glycogen and Acidosis

Topics: Acidosis; Animals; Biological Transport, Active; Extremities; Glycogen; Humans; Hydrogen-Ion Concentration; Hypoglycemic Agents; Lactates; Liver; Metabolic Clearance Rate; Muscles; Physical Exertion; Rats; Splanchnic Circulation

Congenital enzymopathic hyperlactacidemia results from a defect of utilisation of pyruvate either at the level of the pyruvate junction (pyruvate-carboxylase, pyruvate-dehydrogenase and Kreb's cycle), or at the level of the unidirectional enzymes on neo-glucogenesis and of neo-glycogenogenesis, e.g. glucose-6-phosphatase, phosphoenol-pyruvate-carboxykinase and glycogen synthetase. The enzymopathies which affect neoglucogenesis associate hyper-lactacidemia and fasting hypoglycemia and more or less marked hepatomegaly. Type I glycogenesis (von Gierke's disease) is the best known example. Enzymopathies which affect the pyruvate junction and the Krebs cycle, may be manifested in addition by: --either chronic neuropathies, e.g. Leigh's disease, recurrent ataxia, and moderate hyperalactacidemia,--or, as in congenital lactic acidoses, which have a rapid and severe prognosis with major hyperlactacidemia. Functional investigation, in particular, loading tests are of great value in orientation and justify the practice of tissue biopsy which permits the enzyme diagnosis. Recent, still unconfirmed knowledge of the pathogenesis of these diseases emphasizes the considerable importance of estimation of blood lactic acid in the investigation of metabolic acidoses of hereditary origin.

Topics: Acidosis; Ataxia; Brain Stem; Carbohydrate Metabolism, Inborn Errors; Citric Acid Cycle; Encephalomalacia; Fructose-1,6-Diphosphatase Deficiency; Glucose; Glycogen; Glycogen Storage Disease Type I; Glycogen Synthase; Humans; Infant; Infant, Newborn; Intellectual Disability; Lactates; Phosphoenolpyruvate Carboxykinase (GTP); Psychomotor Disorders; Pyruvate Carboxylase Deficiency Disease; Pyruvate Dehydrogenase Complex Deficiency Disease; Pyruvates

Topics: Acidosis; Adenosine Triphosphate; Allosteric Site; Anaerobiosis; Animals; Arteries; Carbohydrate Metabolism; Cell Survival; Coronary Vessels; Creatine Kinase; Enzyme Activation; Fatty Acids; Glucose; Glycogen; Glycolysis; Heart; Hypoxia; Ischemia; Lactates; Mitochondria, Muscle; Myocardium; Necrosis; Oxidation-Reduction; Oxidative Phosphorylation; Phosphofructokinase-1; Phosphorylases; Veins

Topics: Acidosis; Animals; Blood Glucose; Brain; Cattle; Cattle Diseases; Fatty Acids; Fatty Acids, Nonesterified; Glycogen; Ketone Bodies; Kidney; Lipids; Liver; Lung; Mammary Glands, Animal; Muscles; Rumen; Sheep; Sheep Diseases; Species Specificity

Topics: Acidosis; Adipose Tissue; Animals; Animals, Laboratory; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Feeding Behavior; Glycogen; Guinea Pigs; Haplorhini; Hyperglycemia; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Ketone Bodies; Mice; Muscles; Obesity; Pancreas; Prediabetic State; Rats

Topics: Acidosis; Animals; Ascorbic Acid; Ascorbic Acid Deficiency; Deoxyribonucleases; Glycogen; Guinea Pigs; Hydrogen-Ion Concentration; Iron; Lysosomes; Male; Membranes; Mitochondria; Muscles; Oxidation-Reduction; Testis

Topics: Acidosis; Acidosis, Respiratory; Asphyxia Neonatorum; Blood Gas Analysis; Brain; Brain Damage, Chronic; Fetus; Glycogen; Heart Massage; Histocytochemistry; Humans; Hyperbaric Oxygenation; Infant, Newborn; Metabolism; Physiology; Pulmonary Circulation; Respiration; Resuscitation

The AMP-activated protein kinase (AMPK) cascade has been linked to many of the acute effects of exercise on skeletal muscle substrate metabolism, as well as to some of the chronic training-induced adaptations. We determined the effect of 3 wk of intensified training (HIT; 7 sessions of 8 x 5 min at 85% Vo2 peak) in skeletal muscle from well-trained athletes on AMPK responsiveness to exercise. Rates of whole body substrate oxidation were determined during a 90-min steady-state ride (SS) pre- and post-HIT. Muscle metabolites and AMPK signaling were determined from biopsies taken at rest and immediately after exercise during the first and seventh HIT sessions, performed at the same (absolute) pre-HIT work rate. HIT decreased rates of whole body carbohydrate oxidation (P < 0.05) and increased rates of fat oxidation (P < 0.05) during SS. Resting muscle glycogen and its utilization during intense exercise were unaffected by HIT. However, HIT induced a twofold decrease in muscle [lactate] (P < 0.05) and resulted in tighter metabolic regulation, i.e., attenuation of the decrease in the PCr/(PCr + Cr) ratio and of the increase in [AMPfree]/ATP. Resting activities of AMPKalpha1 and -alpha2 were similar post-HIT, with the magnitude of the rise in response to exercise similar pre- and post-HIT. AMPK phosphorylation at Thr172 on both the alpha1 and alpha2 subunits increased in response to exercise, with the magnitude of this rise being similar post-HIT. Acetyl-coenzyme A carboxylase-beta phosphorylation was similar at rest and, despite HIT-induced increases in whole body rates of fat oxidation, did not increase post-HIT. Our results indicate that, in well-trained individuals, short-term HIT improves metabolic control but does not blunt AMPK signaling in response to intense exercise.

