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PubMed1977

Clearance of phenylalanine ammonia-lyase from normal and tumor-bearing mice.

Yeast phenylalanine ammonia-lyase was administered i.p. to normal and tumor-bearing mice, and its clearance from plasma was studied. Single and multiple weekly injections at dosages of 10,20,50 and 100 units/kg were administered to C57BL female, C57BL X DBA/2F1 male, and A/J female mice. L5178Y murine lymphoblastic leukemia, B16 melanoma, BW10232 adenocarcinoma, and 15091A anaplastic carcinoma were implanted 7 to 11 days prior to enzyme injection in the appropriate host. After a single injection, the average plasma half-lives of phenylalanine ammonia-lyase were 18 to 24 hr in all groups studied. While the other tumors had no effect on the plasma level of phenylalanine ammonia-lyase after a single injection, L5178Y murine lymphoblastic leukemia and 15091A anaplastic carcinoma significantly depressed the maximal level of phenylalanine ammonia-lyase attained in the plasma. After repeated injections of phenylalanine ammonia-lyase, the initial plasma enzyme level was significantly reduced when 20 units/kg were administered, and the clearance of the enzyme from the plasma was greatly accelerated regardless of the amount administered. Furthermore, in tumor-bearing mice, the rate of clearance was significantly more rapid than in the appropriate non-tumor-bearing control.

Adenocarcinoma↗

PubMed1997

Helicobacter pylori vacuolating toxin accumulates within the endosomal-vacuolar compartment of cultured gastric cells and potentiates the vacuolating activity of ammonia.

This study explored the relationship between vacuolating toxin and ammonia in the genesis of Helicobacter pylori-induced vacuolation in cultured human gastric cells and investigated the intracellular sites of toxin accumulation. Neutral red dye uptake and electron microscopy were used in the investigation of the respective roles of, and of the reciprocal interaction between, toxin and ammonia in cell vacuolation and ultrastructural immunocytochemistry was used for the identification of the intracellular sites of internalized toxin. Toxin was found to cause an expansion of the endosomal compartment, where it accumulates after cellular internalization. However, toxin does not form large, neutral red-positive vacuoles unless combined with ammonia, whose moderate vacuolating activity is markedly potentiated by the toxin. It is concluded that the toxin accumulated within the endosomal compartment alters the morphology and function of this organelle and plays a permissive role towards cell vacuolation, possibly by increasing the accumulation of protonated ammonia within endosomes. In turn, ammonia induces excessive dilatation of the endosomes with reciprocal fusion of their membranes, thus causing cytoplasmic vacuolation.

Ammonia↗

PubMed1998

Roles of neuroactive amino acids in ammonia neurotoxicity.

Many neurologic disorders are related to congenital or acquired hyperammonemia (HA). Advanced symptoms of HA range from seizures in acute stages to stupor and coma in more chronic conditions, manifesting variable imbalance between the inhibitory and excitatory neurotransmission. Evidence obtained with the use of experimental HA models suggests that acute neurotoxic effects of ammonia are mediated by overactivation of ionotropic glutamate (GLU) receptors, mainly the N-methyl-D-aspartate (NMDA) receptors, and to a lesser degree the KA/AMPA receptors. NMDA receptor-mediated neurotoxicity may be potentiated by impaired control of their function by metabotropic GLU receptors, which are inactivated by ammonia. Prolonged overactivation of the NMDA receptors upon extended ammonia exposure causes their downregulation. The GLU receptor changes may be related to their excessive exposure to extrasynaptic GLU. Ammonia promotes GLU accumulation in the extrasynaptic space by enhancing its release from neurons, and/or by decreasing its reuptake to the nerve endings and astrocytes, where the effect results from inactivation (downregulation) of the astrocytic glutamate transporter GLT1. Excitotoxic effects of ammonia are augmented by increased synthesis of nitric oxide (NO), which is associated with NMDA receptor activation and/or increased synaptic transport of arginine (ARG). A shift toward neural inhibition is promoted by positive modulation of the gamma-aminobutyric acid (GABA)ergic tone resulting from excessive accumulation in the brain of endogenous central benzodiazepine receptor agonists, and from upregulation of astrocytic peripheral benzodiazepine receptors leading to elevated levels of prognenelone-derived neurosteroids, which positively modulate the GABA(A) receptor complex. Inhibitory neurotransmission may also be favored by enhanced release from astrocytes of an inhibitory amino acid, taurine.

