Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolic effects of 60-min exposure to 250-2000 mg gamma-hydroxybutyrate (GHB) per kilogram or 150-1200 mg gamma-butyrolactone (GBL) per kilogram were studied in rats by measurement of the cerebral hemisphere contents of energy phosphates and glycolytic-Krebs' cycle metabolites. A general pattern of increased glycogen and glucose with decreased pyruvate, lactate, alpha-ketoglutarate, and malate was observed. This pattern in association with unchanged adenylates and decreased energy phosphate utilization was consistent with a metabolic adaptation to a state of cerebral depression. The major qualitative difference between the two drugs was that higher doses of GBL were associated with additional decreases of citrate and glutamate. Since these doses of GBL were also associated with acute increases of arterial CO2 tension, it is proposed that these differences were secondary to hypercapnia and not due to a distinctive primary action of GBL. Derivation of the cytoplasmic NAD(P)H:NAD(P)+ ratios indicated that GHB and GBL were not associated with consistent alterations of the cytoplasmic redox state.
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PMID:A comparison of the effects of gamma-hydroxybutyrate and gamma-butyrolactone on cerebral carbohydrate metabolism. 4 Jun 77

[3H]adenine was taken up by a crude hypothalamic synaptosomal fraction and incorporated into mainly nucleotides. The synaptosomes were superfused and after the initial washout a steady fractional release rate of 0.5-1% of the content/min was found. Electrical pulses (2 ms, 50 Hz, 10-20 mA, 4 min) and veratridine (10 microM, 4 min) induced a Ca++-dependent increase in purine release rate. K+ (30 mM, 4 min) caused a largely Ca++-independent increase. Most of the released material co-chromatographed with adenosine, inosine and hypoxanthine, while little or no nucleotide material was detected. Release of endogenous adenosine, inosine and hypoxanthine was detected by high performance liquid chromatography. However, following hypo-osmotic shock most of the released material was in nucleotides. The removal of glucose from the medium increased the fractional release rate 2-3 fold. Histamine, acetylcholine and glutamate were without effect. High amounts of noradrenaline caused an EGTA-inhibited release of purines, which was un-affected by propranolol or phentolamine. It is suggested that purines are released from neuronal structures and that the release reflects increased energy consumption and/or decreased energy production.
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PMID:Release of 3H-nucleosides from 3H-adenine labelled hypothalamic synaptosomes. 22 29

The distribution of radioactivity at branches and terminals of the fast axon in extensor tibiae muscle incubated in the radiolabelled putative neurotransmitter L-glutamate was determined by electron microscopic autoradiography. Quantitative analysis of the distribution of silver grains at the axon branches and terminals in preparations stimulated at a low frequency shows that most of the radioactivity is present in the glial cells. In preparations stimulated to the point of fatigue substantial radioactivity is present in both the glial cells and the axoplasm of the terminals. It is suggested that the uptake of L-glutamate into the axoplasm of the terminals is correlated with the depletion and recovery of vesicle numbers after stimulation.
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PMID:Glutamate uptake after stimulation-induced depletion of vesicle numbers in neuromuscular junctions of Locusta migratoria L. 51 29

Numerous pharmacological and clinical long-term studies on mono-magnesium-L-glutamate-hydrobromide. H2O were reason to undertake another trial in adolescents with reactive behavioral abnormalities. The aim of the study was to assess the effecacy of Psychoverlan in abolishing or improving these symptoms and to reveal any possible drug-induced side effects. In a long-term study 19 young females were treated with Psychoverlan capsules or syrup for an average of 11.4 months. Intolerance phenomena and side-effects were not seen. It was even decided to increase the standard dose. None of the patients developed brominism or bromine intoxication. The general state of health of 13 of the 19 subjects was improved by the harmonizing effect of the drug on psychic and vegetative functions. Tiredness and somnolence were not observed.
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PMID:[Long-term treatment with psychoverlan in children and adolescents with behavior disorders]. 68 Jun 16