Topics: Acetyl-CoA Carboxylase; Acidosis; Adult; AMP-Activated Protein Kinases; Analysis of Variance; Exercise; Glycogen; Humans; Lactic Acid; Multienzyme Complexes; Muscle, Skeletal; Oxygen Consumption; Phosphorylation; Physical Fitness; Protein Serine-Threonine Kinases; Signal Transduction

Onset of intracellular acidosis during muscular exercise has been generally attributed to activation or hyperactivation of nonoxidative ATP production but has not been analyzed quantitatively in terms of H(+) balance, i.e., production and removal mechanisms. To address this issue, we have analyzed the relation of intracellular acidosis to H(+) balance during exercise bouts in seven healthy subjects. Each subject performed a 6-min ramp rhythmic exercise (finger flexions) at low frequency (LF, 0.47 Hz), leading to slight acidosis, and at high frequency (HF, 0.85 Hz), inducing a larger acidosis. Metabolic changes were recorded using (31)P-magnetic resonance spectroscopy. Onset of intracellular acidosis was statistically identified after 3 and 4 min of exercise for HF and LF protocols, respectively. A detailed investigation of H(+) balance indicated that, for both protocols, nonoxidative ATP production preceded a change in pH. For HF and LF protocols, H(+) consumption through the creatine kinase equilibrium was constant in the face of increasing H(+) generation and efflux. For both protocols, changes in pH were not recorded as long as sources and sinks for H(+) approximately balanced. In contrast, a significant acidosis occurred after 4 min of LF exercise and 3 min of HF exercise, whereas the rise in H(+) generation exceeded the rise in H(+) efflux at a nearly constant H(+) uptake associated with phosphocreatine breakdown. We have clearly demonstrated that intracellular acidosis in exercising muscle does not occur exclusively as a result of nonoxidative ATP production but, rather, reflects changes in overall H(+) balance.

Topics: Acidosis; Adult; Anaerobiosis; Bicarbonates; Creatine Kinase; Exercise; Glycogen; Humans; Hydrogen; Kinetics; Magnetic Resonance Spectroscopy; Male; Muscle, Skeletal; Phosphocreatine; Rest

Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10g/kg DEG and blood, kidney and liver tissues were collected at 48h. Both rat strains treated with 10g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10g/kg DEG, but no DGA was present at 2 or 5g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments.

Topics: Acidosis; Alanine Transaminase; Animals; Aspartate Aminotransferases; Blood Urea Nitrogen; Chemical and Drug Induced Liver Injury; Creatine; Dose-Response Relationship, Drug; Ethylene Glycols; Glycogen; Glycolates; Kidney; Kidney Diseases; Liver; Male; Rats, Inbred F344; Rats, Wistar

Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation of the Cu/Zn superoxide dismutase 1 gene) of ALS enters a progressive state of acidosis that is associated with several metabolic (hormonal) alternations that favor lipolysis. Extensive investigation of the major determinants of H(+) concentration (i.e., the strong ion difference and the strong ion gap) suggests that acidosis is also due in part to the presence of an unknown anion. Consistent with a compensatory response to avert pathological acidosis, ALS mice harbor increased accumulation of glycogen in CNS and visceral tissues. The altered glycogen is associated with fluctuations in lysosomal and neutral α-glucosidase activities. Disease-related changes in glycogen, glucose, and α-glucosidase activity are also found in spinal cord tissue samples of autopsied patients with ALS. Collectively, these data provide insights into the pathogenesis of ALS as well as potential targets for drug development.

Topics: Acidosis; Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Disease Progression; Glycogen; Humans; Mice; Mice, Transgenic; Mutation; Superoxide Dismutase

The purpose of the present study was to examine the effects of muscle glycogen reduction on surface electromyogram (EMG) activity and effort sense and ventilatory responses to intense exercise (IE). Eight subjects performed an IE test in which IE [100-105% of peak O(2) uptake ([Formula: see text]), 2 min] was repeated three times (IE(1st), IE(2nd) and IE(3rd)) at 100-120-min intervals. Each interval consisted of 20-min passive recovery, 40-min submaximal exercise at ventilatory threshold intensity (51.5 ± 2.7% of [Formula: see text]), and a further resting recovery for 40-60 min. Blood pH during IE and subsequent 20-min recovery was significantly higher in the IE(3rd) than in the IE(1st) (P < 0.05). Effort sense of legs during IE was significantly higher in the IE(3rd) than in the IE(1st) and IE(2nd). Integrated EMG (IEMG) measured in the vastus lateralis during IE was significantly lower in the IE(3rd) than in the IE(1st). In contrast, mean power frequency of the EMG was significantly higher in the IE(2nd) and the IE(3rd) than in the IE(1st). Ventilation ([Formula: see text]) in the IE(3rd) was significantly higher than that in the IE(1st) during IE and the first 60 s after the end of IE. These results suggest that ventilatory response to IE is independent of metabolic acidosis and at least partly associated with effort sense elicited by recruitment of type II fibers.

