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PubMed1987

Comparison between acute and chronic effects of ammonia on branched-chain amino acid oxidation and incorporation into protein in primary cultures of astrocytes and of neurons.

A comparison was made of acute and chronic effects of ammonia on production of 14CO2 from the [U-14C] labeled branched-chain amino acids (BCAA) leucine, isoleucine, and valine as well as from [1-14C] leucine, and on the incorporation of radioactivity from these amino acids into a perchloric-acid-precipitable protein fraction in astrocytes and neurons in primary cultures. Acute exposure of astrocytes to 3mM ammonium chloride suppressed 14CO2 production from [U-14C] BCAA and especially from [1-14C] leucine. This inhibitory effect was abolished or even reversed [( U-14C] leucine) after chronic exposure to ammonia. Analogously, incorporation of radioactivity into the protein fraction was inhibited after acute exposure but not after chronic exposure of astrocytes to ammonia. The total protein content per culture was increased after chronic exposure. In neurons, production of 14CO2 and incorporation of 14C into proteins were less affected than in astrocytes. These results are discussed in relation to the ability of the two cell types to synthesize glutamine.

Amino Acids, Branched-Chain↗
PubMed2001

Role of glutamine in cerebral nitrogen metabolism and ammonia neurotoxicity.

Ammonia enters the brain by diffusion from the blood or cerebrospinal fluid, or is formed in situ from the metabolism of endogenous nitrogen-containing substances. Despite its central importance in nitrogen homeostasis, excess ammonia is toxic to the central nervous system and its concentration in the brain must be kept low. This is accomplished by the high activity of glutamine synthetase, which is localized in astrocytes and which permits efficient detoxification of incoming or endogenously generated ammonia. The location also permits the operation of an intercellular glutamine cycle. In this cycle, glutamate released from nerve terminals is taken up by astrocytes where it is converted to glutamine. Glutamine is released to the extracellular fluid to be taken up into the nerve cells, where it is converted back to glutamate by the action of glutaminase. Most extrahepatic organs lack a complete urea cycle, and for many organs, including the brain, glutamine represents a temporary storage form of waste nitrogen. As such, glutamine was long thought to be harmless to the brain. However, recent evidence suggests that excess glutamine is neurotoxic. Hyperammonemic syndromes (e.g., liver disease, inborn errors of the urea cycle, Reye's disease) consistently cause astrocyte pathology. Evidence has been presented that hyperammonemia results in increased formation of glutamine directly in astrocytes, thereby generating an osmotic stress to these cells. This osmotic stress results in impaired astrocyte function, which in turn leads to neuronal dysfunction. In this review a brief overview is presented of the role of glutamine in normal brain metabolism and in the pathogenesis of hyperammonemic syndromes.

Ammonia↗
PubMed2006

Comparative model of EutB from coenzyme B12-dependent ethanolamine ammonia-lyase reveals a beta8alpha8, TIM-barrel fold and radical catalytic site structural features.

The structure of the EutB protein from Salmonella typhimurium, which contains the active site of the coenzyme B12 (adenosylcobalamin)-dependent enzyme, ethanolamine ammonia-lyase, has been predicted by using structural proteomics techniques of comparative modelling. The 453-residue EutB protein displays no significant sequence identity with proteins of known structure. Therefore, secondary structure prediction and fold recognition algorithms were used to identify templates. Multiple three-dimensional template matching (threading) servers identified predominantly beta8alpha8, TIM-barrel proteins, and in particular, the large subunits of diol dehydratase (PDB: 1eex:A, 1dio:A) and glycerol dehydratase (PDB: 1mmf:A), as templates. Consistent with this identification, the dehydratases are, like ethanolamine ammonia-lyase, Class II coenzyme B12-dependent enzymes. Model building was performed by using MODELLER. Models were evaluated by using different programs, including PROCHECK and VERIFY3D. The results identify a beta8alpha8, TIM-barrel fold for EutB. The beta8alpha8, TIM-barrel fold is consistent with a central role of the alpha/beta-barrel structures in radical catalysis conducted by the coenzyme B12- and S-adenosylmethionine-dependent (radical SAM) enzyme superfamilies. The EutB model and multiple sequence alignment among ethanolamine ammonia-lyase, diol dehydratase, and glycerol dehydratase from different species reveal the following protein structural features: (1) a "cap" loop segment that closes the N-terminal region of the barrel, (2) a common cobalamin cofactor binding topography at the C-terminal region of the barrel, and (3) a beta-barrel-internal guanidinium group from EutB R160 that overlaps the position of the active-site potassium ion found in the dehydratases. R160 is proposed to have a role in substrate binding and radical catalysis.