Ammonia↗

PubMed2004

Experimental human exposure to inhaled grain dust and ammonia: towards a model of concentrated animal feeding operations.

BACKGROUND: Ammonia and endotoxin-rich dust are present in high concentrations in swine confinement facilities; exposure to this environment is linked to workers' respiratory problems. We hypothesized that experimental exposure to ammonia and dust would impair pulmonary function, and that these exposures would be synergistic. METHODS: We exposed six normal subjects and eight subjects with mild asthma to ammonia (16-25 ppm) and/or endotoxin-rich grain dust (4 mg/m3). Pulmonary function and exhaled NOx were measured before and after exposure. RESULTS: There was no significant change in pulmonary function in the normal subjects following any of the exposure conditions. Among asthmatics, a significant transient decrease in FEV1 was induced by grain dust, but was not altered by ammonia; increased bronchial hyperreactivity was also noted in this group. CONCLUSION: In a vulnerable population, exposure to grain dust results in transient airflow obstruction. Short-term exposure to ammonia does not increase this response.

Adult↗

PubMed2004

Regional differences in cerebral blood flow and cerebral ammonia metabolism in patients with cirrhosis.

Clinical and histopathological findings hint at regional differences in the brain's sensitivity to metabolic changes in cirrhosis. The aim of the present study was to examine regional differences in cerebral ammonia metabolism in patients with cirrhosis and grade 0-to-I hepatic encephalopathy (HE). (13)N-ammonia, (15)O-water positron emission tomography (PET) and magnetic resonance imaging (MRI) were performed. Quantitative values of cerebral blood flow (CBF) and the initial cerebral ammonia uptake rate (K1) were derived for several regions of interest from images of the desired parameters after interactive coregistration with the patients' MRI-studies. CBF (mL/mL/min), K1 (mL/mL/min), and the ammonia extraction fraction (K1/CBF) showed marked regional variance with the highest levels in the thalamus, the lenticular nucleus, and the cerebellum. In conclusion, the regional differences in cerebral ammonia uptake correspond to the distribution of histopathological changes in the brain of patients with cirrhosis as well as clinical features of HE, characterized by signs of basal ganglia and cerebellar dysfunction with corresponding signs of functional impairment, especially of the frontal cortex and cingulate gyrus.

Adult↗

PubMed2001

Ammonia-induced production of free radicals in primary cultures of rat astrocytes.

Elevated levels of ammonia in blood and brain result in derangement of cerebral function. Recently, lipid peroxidation and oxidative stress have been implicated in ammonia neurotoxicity. Because ammonia is primarily detoxified in astrocytes, we postulated that pathophysiological concentrations of ammonia might induce free radical formation in these cells. To test this hypothesis, we examined the extent of free radical production in primary cultures of astrocytes that had been preloaded with the fluorescent dye 5- (and 6-)carboxy-2',7'-dichlorodihydrofluorescein diacetate (DCFDA). DCFDA fluorescence was found to be increased in a dose-dependent manner when astrocytes were exposed to 1, 5, and 10 mM NH(4)Cl. This phenomenon was transitory; it peaked at 2.5 min after exposure and declined subsequently. By 2 hr after treatment, DCFDA fluorescence was below control level. Addition of catalase or superoxide dismutase to 5 mM NH(4)Cl-treated astrocytes reduced free radical formation. Pretreatment with 3 mM methionine sulfoximine, an inhibitor of glutamine synthetase, also suppressed free radical formation by 5 mM NH(4)Cl. The results of this study suggest that elevated concentrations of ammonia induce the formation of free radicals in astrocytes and that this process is associated with the synthesis of glutamine. We propose that astrocyte-derived free radicals may be responsible for some of the pathophysiological changes associated with hyperammonemic conditions.

Ammonium Chloride↗

PubMed2001

Glutamate transporter and receptor function in disorders of ammonia metabolism.