Topics: Acidosis; Adult; Electromyography; Exercise; Glycogen; Humans; Hydrogen-Ion Concentration; Male; Muscle Fibers, Fast-Twitch; Oxygen Consumption; Respiratory Mechanics; Respiratory Muscles; Sensation; Young Adult

The roles of pyruvate dehydrogenase (PDH), glycogen phosphorylase (Phos), and their regulators in lactate (Lac(-)) metabolism were examined during incremental exercise after ingestion of 0.3 g/kg of either NH(4)Cl [metabolic acidosis (ACID)] or CaCO(3) [control (CON)]. Subjects were studied at rest, at rest postingestion, and during continuous steady-state cycling at three stages (15 min each): 30, 60, and 75% of maximal oxygen uptake. Radial artery and femoral venous blood samples, leg blood flow, and biopsies of the vastus lateralis were obtained during each power output. ACID resulted in significantly lower intramuscular concentration of [Lac(-)] (ACID 40.8 vs. CON 56.9 mmol/kg dry wt), arterial whole blood [Lac(-)] (ACID 4.7 vs. CON 6.5 mmol/l), and leg Lac(-) efflux (ACID 3.05 vs. CON 6.98 mmol. l(-1). min(-1)). The reduced intramuscular [Lac(-)] resulted from decreases in pyruvate production due to inhibition of glycogenolysis, at the level of Phos a, and phosphofructokinase, together with an increase in the amount of pyruvate oxidized relative to the total produced. The reduction in Phos a activity was mediated through decreases in transformation, decreases in free inorganic phosphate concentration, and decreases in the posttransformational allosteric regulator free AMP. Reduced PDH activity occurred with ACID and may have resulted from alterations in the concentrations of acetyl-CoA, free ADP, pyruvate, NADH, and H(+), leading to greater relative activity of the kinase. The results demonstrate that imposed metabolic acidosis in skeletal muscle results in decreased Lac(-) production due to inhibition of glycogenolysis at the level of Phos and increased pyruvate oxidation at PDH.

Topics: Acidosis; Adult; Exercise; Fatty Acids, Nonesterified; Glycerol; Glycogen; Humans; Lactic Acid; Leg; Male; Muscle, Skeletal; Oxidation-Reduction; Oxygen Consumption; Phosphates; Pulmonary Gas Exchange; Pyruvic Acid; Regional Blood Flow

The cardioprotective effect of preconditioning is associated with glycogen depletion and attenuation of intracellular acidosis during subsequent prolonged ischemia. This study determined the effects of increasing preconditioning ischemia time on myocardial glycogen depletion and on infarct size reduction. In addition, this study determined whether infarct size reduction by preconditioning correlates with glycogen depletion before prolonged ischemia. Anesthetized rats underwent a single episode of preconditioning lasting 1.25, 2.5, 5, or 10 minutes or multiple episodes cumulating in 10 (2 x 5 min) or 20 minutes (4 x 5 or 2 x 10 min) of preconditioning ischemia time, each followed by 5 minutes of reperfusion. Then both preconditioned and control rats underwent 45 minutes of ischemia induced by left coronary artery (LCA) occlusion and 120 minutes of reperfusion. After prolonged ischemia, infarct size was determined by dual staining with triphenyltetrazolium chloride and phthalocyanine blue dye. Glycogen levels were determined by an enzymatic assay in selected rats from each group before prolonged ischemia. We found that increasing preconditioning ischemia time resulted in glycogen depletion and infarct size reduction that could both be described by exponential functions. Furthermore, infarct size reduction correlated with glycogen depletion before prolonged ischemia (r = 0.98; p < 0.01). These findings suggest a role for glycogen depletion in reducing ischemic injury in the preconditioned heart.

Topics: Acidosis; Animals; Female; Glycogen; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Rats; Rats, Sprague-Dawley; Time Factors

The primary objective of this study was to attempt to induce excessive intraglial acidosis during ischemia by subjecting rats to an initial insult which leads to post insult accumulation of glycogen, presumed to accumulate primarily in astrocytes. The initial insults were 15 min of transient forebrain ischemia, 30 min of hypoglycemic coma, and intraperitonial injection of methionine-sulphoximine (MSO). In the first two of these insults, glycogen content in neocortex increased to 6-7 mM kg(-1) after 6 h of recovery, and in MSO-treated animals even higher values were measured 24 h after administration ( 12 mM kg(-1)). In spite of this glycogen loading, the amount of lactate formed during a subsequent ischemic insult (of 5-30 min duration) did not exceed values usually obtained during complete ischemia in animals with normal glycogen contents (tissue lactate contents of 15 mM kg(-1)) This was because appreciable amounts of glycogen (3-7 mM kg(-1)) remained undegraded even after 30 min of ischemia. The undigested part largely reflected the extra amount of glycogen accumulated after the initial insults. It is discussed whether this part is unavailable to degradation by phosphorylase.

Topics: Acidosis; Animals; Astrocytes; Brain; Brain Ischemia; Coma; Energy Metabolism; Glycogen; Hypoglycemia; Ischemic Attack, Transient; Male; Methionine Sulfoximine; Phosphorylation; Rats; Rats, Wistar; Reperfusion Injury; Seizures

Previously we have shown that hypercarbia produces a larger decrease in agonal glycolytic rate in 1-month-old swine than in newborns. In an effort to understand the mechanism responsible for this difference, we tested the hypothesis that hypercarbia produces age-related changes in the concentration of one or more effectors of phosphofructokinase activity. Specifically, in vivo 31P and 1H NMR spectroscopy was used to compare changes in lactate levels, intracellular pH, free magnesium concentration, and content of phosphorylated metabolites for these two age groups at three intervals during the first 1.5 min of complete ischemia in the presence or absence of hypercarbia (PaCO2 = 102-106 mm Hg). Hypercarbia produced the same drop in intracellular brain pH for both age groups, but the decrease in phosphocreatine level and increase in inorganic phosphate content were greater in 1-month-olds compared with newborns. During ischemia there was no difference between the magnitude of change in intracellular pH and levels of phosphocreatine and inorganic phosphate in hypercarbic 1-month-olds versus newborns. Under control conditions, i.e., normocarbia and normoxia, the free Mg2+ concentration was lower and the fraction of magnesium-free ATP was higher for newborns than 1-month-olds. However, there was no change in these variables for either age group during hypercarbia and early during ischemia. Thus, age-related differences in the relative decrease in agonal glycolytic rate during hypercarbia could not be explained by differences in intracellular pH, inorganic phosphate content, or free magnesium concentration. The [ADP]free at control was higher in newborns compared with 1-month-olds, and there was no age-related difference in [AMP]free. These variables did not change for newborns when exposed to hypercarbia, but for 1-month-olds [ADP]free and [AMP]free increased during hypercarbia relative to control values. High-energy phosphate utilization during ischemia for hypercarbic 1-month-olds was reduced by 74% compared with normocarbic 1-month-olds during ischemia, whereas the reduction in energy utilization (14%) was not significant for hypercarbic versus normocarbic newborns during ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Acidosis; Animals; Animals, Newborn; Brain; Brain Chemistry; Death; Glycogen; Hydrogen; Hydrogen-Ion Concentration; Hypercapnia; Ischemia; Lactates; Magnesium; Magnetic Resonance Spectroscopy; Phosphorus; Swine; Swine, Miniature