Amino Acid Sequence↗
PubMed1998

N-carbamoyl-L-glutamate plus L-arginine can protect ammonia intoxication in rats with reduced functional liver mass.

We previously reported the protective effect of N-carbamoyl-L-glutamate plus L-arginine in rats given a lethal dose (LD99.9) of ammonium acetate (Kim, S. et al., Proc. Natl. Acad. Sci. 69, 3530-3533, 1971; ref.1). The present study was undertaken to find out whether the same compounds could also be effective even after the functional mass of the liver was significantly reduced. Thus, the protective effect of these compounds in 70% partial hepatectomized rats following the injection of sublethal dose of ammonium acetate was assessed. The mixture could significantly decrease blood ammonia level compared with PBS-injected control group. In addition, abnormal behaviors observed in the control rats were significantly improved. The protective effect on the behavioral change seemed to be closely related with their effect on blood ammonia level, showing a strong correlation between the blood ammonia level and the behavioral score. The findings provide a rational basis for the clinical use of N-carbamoyl-L-glutamate plus L-arginine in the prevention and treatment of hyperammonemia encountered in liver diseases.

Acetates↗
PubMed2000

Using constructed wetlands to treat biochemical oxygen demand and ammonia associated with a refinery effluent.

This study evaluated the effectiveness of constructed wetlands for tertiary treatment of a petroleum refinery effluent. Specific performance objectives were to decrease 5-day biochemical oxygen demand (BOD(5)) and ammonia by at least 50% and to reduce toxicity associated with this effluent. Two bench-scale wetlands (replicates) were constructed in a greenhouse to provide tertiary treatment of effluent samples shipped from the refinery to the study site. Integrated wetland features included Typha latifolia Linnaeus planted in low organic (0.2%), sandy sediment, 48-h nominal hydraulic retention time, and 15-cm overlying water depth. Targeted constituents and aqueous toxicity were monitored in wetland inflows and outflows for 3 months. Following a 2 to 3-week stabilization period, effective and consistent removal of BOD(5) and ammonia (as NH(3)-N) from the effluent was observed. Average BOD(5) removal was 80%, while NH(3)-N decreased by an average of 95%. Survival of Pimephales promelas Rafinesque and Ceriodaphnia dubia Richard (7-day, static, renewal exposures) increased by more than 50% and 20%, respectively. Reproduction of C. dubia increased from zero in undiluted wetland inflow to 50% of controls in undiluted wetland outflow. This study demonstrated the potential for constructed wetlands to decrease BOD(5), ammonia, and toxicity in this refinery effluent.

Ammonia↗
PubMed1988

Dynamic positron emission tomography with 13N-ammonia in liver tumors.

Dynamic positron emission tomography (PET) of the liver tumor was performed with a whole body multi slice PET device and 13N-ammonia. Sixteen patients with hepatocellular carcinoma (HCC) and seven patients with metastatic liver tumor were studied. In 12 of 16 patients with HCC, in which cases rich tumor vessels and dense tumor stain were proven by hepatic angiography, the tumors showed remarkable uptake of 13N-ammonia from the first scan, whereas the radionuclide accumulation was more gradual in the other part of the liver, and high tumor to liver ratio (T/L ratio) (2.62 +/- 1.09) was observed in the 1st scan, so that the tumor was clearly visualized by high contrast. However, HCC with poor blood supply from the hepatic artery or central necrosis of the tumor were demonstrated as low T/L ratio. In seven cases with metastatic liver tumor, the accumulation of 13N-ammonia was also lower than the normal liver throughout the scan. The results suggested that hepatic arterial blood flow of the liver tumors can be assessed with dynamic PET, which may provide valuable information for the characterization of tumors as well as for the evaluation of the treatment.

Ammonia↗
PubMed1985

Myocardial positron computed tomography with 13N-ammonia at rest and during exercise.

To assess the value of myocardial-perfusion positron computed tomography (PCT) for the evaluation of coronary artery disease (CAD), 13N-ammonia PCT using a whole-body multislice PCT device was performed at rest and during exercise in 6 normal subjects and 19 patients with angiographically documented CAD. The 13N-ammonia distribution in the myocardium was assessed both qualitatively and quantitatively. At rest and during exercise, the tracer distribution was homogeneous in the 6 normal cases. In the 19 patients with CAD, regional hypoperfusion was observed in 14 cases (74%) at rest and in 18 cases (95%) during exercise. Additional perfusion abnormalities were detecting during exercise in 12 cases. Segmental analysis of the myocardial perfusion identified 30 out of 34 stenosed vessels (88%) during exercise, with only one false-positive finding of diseased vessels (specificity, 98%). For the quantitative analysis of myocardial perfusion by PCT, the percentage of change in the tracer concentration in the same region between the rest and stress images was calculated. The concentration was slightly increased in normal myocardial segments (14.4% +/- 5.8%; P less than 0.001), whereas in CAD, it was significantly decreased in segments with stenosed vessels (-18.0% +/- 18.3%; P less than 0.02). We conclude that 13N-ammonia PCT at rest and during exercise provides high-quality images, and is a sensitive and effective technique for detecting CAD and identifying individual stenosed vessels. Furthermore, this technique makes possible quantitative assessment of the coronary reserve function.

