracellular bicarbonate ( (HCO{dollar}sb3sp{lcub}-{rcub}{dollar}) {dollar}sb{lcub}rm i{rcub}{dollar}) in ischemic injury. The effects of (1) 12 vs 30 min ischemic durations, (2) hyperglycemia (glucose {dollar}simeq{dollar} 400 mg/dl) and (3) hypercapnia (arterial PCO{dollar}sb2{dollar} {dollar}simeq{dollar} 450 mmHg) were studied during incomplete ischemia produced by intracranial pressure elevation in anesthetized dogs. Recovery of high energy phosphates and pH{dollar}sb{lcub}rm i{rcub}{dollar} were measured over 4 hours of reperfusion with {dollar}sp{lcub}31{rcub}{dollar}P magnetic resonance spectroscopy. Electrophysiological recovery was determined by measuring somatosensory evoked potentials (SEP) and electroencephalogram (EEG). Cerebral blood flow (CBF), as measured by radiolabelled microspheres, was reduced during ischemia to {dollar}simeq{dollar} ml/min/100g in all groups.; Ischemic pH{dollar}sb{lcub}rm i{rcub}{dollar} fell to 6.41 {dollar}pm{dollar} 0.17 after 12 min ischemia (n = 5) and to 6.18 {dollar}pm{dollar} 0.09 after 30 min (n = 6) in normoglycemic animals. The rate of pH{dollar}sb{lcub}rm i{rcub}{dollar} and high energy phosphate recovery and the reappearance of the SEP was slowed after prolonged normoglycemic ischemia, and steady state ATP recovery was less complete (12 Min = 100 {dollar}pm{dollar} 5% 30 Min = 84 {dollar}pm{dollar} 4% of control).; End-ischemic pH{dollar}sb{lcub}rm i{rcub}{dollar} was similar after 12 min normoglycemic and hyperglycemic ischemia (6.30 {dollar}pm{dollar} 0.17, n = 5). Recovery of pH{dollar}sb{lcub}rm i{rcub}{dollar} occurred by 8 and 12 min reperfusion in the respective groups, and metabolic recovery was complete in both groups. CBF recovery was not different between groups. These experiments demonstrated that recovery is not affects by ischemic hyperglycemia when the ischemic fall in pH{dollar}sb{lcub}rm i{rcub}{dollar} is not severe, and pH{dollar}sb{lcub}rm i{rcub}{dollar} and (HCO{dollar}sb3sp{lcub}-{rcub}{dollar}) {dollar}sb{lcub}rm i{rcub}{dollar} are rapidly restored. In contrast, 30 Min hyperglycemic ischemia can produce irreversible injury. A subgroup of hyperglycemic animals (n = 4 out of 7, Cerebral Deaths) exhibited incomplete pH{dollar}sb{lcub}rm i{rcub}{dollar} and (HCO{dollar}sb3sp{lcub}-{rcub}{dollar}) {dollar}sb{lcub}rm i{rcub}{dollar} recovery, a secondary decay in high energy phosphate levels and progressive loss of CBF. The major difference in these animals was the severity of the fall in ischemic pH{dollar}sb{lcub}rm i{rcub}{dollar} (5.27 {dollar}pm{dollar}.08) to within a range known to cause direct neuronal injury in vitro. Hypercapnia produced a severe fall in pH{dollar}sb{lcub}rm i{rcub}{dollar} (5.72 {dollar}pm{dollar}.09) by the end-ischemia (30 Min, n = 7), yet (HCO{dollar}sb3sp{lcub}-{rcub}{dollar}) {dollar}sb{lcub}rm i{rcub}{dollar} was partly conserved (6.0 {dollar}pm{dollar} 1.2mM). Recovery time of pH{dollar}sb{lcub}rm i{rcub}{dollar} and (HCO{dollar}sb3sp{lcub}-{rcub}{dollar}) {dollar}sb{lcub}rm i{rcub}{dollar} were 14 and 10 minutes, respectively. Rapid, complete metabolic recovery and reappearance of the SEP was observed in all animals. The end-ischemia pH{dollar}sb{lcub}rm i{rcub}{dollar} did not explain the different recovery patterns. The major difference between hypercapnic animals and the Cerebral Death was the relative conservation of (HCO{dollar}sb3sp{lcub}-{rcub}{dollar}) {dollar}sb{lcub}rm i{rcub}{dollar} during ischemia and prompt (HCO{dollar}sb3sp{lcub}-{rcub}{dollar}) {dollar}sb{lcub}rm i{rcub}{dollar} recovery. This study demonstrated that severe intracellular acidosis itself does not produce irreversible injury. Conservation of (HC...