Does the stimulatory effect of circulating catecholamines counteract the inhibitory effect of acidosis on skeletal muscle metabolism? To investigate this possibility, we studied gastrocnemii in dogs breathing either air (n = 10) or 4% carbon dioxide in air (n = 10) at rest and during contractions. In five dogs from each group, we infused propranolol into the arterial supply of the right and left muscles for 40 min. After 30 min of infusion, the left muscle was stimulated at 3 Hz for 10 min. During the 10th min of contractions, we removed and froze both muscles in liquid nitrogen. Oxygen uptake and blood flow to the left muscle prior to or during stimulation was not affected by acidosis either with or without propranolol. Glycogen concentration in resting muscle was unaffected by acidosis with or without propranolol. There was an acidosis related decrease of approximately 50% in the glycolytic intermediates (glucose 6-phosphate, fructose 1,6-diphosphate, alpha-glycerol phosphate, and dihydroxyacetone phosphate) in unstimulated muscles without beta-blockade. At rest, acidosis decreased muscle lactate by 50% with and 64% without propranolol, but lactate release was decreased only with acidosis without propranolol (1.4-0.1 mumols/kg.s). Acidosis without propranolol had no effect on the changes in glycogen concentration or the change in the concentration of glycolytic intermediates resulting from contractions. In beta-blocked muscle, the difference between stimulated and unstimulated concentrations of glycogen and glycolytic intermediates including lactate was 20-50% smaller with acidosis. Thus, with beta-blockade, the acidotic effects at rest disappeared and an inhibition of the metabolic adjustment to contractions appeared, indicating that circulating catecholamines do modify some metabolic effects of acidosis.

Topics: Acidosis; Aerobiosis; Animals; Carbon Dioxide; Dogs; Female; Glycogen; Glycolysis; Lactates; Male; Muscle Contraction; Muscles; Oxidation-Reduction; Oxygen Consumption; Phosphofructokinase-1; Propranolol

Post-exercise ketosis is known to be suppressed by physical training and by a high carbohydrate diet. As a result it has often been presumed, but not proven, that the development of post-exercise ketosis is closely related to the glycogen content of the liver. We therefore studied the effect of 1 h of treadmill running on the blood 3-hydroxybutyrate and liver and muscle glycogen concentrations of carbohydrate-loaded trained (n = 72) and untrained rats (n = 72). Resting liver and muscle glycogen levels were 25%-30% higher in the trained than in the untrained animals. The resting 3-hydroxybutyrate concentrations of both groups of rats were very low: less than 0.08 mmol.l-1. Exercise did not significantly influence the blood 3-hydroxybutyrate concentrations of trained rats, but caused a marked post-exercise ketosis (1.40 +/- 0.40 mmol.l-1 h after exercise) in the untrained animals, the time-course of which was the approximate inverse of the changes in liver glycogen concentration. Interpreting the results in the light of similar data obtained after a normal and low carbohydrate diet it has been concluded that trained animals probably owe their relative resistance to post-exercise ketosis to their higher liver glycogen concentrations as well as to greater peripheral stores of mobilizable carbohydrate.

Topics: 3-Hydroxybutyric Acid; Acidosis; Animals; Body Weight; Dietary Carbohydrates; Glycogen; Hydroxybutyrates; Ketone Bodies; Ketosis; Liver Glycogen; Malate Dehydrogenase; Male; Muscles; Physical Conditioning, Animal; Physical Exertion; Rats

Exhaustive 'burst-type' exercise in the rainbow trout resulted in a severe acidosis in the white muscle, with pHi dropping from 7.21 to a low of 6.62, as measured by DMO distribution. An accumulation of lactate and pyruvate, depletions of glycogen, ATP and CP stores, and a fluid shift from the extracellular fluid to the intracellular fluid of white muscle were associated with the acidosis. The proton load was in excess of the lactate load by an amount equivalent to the drop in ATP, suggesting that there was an uncoupling of ATP hydrolysis and glycolysis. Initially, lactate was cleared more quickly than protons from the muscle, a difference that was reflected in the blood. It is suggested that during the early period of recovery (0-4 h), the bulk of the lactate was oxidized in situ, restoring pHi to a point compatible with glyconeogenesis. At that time, lactate and H+ were used as substrates for in situ glyconeogenesis, which was complete by 24 h. During this time, lactate and H+ disappearance could account for about 75% of the glycogen resynthesized. The liver and heart showed an accumulation of lactate, and it is postulated that this occurred as a result of uptake from the blood. Associated with the lactate load in these tissues was a metabolic alkalosis. Except for an apparent acidosis immediately after exercise, the acid-base status of the brain was not appreciably affected. Despite the extracellular acidosis, red cell pHi remained nearly constant.