Adult↗
PubMed1991

The influence of dietary manipulation on plasma ammonia accumulation during incremental exercise in man.

The influence of a pattern of exercise and dietary manipulation, intended to alter carbohydrate (CHO) availability, on pre-exercise acid-base status and plasma ammonia and blood lactate accumulation during incremental exercise was investigated. On three separate occasions, five healthy male subjects underwent a pre-determined incremental exercise test (IET) on an electrically braked cycle ergometer. Each IET involved subjects exercising for 5 min at 30%, 50%, 70% and 95% of their maximal oxygen uptake (VO2max) and workloads were separated by 5 min rest. The first IET took place after 3 days of normal dietary CHO intake. The second and third tests followed 3 days of low or high CHO intake, which was preceded by prolonged exercise to exhaustion in an attempt to deplete muscle and liver glycogen stores. Acid-base status and plasma ammonia and blood lactate levels were measured on arterialised venous blood samples immediately prior to and during the final 15 s of exercise at each workload and for 40 min following the completion of each IET. Three days of low CHO intake resulted in the development of a mild metabolic acidosis in all subjects. Plasma ammonia (NH3) accumulation on the low-CHO diet tended to be greater than normal at each exercise workload. Values returned towards resting levels during each recovery period. After the normal and high-CHO diets plasma NH3 levels did not markedly increase above resting values until after exercise at 95% VO2max. Plasma NH3 levels after the high-CHO diet were similar to those after the normal CHO diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗
PubMed1987

The effect of propranolol on the rise in plasma ammonia during modest exercise.

Changes in plasma ammonia in response to exercise with and without pretreatment with propranolol have been studied. A standardised submaximal treadmill exercise test was used to assess the effects of placebo or propranolol 40 mg, 80 mg, or 160 mg twice daily given in random order for 3 days, the last dose being taken 90 min before exercise. After placebo the mean incremental rise in plasma ammonia in response to exercise was 16 mumol X 1(-1). The corresponding rise after propranolol 40 mg was 56 mumol X 1(-1) (p less than 0.01). All three doses of propranolol produced similar effects on plasma ammonia and exercise heart rates.

Adolescent↗
PubMed1985

Effect of chronic metabolic acidosis on ammonia production from L-glutamine in microdissected rat nephron segments.

To evaluate the role of each nephron segment in renal ammoniagenesis, distribution of renal ammoniagenic activity along the nephron in control and acidotic rats was examined. We used our original aerobic incubation system and ammonia produced from glutamine in 7 defined segments of microdissected nephron was measured using the enzymatic cycling method. When ammonia production in the control was compared in each nephron segment, the highest specific activity of ammoniagenesis per mm tubular length and that per microgram protein were observed in the proximal straight tubule (PST) and the thick ascending limb of Henle's loop, respectively. Chronic metabolic acidosis increased ammonia production per mm tubular length markedly in the proximal convoluted tubule (PCT) (+171%), moderately in the medullary collecting tubule (+123%) and PST (+77%), and slightly in the distal convoluted tubule (+52%), revealing that the highest activity of ammoniagenesis was located in PCT and PST in acidosis. These data indicate that proximal tubules have major roles in renal ammoniagenesis both in the control and in acidosis. From the early observation of glutaminase I isoenzyme distribution along the nephron, our data suggest that not only phosphate-dependent glutaminase but also phosphate-independent glutaminase may have important roles in renal ammoniagenesis.

Acidosis↗
PubMed1982

The effect of pulmonary stretch receptor activity on the respiratory response to ammonia-inhalation.

