Lactic Acidosis and Recovery of Mitochondrial Function following Forebrain Ischemia in the Rat

Abstract

Summary:The effect of different degrees of lactic aci dosis on the recovery of brain mitochondrial function, measured as respiratory activity in isolated mitochondria or cortical concentrations of labile phosphates and car bohydrate substrates, was studied during 30 min of recir culation following 15 min of near-complete forebrain isch emia in rats. During ischemia, there was a marked de crease in mitochondrial State 3 respiration in vitro and a depletion of energy stores (i,e" phosphocreatine, ATP, glucose, and glycogen) in vivo that was similar in the high-and low-lactate ischemia groups, However, lactate concentrations differed markedly (20 and 10 /-Lmol g-I, respectively). During recirculation, there was a near complete recovery of both respiratory activity in vitroIt is now well established that hyperglycemia ad versely affects revival of cell function following transient brain ischemia, probably by enhancing lactic acidosis at the tissue level (see Myers, 1979; Kalimo et aI. , 198]; Rehncrona et aI., ]98]; Siesjo, 1981; Pulsinelli et aI., 1982;Plum, 1983;Longstreth and Inui, ]984). Some results hint that there is a critical concentration of lactic acid in the IS-to 2S /-Lmol g-1 range (Siesjo, 1981; Plum, ]983; Siesjo and Wieloch, 1984). However, the existence of such a threshold value has not been proven, nor is it known by what mechanisms the lactic acidosis ex erts its harmful effects.Circumstantial evidence exists that failure of mi tochondrial function following long periods of isch emia may be due to excessive lactic acidosis. Thus, such recovery was noted following 30 min of com- 259and adenylate energy charge (EC) in vivo regardless of the differences in lactic acidosis during ischemia. Respi ratory activity and EC were well correlated, The changes in Ca2 + homeostasis during ischemia, an increase in tissue and a decrease in mitochondrial Ca2+ content, were reversed rapidly after ischemia in both high-and low lactate ischemia animals and did not hinder an early re covery of mitochondrial function. It is concluded that lactic acidosis. with lactate levels reaching 20 /-Lmol g-I during IS-min ischemia, does not adversely affect early postischemic recovery of mitochondrial function.

Accumulation of Calcium and Loss of Potassium in the Hippocampus following Transient Cerebral Ischemia: A Proton Microprobe Study

“…Since calcium does not readily pass the blood brain barrier, it is hardly justified to discuss the ini tial shift of calcium from extra-to intracellular fluids in terms of "calcium overload. " This conclu sion is corroborated by results showing that the total tissue calcium content does not rise in the minutes and hours following transient ischemia of a duration that will, at a later stage, cause dense neu ronal necrosis (Dienel, 1984;Hillered et al, 1985;Deshpande et al , 1987).…”

NMR Spectroscopic Investigation of the Recovery of Energy and Acid—Base Homeostasis in the Cat Brain after Prolonged Ischemia

“…Recovery of acid-base and ion homeostasis was observed in both groups of animals, although the extracellular pH decreased by 1 unit near the end of ischemia. Isolated mitochon dria resumed respiratory oxidation after 15 min of complete ischemia when incubated in 10 or 20 mmollL lactate (Hillered et al, 1985). In view of these results, Hillered et al (1985) proposed that acidosis is detrimental to the brain only if the isch emia has lasted for more than 15 min.…”

“…This result supports conclusions drawn from earlier studies that postischemic recovery of metab olism is not determined entirely by the duration of ischemia. Tissue acidosis is among those factors that influ ence postischemic recovery (Siesjo, 1985). In 1976, Myers and Yamaguchi reported that hyperglycemic animals suffer more severe ischemic brain damage than those with low blood glucose levels; the degree and extent of tissue damage was correlated with the content of lactic acid (Myers, 1979).…”

Hyperglycemia Enhances Extracellular Glutamate Accumulation in Rats Subjected to Forebrain Ischemia

“…With this model, hyperglycemia results in such a severe insult that survival is no longer possible, mainly because intractable seizures develop. 6,7 However, the ischemia does not compromise reflow since the bioenergetic state recovers upon reperfusion 16 and capillary patency remains intact. 17 It is thus possible to use the first hour of reperfusion to study events that prime the tissue for seizures and secondary bioenergetic failure.…”