Topics: Acid-Base Equilibrium; Acidosis; Adenosine Triphosphate; Animals; Body Fluids; Carbon Radioisotopes; Female; Glycogen; Glycolysis; Hydrogen-Ion Concentration; Intracellular Fluid; Lactates; Male; Muscles; Phosphocreatine; Physical Exertion; Tritium; Trout

Cerebral ischemic insult is one of the most clinically significant conditions leading to irreversible brain cell damage and death. Animal studies have suggested that lowered intracellular pH due to the severe brain lactic acidosis following ischemia interferes with normal cell structure and function and leads to brain cell necrosis. Therefore, efforts directed to decreasing brain lactate may be beneficial in preventing brain cell damage and death. The goal of our study was to evaluate the effectiveness of postinsult treatment with dichloroacetate (DCA) in controlling increases in brain lactate following partial global ischemia (PGI) in rats. PGI was induced by bilateral carotid artery occlusion and induced hypotension. Animals that received DCA immediately after a 30-minute ischemic insult (n = 5) or 15 minutes after the end of an ischemic insult (n = 5) had cortical lactate levels that were significantly lower (P less than .005) than lactate levels in untreated insulted animals and that were not significantly different than those previously obtained with preinsult DCA treatment in rats subjected to 30 minutes of PGI. Treatment of rats with DCA following PGI may be effective in reducing cortical lactate levels and hence may limit irreversible damage to brain cells following cerebral ischemia.

Topics: Acetates; Acidosis; Animals; Blood Glucose; Blood Pressure; Brain; Brain Chemistry; Brain Ischemia; Dichloroacetic Acid; Electroencephalography; Glucose; Glycogen; Hydrogen-Ion Concentration; Lactates; Male; Rats; Rats, Inbred Strains

Endurance-trained animals and human subjects have been reported to exhibit a lesser degree of postexercise ketosis than nontrained controls. We have studied the mechanism of this adaptation. Trained (2 h/day, 6 wk) and nontrained rats were fasted overnight and then run at 16 m/min up a 15% grade for 90 min. Trained rats had lower blood 3-hydroxybutyrate during exercise and during a 90-min postexercise period than nontrained rats. Liver malonyl coenzyme A (CoA), carnitine, and glycogen were not significantly different in the two groups at any time during and after exercise. Therefore these factors cannot be responsible for the difference in ketonemia. Plasma free-fatty acids and hepatic adenosine 3',5'-cyclic monophosphate were elevated in nontrained rats with respect to trained rats. These two differences could conceivably be responsible for a different ketogenic rate. In addition, 3-ketoacid CoA transferase activity of gastrocnemius muscle was increased by training. The increase in ketone oxidizing enzymes of muscle may also be partially responsible for the training-induced attenuation of postexercise ketonemia in these fasted rats.

Topics: 3-Hydroxybutyric Acid; Acidosis; Adaptation, Physiological; Animals; Carnitine; Cyclic AMP; Fasting; Fatty Acids, Nonesterified; Glucagon; Glycogen; Hydroxybutyrates; Ketosis; Liver; Male; Motor Activity; Physical Conditioning, Animal; Physical Endurance; Rats; Rats, Inbred Strains

The metabolism and performance of a perfused rat hindquarter preparation was examined during heavy exercise in three conditions: control (C), metabolic acidosis (MA, decreased bicarbonate concentration), and respiratory acidosis (RA, increased CO2 tension). A one-pass system was used to perfuse the hindquarters for 30 min at rest and 20 min during tetanic stimulation via the sciatic nerve. The isometric tension generated by the gastrocnemius-plantaris-soleus muscle group was recorded, and biopsies were taken pre- and postperfusion. Initial isometric tensions were similar in all conditions, but the rate of tension decay was largest in acidosis; the 5-min tensions for C, MA, and RA were 1,835 +/- 63, 1,534 +/- 63, and 1,434 +/- 73 g, respectively. O2 uptake in C was greater than in MA and RA (23.4 +/- 1.3 vs. 17.0 +/- 1.4 and 16.5 +/- 2.3 mumol X min-1), paralleling the tension findings. Hindquarter lactate release was greatest in C, least in MA, and intermediate in RA. Acidosis resulted in less muscle glycogen utilization and lactate accumulation than during control. Muscle creatine phosphate utilization and ATP levels were unaffected by acidosis. Acidosis decreased the muscle's ability to generate isometric tension and depressed both aerobic and anaerobic metabolism. During stimulation in this model lactate left the muscle mainly as a function of the production rate, although a low plasma bicarbonate concentration at pH 7.15 depressed muscle lactate release.

Topics: Acidosis; Acidosis, Respiratory; Adenosine Triphosphate; Animals; Bicarbonates; Carbon Dioxide; Electric Stimulation; Energy Metabolism; Glycogen; Hindlimb; Hydrogen-Ion Concentration; Lactates; Lactic Acid; Male; Muscle Contraction; Muscles; Oxygen Consumption; Perfusion; Phosphocreatine; Physical Exertion; Rats; Time Factors

We have compared the capacity of major organs to produce lactic acid from endogenous sources relative to their ability to buffer that proton load. We deduced that the ultimate source for the rapid production of a very large amount of lactic acid must be hepatic and/or muscle glycogen or exogenous glucose, because the quantity of endogenous glucose is quite small and the rate of net protein catabolism is too slow. Of the organs examined, only the liver of fed persons can produce sufficient lactic acid to markedly overwhelm its own buffer capacity plus that of the ECF and other tissues. Moreover, it is important to realize that a fasted (low hepatic glycogen) subject who lacks the stimulus for muscle glycogenolysis can only develop a modest degree of acute lactic acidosis owing to a limited precursor availability; under these circumstances, hypoglycemia and/or localized tissue necrosis could be the major threats to that patient. We present two examples with more chronic lactic acidosis without hypoxia emphasizing that tissue catabolism may be necessary to support high rates of lactic acid production, and we suggest that a high plasma lactate concentration need not be present to observe a large turnover of this metabolite.