The contribution of pulmonary stretch receptor (SR) activity to the changes in breathing pattern (f, VT, tI, tE, tI: tE) following inhalation of ammonia vapour has been studied in rabbits at three levels of lung distension, i.e., three levels of SR activity, and during reversible SO2-blockade of SR. The result show that the increase in breathing frequency (f) and the decrease in tidal volume (VT) due to ammonia inhalation are almost identical for animals with and without blockade of SR, whereas the duration of inspiration and expiration (tI, tE) as well as their relationship (tI:tE) vary considerably, the variations depending on the level of SR activity. For a given tI the expiration was longer in animals with SR intact than in animals with SR blocked. It is concluded that in rabbits the increased activity of SR after inhalation of ammonia counteracts significantly the predominant effects of irritant (deflation) receptor stimulation, thus rendering possible a longer expiration.

Ammonia↗
PubMed1978

Transient change in the ATP pool of Anabaena cylindrica associated with ammonia assimilation.

When N2-grown cells of Anabaena cylindrica were exposed to ammonia (50 micron to 5 mM) in the dark, the size of the ATP pool was reduced by 40% within 1 min, but restored after 5 or 6 min. The decrease in ATP was accompanied by increases in ADP and AMP, while the total adenylate content remained unaltered. The ammonia-induced change in the ATP pool was completely eliminated when algal cells were treated with L-methionine-DL-sulfoximine, an inhibitor of glutamine synthesis. These results suggest that ammonia is rapidly assimilated through the pathway mediated by glutamine synthetase accompanied by reduction of the ATP pool.

Adenosine Diphosphate↗
PubMed1984

Novel formation of alpha-amino acids from alpha-oxo acids and ammonia in an aqueous medium.

In the course of a study of possible mechanisms for chemical evolution in the primeval sea, we found the novel formation of alpha-amino acids and N-acylamino acids from alpha-oxo acids and ammonia in an aqueous medium. Glyoxylic acid reacted with ammonia to form N-oxalylglycine, which gave glycine in a 5-39% yield after hydrolysis with 6N HC1. Pyruvic acid and ammonia reacted to give N-acetylalanine, which formed alanine in a 3-7% overall yield upon hydrolysis. The pH optima in these reactions were between pH 3 and 4. These reactions were further extended to the formation of other amino acids. Glutamic acid, phenylalanine and alanine were formed from alpha-ketoglutaric acid, phenylpyruvic acid and oxaloacetic acid, respectively, under similar conditions. N-Succinylglutamic acid was obtained as an intermediate in glutamic acid synthesis. Phenylacetylphenylalanineamide was also isolated as an intermediate in phenylalanine synthesis. Alanine, rather than aspartic acid, was produced from oxaloacetic acid. These reactions provide a novel route for the prebiotic synthesis of amino acids. A mechanism for the reactions will be proposed.

Amino Acids↗
PubMed1982

Regulation of glutaminase by exogenous glutamate, ammonia and 2-oxoglutarate in synaptosomal enriched preparation from rat brain.

Phosphate activated glutaminase in synaptosomal enriched preparation from rat brain is very sensitive to inhibition by low concentration of glutamate, ammonia and 2-oxoglutarate when added to the incubation medium at pH 7.6. By increasing the concentration of either of these compounds up to 0.5 mM a pronounced initial inhibition is followed by little or no further effect when the concentration is increased beyond this level. By lowering the pH of the reaction mixture to 7.0, the inhibition by glutamate is almost abolished and that of ammonia reduced. Glutamate inhibits mainly the N-ethylmaleimide-sensitive fraction of glutaminase which previously is suggested to be localized to the outer phase of the mitochondrial inner membrane whereas ammonia inhibits both the N-ethylmaleimide-sensitive and -insensitive fraction. Evidence has been produced to show that the inhibition by 2-oxoglutarate is caused by glutamate formation by aminotransferase reactions. Since 2-oxoglutarate is produced by the tricarboxylic acid cycle, the operation of this cycle may regulate the glutaminase reaction by controlling glutamate formation via the aminotransferase reactions.

Ammonia↗
PubMed1994

Effects of chronic exposure to ammonia on glutamate and glutamine interconversion and compartmentation in homogeneous primary cultures of mouse astrocytes.

Accumulation of radioactivity was studied in primary cultures of mouse astrocytes as a function of time of exposure (4-60 min) to 50 microM glutamate and 200 microM glutamine (initial concentrations), of which either glutamate or glutamine was 14C-labeled. Both the glutamate pool and the glutamine pool were compartmentalized. Initially, by far the major intracellular glutamate pool (> or = 90%) was derived from extracellular glutamate and could be converted to glutamine. This allowed a rather accurate determination of metabolic flux from glutamate to glutamine, which under control conditions amounted to 2.0-2.2 nmol/min per mg protein. After chronic exposure to 3 mM ammonia for 3 days this flux was significantly increased to 3.1-3.6 nmol/min per mg protein. Acute exposure to ammonia caused a smaller, apparent increase, which was not statistically significant. The glutamine content was compartmentalized at all stages of the incubation. It consisted of at least two different pools. One of these was accessible to extracellular glutamine and could be converted to intracellular glutamate (constituting a sizeable fraction of the total glutamate pool after longer incubation), whereas the other constituted endogenously derived glutamine, formed from accumulated glutamate. The specific activity of the precursor pool for glutamate synthesis could not be accurately determined and relatively exact fluxes therefore not be calculated. There was, however, no evidence that chronic exposure to ammonia decreases the rate of glutamine hydrolysis.