L-Malate repressed sporulation in the wild-type strain of Bacillus subtilis. When 75 mM L-malate was added to the growth medium at the time of inoculation, the appearance of heat-resistant spores was delayed 6 to 8 h. The synthesis of extracellular serine protease, alkaline phosphatase, glucose dehydrogenase, and dipicolinic acid was similarly delayed. Sporulation was not repressed when malate was added to the culture at t4 or later. A mutant was selected for ability to sporulate in the presence of malate. This strain could also sporulate in the presence of glucose. The malate-resistant mutant grew poorly with malate as sole carbon source, although it possessed an intact citric acid cycle, and it showed increased levels of malic enzyme. This indicates a defect in the metabolism of malate in the mutant. A mutant lacking malate dehydrogenase activity was also able to sporulate in the presence of malate. A model for the regulation of sporulation by malate is presented and discussed. Citric acid cycle intermediates other than malate did not affect sporulation. In contrast to previous results, sporulation of certain citric acid cycle mutants could be greatly increased or completely restored by the addition of intermediates after the enzymatic block. The results indicate that the failure of citric acid cycle mutants to sporulate can be adequately explained by lack of energy and lack of glutamate.
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PMID:Repression of sporulation in Bacillus subtilis by L-malate. 81 66

Recent investigations from our and other laboratories indicate that glycogen is a carbon-chain precursor in muscle for the synthesis of TCA cycle intermediates and glutamine. During intense exercise and in conditions of a relative lack of energy (hypoxia, trauma, sepsis) the metabolism of branched-chain amino acids (BCAA) is accelerated in muscle. In the primary BCAA aminotransferase reaction 2-oxoglutarate is used as amino-group acceptor (putting a carbon-drain on the TCA cycle) under formation of glutamate. Glutamate will subsequently react with ammonia, generated in the AMP deaminase reaction or by deamination of amino acids, under formation of glutamine in a reaction catalysed by glutamine synthetase (glutamate + ammonia + ATP--> glutamine + ADP). Muscle glycogen stores may be smaller or less available at high altitude. It is hypothesized that this will lead to premature fatigue (due to both a lack of fuel and of TCA cycle carbon-precursor) and to a reduction in the synthesis rate of glutamine. A chronic reduction in the synthesis rate of glutamine during a long term stay at high altitude on its turn may lead to gut atrophy, bacterial translocation, endotoxemia, muscle protein catabolism and a weakened immune status.
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PMID:Amino acid metabolism, muscular fatigue and muscle wasting. Speculations on adaptations at high altitude. 148 45

The relationship between elevated plasma ammonia (NH3) levels, fatigue development and muscle metabolism were examined in horses during a submaximal fatigue test. Eight Quarter Horse mares were intravenously infused prior to exercise with either sodium acetate (control) or ammonium acetate (AMINF), and exercised to fatigue on an 11% grade treadmill, carrying 27 kg of lead. Time to fatigue was not different (P greater than 0.05) between groups. Intramuscular NH3 and lactate increased (P less than 0.001) during exercise; however, the treatment did not (P greater than 0.05) affect either. A treatment by exercise interaction (P less than 0.01) occurred for plasma NH3. The reciprocal relationship between changes in plasma and intramuscular alanine (ala) and glutamate (glu) indicated activation of the glucose-alanine cycle. Plasma glutamine (gln) increased (P less than 0.001) during exercise; however intramuscular gln was not (P greater than 0.05) altered. The excretion of urea-N was depressed as a result of exercise while the orotic acid/creatinine ratio did not (P greater than 0.05) change. The amino acids and urinary metabolites were not (P greater than 0.05) affected by treatment. These results did not show any metabolic evidence for a role of increased plasma NH3 levels in fatigue development. However this study did provide insight into other aspects of nitrogen metabolism during exercise in the horse.
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PMID:Metabolic responses to ammonium acetate infusion in exercising horses. 168 73