Topics: Acid-Base Equilibrium; Acidosis; Adenosine Triphosphate; Animals; Bone and Bones; Extracellular Space; Glucose; Glycogen; Humans; Hydrogen-Ion Concentration; Hypoxia; Intracellular Fluid; Kidney; Lactates; Liver; Muscle Proteins; Muscles; NAD

The significance of ketosis in this syndrome has been evaluated from several viewpoints. With respect to acid-base considerations (pH, anion gap), ketosis was not very significant. However, with respect to sustained hyperglycemia, the combustion of less glucose than normal by the brain is critical and it is likely that ketone body metabolism plays an important role in this regard. This point can be underscored by a quantitative example. First, assume that the maximum rate of new glucose production in a fasted subject is less than 100 g of glucose per day. Second, since the brain will burn 100 g of glucose per day in a non-ketotic subject, it follows that, even in the absence of glucosuria, there will be a net daily consumption of glucose. Since the hyperglycemic individual has only an extra 100 or so g of glucose, it follows that the blood glucose concentration would approach the renal threshold in several days in the absence of ketosis. Recall that this is a minimum estimate because glucose oxidation in other organs and glucosuria will remove an additional quantity of glucose. Hyperglycemia can only be maintained in the absence of glucose intake if there is a reduced rate of glucose metabolism in the brain. The brain can diminish its rate of glucose catabolism by several mechanisms, including a diminished metabolic rate in the brain and/or the consumption of non-glucose fuels (free fatty acids or beta-hydroxybutyrate) by this organ.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetone; Acidosis; Brain; Diabetic Coma; Glucose; Glycerides; Glycerol; Glycogen; Humans; Hyperglycemia; Hyperglycemic Hyperosmolar Nonketotic Coma; Ketosis; Proteins; Syndrome

A 2-week-old boy had profound generalized weakness, hypotonia, hyporeflexia, macroglossia, and severe lactic acidosis. The infant improved spontaneously: he held his head at 4 1/2 months, rolled over at 7 months, and walked by 16 months. At 33 months of age, he had mild proximal weakness. Macroglossia disappeared by age 4 months. Blood lactic acid declined steadily and was normal by 14 months of age. Histochemical and ultrastructural studies of muscle biopsy specimens obtained at 1 and 7 months of age showed excessive mitochondria, lipid, and glycogen; a third biopsy at age 36 months showed only atrophy of scattered fibers. Cytochrome c oxidase stain was positive in fewer than 5% of fibers in the first biopsy, in approximately 60% of fibers in the second biopsy, and in all fibers in the third biopsy. Biochemical analysis showed an isolated defect of cytochrome c oxidase activity, which was only 8% of the lowest control level in the first biopsy; the activity increased to 47% in the second biopsy and was higher than normal in the third. In contrast to that in the fatal infantile form of cytochrome c oxidase deficiency, the enzyme defect in this condition is reversible. The biochemical basis for this difference remains to be explained.

Topics: Acidosis; Biopsy; Child, Preschool; Cytochrome-c Oxidase Deficiency; Glycogen; Humans; Lactates; Lipid Metabolism; Male; Microscopy, Electron; Mitochondria, Muscle; Muscle Hypotonia; Muscles

To study the effect of chronic ketosis on exercise performance in endurance-trained humans, five well-trained cyclists were fed a eucaloric balanced diet (EBD) for one week providing 35-50 kcal/kg/d, 1.75 g protein/kg/d and the remainder of kilocalories as two-thirds carbohydrate (CHO) and one-third fat. This was followed by four weeks of a eucaloric ketogenic diet (EKD), isocaloric and isonitrogenous with the EBD but providing less than 20 g CHO daily. Both diets were appropriately supplemented to meet the recommended daily allowances for vitamins and minerals. Pedal ergometer testing of maximal oxygen uptake (VO2max) was unchanged between the control week (EBD-1) and week 3 of the ketogenic diet (EKD-3). The mean ergometer endurance time for continuous exercise to exhaustion (ENDUR) at 62%-64% of VO2max was 147 minutes at EBD-1 and 151 minutes at EKD-4. The ENDUR steady-state RQ dropped from 0.83 to 0.72 (P less than 0.01) from EBD-1 to EKD-4. In agreement with this were a three-fold drop in glucose oxidation (from 15.1 to 5.1 mg/kg/min, P less than 0.05) and a four-fold reduction in muscle glycogen use (0.61 to 0.13 mmol/kg/min, P less than 0.01). Neither clinical nor biochemical evidence of hypoglycemia was observed during ENDUR at EKD-4. These results indicate that aerobic endurance exercise by well-trained cyclists was not compromised by four weeks of ketosis. This was accomplished by a dramatic physiologic adaptation that conserved limited carbohydrate stores (both glucose and muscle glycogen) and made fat the predominant muscle substrate at this submaximal power level.