Ammonia↗
PubMed1994

Functional relationship between ammonia and gangliosides in brain.

The functional significance of ammonia production in brain under physiological or pathological conditions is not clearly known. NH4+ stimulates Na+, K+ activated ATPase causing stabilization of neuronal membranes of which gangliosides are major structural components. Moreover ammonia is known to inhibit lysosomal enzymes which include enzymes degrading gangliosides. Gangliosides have been shown to stimulate neuritogenesis in neuronal cultures and prevent the damage of the neurons from glutamate toxicity particularly in areas of brain ischemia. Hyperammonemia without any behavioural changes was induced in experimental rats by intraperitoneal administration of either a single dose (0.8 mmol/100 g wt.) or by six 'hourly' doses (0.6 mmol/100 g wt.) of ammonium acetate. An increase in the content of gangliosides along with a rise in the content of GD1A and GD1B without any change in beta-galactosidase and N-acetylhexosaminidase was observed in cerebral cortex, cerebellum, and brain stem, following the administration of single dose of ammonium acetate. Gangliosides, after extraction from the different brain regions, were estimated by the thiobarbituric acid method and expressed in terms of sialic acid. Individual gangliosides were separated and estimated by thin layer chromatography using resorcinol as the staining agent. These results suggest that ammonia production in the neuronal pathways in brain either as a result of repeated stimulation under physiological conditions or as a result of focal ischemia or injury, may likewise cause an increase in the content of gangliosides which may help in neuritic growth (physiological conditions facilitating synaptic plasticity) and may exert a protective effect on the neurons in the ischemic area against glutamate toxicity.

Acetates↗
PubMed1989

The effect of ammonia infusion on brain monoamine metabolism in portacaval-shunted rats.

The effect of ammonia infusion on monoamine metabolism was studied in the rat brain. Seven days after portocaval shunt (PCS) or sham operation animals were infused with ammonia or saline. Brain metabolism of serotonin and norepinephrine was studied after injection of a decarboxylase inhibitor (m-hydroxybenzylhydrazine, NSD 1015) which blocks the conversion of 5-hydroxytryptophan to serotonin and dihydroxyphenylalanine to dopamine. Neurologic testing was conducted before killing. Plasma and brain amino acids were measured. PCS animals infused with ammonia were in deep coma after 6 h infusion, whereas sham-operated animals were virtually unaffected. Brain amino acid analyses demonstrated increased concentrations of the aromatic amino acids and a tenfold increase in glutamine. Serotonin metabolism was diminished after 6 h. Dopamine synthesis was normal, but norepinephrine levels were low after 6h. The study suggests that hyperammonemia in PCS rats results in a depression of the serotonin synthesis rate in accordance with two previous studies but in contrast to previous hypotheses on the regulation of serotonin metabolism.

5-Hydroxytryptophan↗
PubMed1985

Effect of ammonia on plasma and cerebrospinal fluid amino acids in dogs with and without portacaval anastomoses.

To elucidate the possible connection between ammonia-induced changes of plasma and cerebrospinal fluid (CSF) amino acid levels and the development of hepatic encephalopathy in dogs, beagle dogs were given an ammonium acetate infusion both before and following portacaval shunt (PCS). During ammonia-induced coma and after recovery in the dogs prior to PCS the plasma and CSF concentrations of most amino acids were decreased. Following PCS the plasma and CSF concentrations of the aromatic amino acids (AAA), phenylalanine and tyrosine, increased and the levels of the branched chain amino acids (BCAA), valine, leucine, and isoleucine, decreased during ammonia-induced coma. The CSF/plasma molar ratio for the AAA exhibited a marked increase after recovery as compared to the value during coma in the Eck-fistula dogs. With respect to the AAA, no correlation was observed between signs of neurologic impairment in the animals and the following parameters: glutamine and methionine levels of CSF, and the plasma molar ratio (Formula: see text). The data obtained do not support the hypothesis that high concentrations of phenylalanine and tyrosine in the brain may be primarily responsible for altered neurotransmission leading to the development of hepatic encephalopathy.

Amino Acids↗