We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations with superimposed episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia. Cycle exercise testing revealed low maximal oxygen uptake (12 ml/min per kg; healthy sedentary men = 39 +/- 5) with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise. The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v O2 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7 +/- 2.1) despite normal oxygen carrying capacity and Hgb-O2 P50. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Qmax, patient = 303 ml/min per kg, normal men 238 +/- 36) and the slope of increase in Q relative to VO2 (i.e., delta Q/delta VO2) from rest to exercise was exaggerated (delta Q/delta VO2, patient = 29, normal men = 4.7 +/- 0.6) indicating uncoupling of the normal approximately 1:1 relationship between oxygen delivery and utilization in dynamic exercise. Studies of isolated skeletal muscle mitochondria in our patient revealed markedly impaired succinate oxidation with normal glutamate oxidation implying a metabolic defect at the level of complex II of the mitochondrial respiratory chain. A defect in Complex II in skeletal muscle was confirmed by the finding of deficiency of succinate dehydrogenase as determined histochemically and biochemically. Immunoblot analysis showed low amounts of the 30-kD (iron-sulfur) and 13.5-kD proteins with near normal levels of the 70-kD protein of complex II. Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase assessed enzymatically and immunologically whereas activities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consistent with the hypothesis that this defect impairs muscle oxidative metabolism by limiting the rate of NADH production by the tricarboxylic acid cycle.
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PMID:Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect. 191 74

The effects of microiontophoretic application of glutamate, GABA and the GABA antagonist, bicuculline methiodide were tested on the degree of adaptation exhibited by striate cortical cells to moving sin wave grating patterns. Application of GABA, which prevents firing of the cell and thereby any fatigue of the cell, did not reduce the degree of adaptation. Administration of either glutamate or GABA, without simultaneous exposure to the adapting high-contrast gratings did not reduce the sensitivity of the cell to subsequent exposure of a low-contrast grating, showing that adaptation is not caused by the excitatory or inhibitory activity of the cell itself. Application of the GABA antagonist, bicuculline did not prevent pattern adaptation, indicating that the lowered sensitivity of the cell is not mediated by a GABAergic inhibition acting on the cell. Thus adaptation of a striate neuron is not due to altered sensitivity of the cell to a constant input but depends upon changes in the input itself. It is most likely that these changes occur in a co-operative cortical network, whose effect on individual cortical cells is mediated by intracortical excitatory connections.
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PMID:Pattern adaptation in cat visual cortex is a co-operative phenomenon. 221 17

In a recent study, the total tissue contents of glutamate (Glu), ammonium (NH+4), and 2-oxoglutarate (2-OG) were used to estimate changes in the mitochondrial redox state ([NAD+]/[NADH]) of contracting skeletal muscle with intact circulation [Am. J. Physiol. 253 (Cell Physiol. 22): C263-C268, 1987]. These metabolites participate in the glutamate dehydrogenase (GDH) reaction, which, based on a number of assumptions, theoretically enables calculation of the mitochondrial redox state as follows (brackets indicate concentrations): [NAD+]/[NADH] = ([NH+4] [2-OG])/[( Glu]Kapp), where Kapp is the apparent equilibrium constant for GDH. The purpose of this study was to determine whether changes in the total tissue contents of Glu, NH+4, and 2-OG could be used to predict a reduction of the mitochondrial redox state in anoxic skeletal muscle. Anoxia was induced in the quadriceps femoris muscle by 10 min of circulatory occlusion (low metabolic rate) and isometric contraction to fatigue (high metabolic rate). The mean (+/- SE) value for the metabolite ratio ([NH+4][2-OG]/[Glu]) at rest was 6 +/- 3 mmol/kg dry wt (x 10(-4]. No significant change occurred after circulatory occlusion (4 +/- 2 x 10(-4); P greater than 0.05), whereas an almost 60-fold increase was observed after isometric contraction (P less than 0.05). Because the muscle was anoxic under both conditions, a significant decrease in the metabolite ratio should have occurred. These data demonstrate that changes in total tissue contents of Glu, NH+4, and 2-OG cannot be used to estimate changes in the redox and oxygenation state of mitochondria in intact human skeletal muscle.
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PMID:Failure of glutamate dehydrogenase system to predict oxygenation state of human skeletal muscle. 237 48


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