Topics: Acidosis; Adult; Blood Glucose; Carbohydrate Metabolism; Diet; Energy Intake; Glycogen; Humans; Ketosis; Male; Muscles; Oxygen Consumption; Physical Endurance; Physical Exertion

The role of the respiratory muscles in the evolution of experimental low cardiac output and lactic acidosis was studied in 2 groups of dogs. One group (6 dogs) was paralyzed and artificially ventilated, and the other (6 dogs) was breathing spontaneously. Shock was induced by cardiac tamponade; cardiac output during shock amounted to 25 to 35% of control values in both groups. All the spontaneously breathing dogs died from ventilatory failure (mean time, 2 h), whereas the artificially ventilated dogs were still alive 3 h after the onset of cardiogenic shock. At any given time after the onset of shock, arterial pH was significantly lower in the spontaneously breathing dogs than in the artificially ventilated ones. This was due to a greater increase in arterial blood lactate in the spontaneously breathing dogs than in the artificially ventilated ones (9.47 +/- 2.7 versus 4.74 +/- 56 mmoles/L at 2 h, respectively). Greater glycogen depletion associated with higher muscle lactate concentrations were found in the respiratory muscles of the spontaneously breathing dogs when compared with that in the artificially ventilated ones. It is concluded that artificial ventilation in cardiogenic shock decreases substantially the severity of lactic acidosis and prolongs survival.

Topics: Abdominal Muscles; Acidosis; Animals; Cardiac Output, Low; Diaphragm; Dogs; Glycogen; Intercostal Muscles; Lactates; Muscles; Respiration; Shock, Cardiogenic

During vigorous, strong contractions there is a rapid decline in the mechanical output or tension development in skeletal muscle. Several studies have indicated that this rapid decline in force development (often referred to as fatigue), is caused by metabolic changes in the muscles. During brief intense exercise there is a rapid breakdown of phosphocreatine and glycogen and a concomitant increase in the lactate and hydrogen ion concentration. The muscle lactate concentration is increased from about 1-2 mmol kg-1 wet weight at rest before exercise to approximately 25-30 mmol kg-1 wet weight immediately after intensive brief exercise to exhaustion. The muscle pH (i.e. the pH of muscle homogenates) falls from about 7.0 at rest to approximately 6.4 at exhaustion. The changes in the concentrations of ATP, ADP, and AMP are small. It is suggested that the changes in intracellular pH might affect the force generation of skeletal muscle by two different mechanisms: (1) The fall in intracellular pH reduces the activity of key enzymes in glycolysis, thus reducing the rate of ATP resynthesis, and (2) the increased hydrogen ion concentration has a direct effect on the contractile processes, thus reducing the rate of ATP utilization. It is suggested that the increased hydrogen ion concentration might be the common regulator for the maximal rate at which ATP is being utilized and the maximal rate at which it is being resynthesized.

Topics: Acidosis; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Glycogen; Humans; Hydrogen-Ion Concentration; Lactates; Muscle Contraction; Muscle Tonus; Muscles; Phosphocreatine; Physical Exertion; Time Factors

1. Phosphorus-nuclear-magnetic-resonance measurements were made on perfused rat hearts at 37 degrees C. 2. With the improved sensitivity obtained by using a wide-bore 4.3 T superconducting magnet, spectra could be recorded in 1 min. 3. The concentrations of ATP, phosphocreatine and Pi and, from the position of the Pi resonance, the intracellular pH (pHi) were measured under a variety of conditions. 4. In a normal perfused heart pHi = 7.05 +/- 0.02 (mean +/- S.E.M. for seven hearts). 5. During global ischaemia pHi drops to 6.2 +/- 0.06 (mean +/- S.E.M.) in 13 min in a pseudoexponential decay with a rate constant of 0.25 min-1. 6. The relation between glycogen content and acidosis in ischaemia is studied in glycogen-depleted hearts. 7. Perfusion of hearts with a buffer containing 100 mM-Hepes before ischaemia gives a significant protective effect on the ischaemic myocardium. Intracellular pH and ATP and phosphocreatine concentrations decline more slowly under these conditions and metabolic recovery is observed on reperfusion after 30min of ischaemia at 37 degrees C. 8. The relation between acidosis and the export of protons is discussed and the significance of glycogenolysis in ischaemic acid production is evaluated.

Topics: Acidosis; Adenosine Triphosphate; Animals; Coronary Disease; Glycogen; Hydrogen-Ion Concentration; In Vitro Techniques; Intracellular Fluid; Kinetics; Magnetic Resonance Spectroscopy; Male; Myocardium; Perfusion; Phosphocreatine; Phosphorus; Rats

Topics: Acidosis; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Blood Glucose; Blood Pressure; Body Temperature; Brain; Creatine; Energy Metabolism; Glucosephosphates; Glycogen; Hydrogen-Ion Concentration; Hyperglycemia; Hypoglycemia; Ischemia; Lactates; Phosphocreatine; Pyruvates; Rats

Topics: Acidosis; Animals; Blood Glucose; Body Weight; Carbon Dioxide; Diabetes Mellitus, Experimental; Gluconeogenesis; Glucosephosphate Dehydrogenase; Glycogen; Glycolysis; Hexokinase; Hydrogen-Ion Concentration; Intestinal Mucosa; Jejunum; Kidney; Kidney Cortex; Ligases; Liver; Malate Dehydrogenase; Male; Organ Size; Phosphofructokinase-1; Phosphogluconate Dehydrogenase; Pyruvate Kinase; Rats

1. The purpose of this study was to determine the nature of the metabolic changes associated with carbohydrate and fat metabolism that occurred in the blood and liver of lactating dairy cows during starvation for 6 days. 2. During starvation, the blood concentrations of the free fatty acids and ketone bodies increased, whereas that of citrate decreased. After an initial increase, the blood concentration of glucose subsequently declined as starvation progressed. Starvation caused a significant decrease in the plasma concentration of serine and a significant increase in that of leucine. 3. After 6 days of starvation the hepatic concentrations of oxaloacetate, citrate, phosphoenolpyruvate, 2-phosphoglycerate, 3-phosphoglycerate, glucose, glycogen, ATP and NAD(+) had all decreased, as had the hepatic activities of phosphopyruvate carboxylase (EC 4.1.1.32) and pyruvate kinase (EC 2.7.1.40). 4. The above metabolic changes are similar to those previously found to occur in cows suffering from spontaneous ketosis (Baird et al., 1968; Baird & Heitzman, 1971). 5. Milk yield decreased progressively during starvation. 6. There were marked differences in the ability of individual animals to resist the onset of severe starvation ketosis.

