Relationship between plasma glucose, brain lactate, and intracellular pH during cerebral ischemia in gerbils.

Abstract

The dose-response relation between plasma glucose and brain lactate and the relation of these parameters to intracellular pH during severe cerebral ischemia have not been well characterized over a wide range of plasma glucose levels. Experiments to delineate these relations in the gerbil model of global ischemia were performed by using phosphorus-31 nuclear magnetic resonance spectroscopy to measure intracellular pH and a new method to measure brain lactate. Ischemia increased final brain lactate linearly 4 /tmol/g for every 100 mg/dl increase in plasma glucose up to 650 mg/dl (p=0.0001, ^=0.9); beyond 650 mg/dl, saturation of the glucose transport-glycolysis system occurred. Plasma glucose correlated better with ischemic intracellular pH than did brain lactate. However, when brain lactate levels are compared with intracellular pH during ischemia, the relation may be threshold rather than linear. A narrow transition zone, during which ischemic intracellular pH decreased precipitously with increasing brain lactate, was observed between 17 and 22 fimoUg; below 17 fimollg, intracellular pH remained stable at 6.8-6.9, whereas above 22 /imol/g, intracellular pH decreased maximally to about 62. The marked decrease in intracellular pH that occurs when brain lactate surpasses 17 /unol/g suggests that this sudden drop in intracellular pH may account for the "lactate threshold" for increased cerebral ischemic damage. (Stroke 1990^21:936-942) S ince the observation by Myers and Yamaguchi 1 that glucose infusion increased brain injury from cardiac arrest, the ability of hyperglycemia to enhance cerebral ischemic damage after transient ischemia has become well accepted. "5 The increased ischemic brain damage in the presence of hyperglycemia is believed to be related to increased production of lactate and to the accompanying increase in tissue acidosis. Hyperglycemia produces substantial increases in brain lactate during ischemia, Received September 6, 1989; accepted February 22, 1990. glycolytic inhibitor can block hyperglycemia-enhanced damage. 7 Measurement of interstitial pH and calculation of intracellular pH (pHj) during cerebral ischemia indicate that increased acidosis accompanies increased tissue lactate. -10Nevertheless, hyperglycemia studies are often restricted to comparisons of normoglycemic animals with animals that have been made hyperglycemic by one dose of glucose.2 -6 The dose-response relation between blood glucose and brain lactate over a wide range of blood glucose levels has not been well described in a model of severe cerebral ischemia. Furthermore, the relation between brain lactate and brain pHj during severe global ischemia has not been well characterized over an extensive range of hyperglycemia. The understanding of such relations is especially important in light of the recent finding that brain pathology may be enhanced more by lactic acidosis than by other types of acidosis. 11In these experiments, the relation between plasma glucose, brain lactate, and intracellular pH is described over a wide...

Brain Cell Membrane Function during Hypoxia in Hyperglycemic Newborn Piglets

“…This finding is consistent with previous studies in newbo rn animals that demonstrated that hyperglycemia either had no significant effect on the cereb ral response to hypoxia/ischemia (13,29) or improved outcome as indicated by improved surviva l (16,30) or decreased infarct size (31). In contra st, severa l studi es of cerebral hypoxia/ischemi a in adult animals found that hyperglycemia during or after the insult is associated with decre ased survival (32,33), signific ant increases in cereb ral lactate concentration, and reduced intracellular pH (7,9), as well as more extensive neuronal necros is and infarct size (4,33,34).…”

“…In adult an imal mo dels, outco me afte r ce reb ral ischemia was improved by mild hypoglycemia, and neuro log ic da mage was more extensive in animals that were hypergl ycemic during or after the insult (2,7,8). Th ese findings have been attributed to the effects of intrace llular lac tic acidosis res ulting from increased anae robic glycolysis in hypergl ycemic anim als (7,9,10). untreated animals, cerebral tissue hypoxia caused a 25% reduction in Na+,K+-ATPase activity compared with normoxic controls and an increase in conjugated dienes and fluorescent compounds, markers of lipid peroxidation.…”

Hyperpolarized MR Imaging: Neurologic Applications of Hyperpolarized Metabolism

“…Two hyperpolarized 13 C resonances within the brain of a rat manifesting stroke (Fig 11, inset) may represent unmetabolized 13 C succinate at an acid pH and a reduced metabolic product, 13 C malate, within the stroke. 28 The latter may reflect the altered mitochondrial redox state expected in stroke brain. 29 If confirmed, one could imagine an extension of current emergency stroke MR imaging protocol to include a subsecond assay of tissue pH and redox state by using HD-MR imaging, because this may be more predictive of tissue viability than an assay of lactate or diffusion-weighted imaging alone.…”

Why Does Acute Hyperglycemia Worsen the Outcome of Transient Focal Cerebral Ischemia?

“…2 Yet, the actual mechanisms involved in these negative effects remain unclarified. Although much attention was focused in the past on the worsening effect of increased lactate production, 3,4 extracellular lactate accumulation is not a crucial determinant of brain injury. 5 Also, glucose per se, but not lactate, in combination with acidosis mediates the detrimental hyperglycemic effect in organotypic hippocampal slices.…”