The Effect of Hypercapnic Acidosis Upon Some Glycolytic and Krebs Cycle‐associated Intermediates in the Rat Brain

Abstract

In order to study the influence of intracellular pH on the carbohydrate metabolism of brain tissue, the concentrations of glucose, glucose-6-phosphate, pyruvate, lactate, citrate, a-oxoglutarate, malate, glutamate, aspartate and ammonia were measured in rats exposed to &40% CO, for 45 min. Hypercapnia of increasing severity gave rise to progressive increases in the concentrations of glucose, glucose-6-phosphate and ammonium ion and to progressive decreases in the concentrations of all metabolic acids measured. The results fit with a H + inhibition of a rate-limiting step between glucose-6-phosphate and pyruvate, and by inference from the results published by others it may be assumed that this step is the phosphofructokinase reaction. Since the proportionally largest decrease occurred in a a-oxoglutarate, the results might be compatible either with an inhibition of a second rate-limiting step such as isocitrate dehydrogenase, or with a loss of a-oxoglutarate through carboxylation to citrate.ACID-BASE changes in tissues are known to affect enzymes which exert rate-limiting control upon metabolic reactions. The best known of these reactions is the activation of glycolysis of muscle tissue which occurs in alkalotic situations (DELCHER and SHIPP, 1966; SCHEUER and BERRY, 1967; DANFORTH, 1968), an effect which seems to be due to a pH-activation of phosphofructokinase (LOWRY and PASSONNEAU, 1966).Since this activation occurs without any accompanying increase in the rate of oxidative metabolism (DELCHER and SHIPP, 1966), the end result is an increase in the steadystate levels of glycolytic intermediates distal to the phosphofructokinase step (see SCHEUER and BERRY, 1967). In the brain, alkalosis due to hyperventilation is known to Iead to increases in the steady-state contents of lactate and pyruvate (LEUSEN, LACROIX and DEMEESTER, 1967; POSNER and PLUM, 1967; GRANHOLM and SIESJO, 1969;KJALLQUIST, NARDINI and SIESJO, 1969), as well as of a-oxoglutarate and glutamate (SIESJO and MESSETER, 1971 ; SIESJO, FOLBERGROVA and MESSETER, 19723). The effect of hyperventilation in releasing metabolic acids seems to provide an efficient mechanism which prevents an excessive increase in intracellular pH' ( SIESJO and MESSETER, 1971 ; SIESJO et al., 19723) and it would appear that the sensitivity to pH of ratelimiting glycolytic enzymes like phosphofructokinase therefore provides metabolic control of pH',.There are several reports which show that the fall in pH', elicited by hypercapnia leads to a decrease in the steady-state tissue contents of lactate, pyruvate, a-0x0glutarate and glutamate (BAIN and KLEIN, 1949; LEUSEN et al., 1967; GRANHOLM and SIESJO, 1969; MESSETER and S I E S J~, 1971; WEYNE and LEUSEN, 1971; SIESJO el al.,

The effects of host carbogen (95% oxygen/5% carbon dioxide) breathing on metabolic characteristics of Morris hepatoma 9618a

“…Because the tumour represents only 1-2% of the body weight of the animal, the decreases observed in tumour and extracellular lactate would not be expected to be reflected in plasma lactate concentration. Increases in blood and tissue glucose and decreases in tissue lactate have been observed previously in experiments looking at the effects of hypercapnia in brain (Folbergrova et al, 1972;Miller et al, 1976).…”

Tissue Pco2in Brain Ischemia Related to Lactate Content in Normo- and Hypercapnic Rats

“…This prob ably reflects the higher tissue/plasma glucose con centration ratio in hypercapnic animals (Folber- , 1972a, 1974Rehncrona et aI., 198 1). Predictably, hypercapnic animals had a higher CO2 content than normocapnic ones.…”

O2Dependence of in vivo Brain Cytochrome Redox Responses and Energy Metabolism in Bloodless Rats

“…Samples of the parietal cortex were carefully removed, weighed, and extracted with HCI methanol. All samples were brought to O°C and per chloric acid extraction was performed using the methods of Folbergrova et al (1972). Neutralized extracts were stored at -80°C until groups of six or more samples were accumulated.…”