Topics: Acidosis; Adenosine Triphosphate; Animals; Blood Glucose; Cattle; Cattle Diseases; Citrates; Fatty Acids, Nonesterified; Female; Glucose; Glycogen; Ketone Bodies; Lactation; Leucine; Liver; NAD; Oxaloacetates; Phosphoenolpyruvate; Pregnancy; Serine; Starvation

Topics: Acid-Base Equilibrium; Acidosis; Analysis of Variance; Animals; Animals, Newborn; Blood; Blood Glucose; Carbon Dioxide; Cold Temperature; Epinephrine; Fatty Acids, Nonesterified; Glycerol; Glycogen; Hydrogen-Ion Concentration; Lactates; Muscles; Norepinephrine; Oxygen; Sheep

Topics: Acidosis; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Cardiac Surgical Procedures; Dogs; Fructosephosphates; Glucose; Glycogen; Heart Arrest; Heart Rate; Hematocrit; Hemoglobins; Hydrogen-Ion Concentration; Hypoxia; Lactates; Methods; Myocardium; Oxygen Consumption; Perfusion; Phosphates; Potassium; Water-Electrolyte Balance

Topics: Acidosis; Adenosine Triphosphatases; Adenosine Triphosphate; Amino Acids; Animals; Blood Glucose; Blood Pressure; Blood Proteins; Blood Transfusion; Blood Volume; Disease Models, Animal; Dogs; Fructose; Glycogen; Hydrogen-Ion Concentration; Hyperbaric Oxygenation; Hypotension; Lactates; Methods; Phosphates; Phosphocreatine; Pulse; Pyruvates; Respiration

Topics: Acetoacetates; Acidosis; Adult; Alcoholic Intoxication; Amino Acids; Fatigue; Fatty Acids, Nonesterified; Female; Glucose; Glycogen; Glycolysis; Humans; Hydrogen-Ion Concentration; Hydroxybutyrates; Lactates; Liver; Muscles; NAD; Phosphates; Physical Exertion; Pyruvates; Uric Acid

Topics: Acidosis; Animals; Blood Glucose; Cell Nucleus; Cricetinae; Cytoplasmic Granules; Diabetes Mellitus; Disease Models, Animal; Endoplasmic Reticulum; Glucagon; Glycogen; Golgi Apparatus; Insulin; Islets of Langerhans; Lysosomes; Male; Microscopy, Electron

Topics: Acidosis; Ammonium Chloride; Animals; Blood Glucose; Carbohydrate Metabolism; Female; Glucose; Glucosyltransferases; Glycogen; Glycolysis; Liver; Liver Glycogen; Muscles; Rats

Topics: Acidosis; Animals; Cats; Culture Media; Culture Techniques; Cytogenetics; Diploidy; Dogs; Enzymes; Glucosephosphate Dehydrogenase; Glucosephosphate Dehydrogenase Deficiency; Glycogen; Glycolysis; Guinea Pigs; Humans; Methods; Mice; Microscopy, Electron; Molecular Biology; Oxygen Consumption; Polyploidy; Trisomy

Topics: Acidosis; Aminohippuric Acids; Ammonia; Ammonium Chloride; Animals; Blood Flow Velocity; Blood Glucose; Carbon Dioxide; Dogs; Female; Gluconeogenesis; Glucose; Glutamates; Glycogen; Glycosuria; Hydrogen-Ion Concentration; Kidney; Liver; Male; Methods; Regional Blood Flow

Topics: Acidosis; Brain; Edema; Glycogen; Hemodynamics; Humans; Liver; Mitochondria; Models, Theoretical; Peptide Hydrolases; Plasma Substitutes; Shock, Traumatic

Topics: Acidosis; Carbohydrate Metabolism; Child; Diet; Glycogen; Humans; Hypoglycemia; Ketones; Metyrapone; Mineralocorticoid Receptor Antagonists; Pituitary-Adrenal Function Tests; Seizures; Thyroid Function Tests; Urine

Topics: Absorption; Acidosis; Amylases; Biomedical Research; Blood Glucose; Coloring Agents; Diabetes Mellitus; Fibrinogen; Glycogen; Glycosuria; Heparin; Histocytochemistry; Humans; Insulin; Leukocytes; Neutrophils; Periodic Acid; Pharmacology; Research; Spectrophotometry; Staining and Labeling; Sulfuric Acids

Topics: Acidosis; Adolescent; Alkalosis; Child; Dehydration; Glycogen; Humans; Hyponatremia; Infant; Infant, Newborn; Metabolism; Parenteral Nutrition; Physiology; Potassium; Potassium Deficiency

Topics: Acidosis; Acidosis, Lactic; Blood Chemical Analysis; Carbohydrate Metabolism; Diabetes Mellitus; Glycogen; Humans; Lactates; Metabolism

Topics: Acidosis; Glycogen; Ketosis; Liver; Liver Glycogen

Topics: Acidosis; Animals; Biopsy; Cattle; Cattle Diseases; Female; Glycogen; Liver; Liver Glycogen

Topics: Acidosis; Animals; Blood Glucose; Glycogen; Ketosis; Liver; Liver Glycogen; Ruminants

Topics: Acidosis; Biopsy; Diabetes Mellitus; Diabetic Ketoacidosis; Glycogen; Humans; Liver; Liver Glycogen

Topics: Acidosis; Blood; Glycogen; Humans; Ketone Bodies; Ketosis