Disorders of ammonia metabolism including urea cycle enzymopathies, Reye Syndrome, and liver failure are associated with brain edema and severe neurological impairment. Excess blood-borne ammonia crosses the blood-brain barrier by diffusion as NH(3) where it interacts with various cellular processes involved in neurotransmission and brain energy metabolism. Ammonia exerts a potent effect on glutamate (AMPA) receptor-mediated neurotransmission. Ammonia also inhibits high affinity transport of glutamate by an action on astrocytic glutamate transporter expression, an action which results in increased extracellular concentrations of glutamate. Acute hyperammonemia directly activates the NMDA subclass of glutamate receptors resulting in increased intracellular Ca(2+) and increased synthesis of nitric oxide and cGMP. Chronic hyperammonemia, on the other hand, results in a loss of NMDA receptor sites. Activation of NMDA receptors in acute ammonia toxicity results in depletion of ATP in brain. Neuropathologic studies in experimental animals with congenital urea cycle disorders and severe hyperammonemia reveal evidence of neuronal cell death which is excitotoxic in nature. These findings suggest that overactivation of NMDA receptors is a significant feature of acute hyperammonemic syndromes and that antagonists of these receptors or of their signal transduction pathway enzymes such as nNOS could be beneficial in the treatment of the central nervous system manifestations (encephalopathy, brain edema) which are characteristic of hyperammonemic disorders.

Adenosine Triphosphate↗

PubMed2000

Calibrationless determination of creatinine and ammonia by coulometric flow titration.

A precise and sensitive working microflow titration procedure was developed to determine creatinine and ammonia in urine samples. This procedure is based on enzymatic conversion of creatinine, gas diffusional membrane separation of the released ammonia into an acid acceptor stream, and coulometric titration of ammonia with hypobromite. The hypobromite is formed after the electrogeneration of bromine in an electrolyte containing 1.0 M NaBr and 0.1 M sodium borate adjusted to pH 8.5. The electrolysis current follows a triangle-programmed current-time course. An amperometric flow detector records the resulting mirror symmetrical titration curves, which show two equivalence points. The analyte concentration is calculated from the time difference between the equivalence points. For quantitative conversion of creatinine and quantitative separation of present and released ammonia no calibration is necessary to get accurate results. Both ammonia/ammonium and creatinine were determined in the range between 2 microM and 2 mM with relative standard deviations between 3.0 and 1.0% (n = 5). High recoveries were obtained for the analysis of diluted urine samples for both creatinine and ammonia.

Aminohydrolases↗

PubMed1995

Histopathological changes induced by chronic nonlethal levels of elsan, mercury, and ammonia in the small intestine of Channa punctatus (Bloch).

Histopathological changes in the intestine of Channa punctatus induced by chronic nonlethal levels of Elsan (211 ppb), mercury (16.7 ppb), and ammonia (15.64 ppm) were studied at 7-day intervals for 90 days and the data were presented only for days (7, 28, 63, and 90) when the most conspicuous changes were noted after treatment. In the earlier phases of Elsan treatment (7 and 28 days) overall destruction of the structure of villus and other layers was prominent. Histopathology of the intestine of C. punctatus, after 63-day Elsan exposure, could be described as collapsed villi with the tips merged with each other to give a flattened appearance. Ninety-day Elsan exposure demonstrated severe damage in the longitudinal muscle layer. After 7-day mercury treatment a high degree of necrosis was indicated by submucosal area, whereas 28-day mercury treatment revealed collapsed villi due to necrotic mucosal cells and goblet cells. Mercury treatment for 63 days caused disarray of all the layers, but some improvement of villus organization was noted in fish treated with mercury for 90 days. Seven-day exposure to ammonia deteriorated the normal structure of the villus, whereas in 28-day ammonia exposure, lesions were predominant in the submucosal layers. Sixty-three-day ammonia treatment demonstrated an effect similar to that produced by Elsan, associated with a more complete destruction of all the layers. Fishes under ammonia treatment for 90 days demonstrated extensive damage to the mucosal folds. The major changes in thickness of different layers of the intestine were also evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonia↗

PubMed1982

The regulation of the ammonia assimilatory enzymes in Rel+ and Rel- strains of Salmonella typhimurium.

The influence of the relA1 mutation on the regulation of the ammonia assimilatory enzymes, glutamate dehydrogenase (EC 1.4.1.4), glutamine synthetase (EC 6.3.1.2), and glutamate synthase (EC 1.4.1.3), was examined. When cells grown in rich media (either Luria broth or glucose-ammonia plus casamino acids) were transferred to a glucose-ammonia medium, the relA mutant failed to resume growth and did not have the same increase in any of the assimilatory enzyme activities as the rel+ strain. This effect was particularly dramatic for glutamate dehydrogenase, which increased 6-fold in the rel+ strain. Measurements of the guanosine nucleotide concentrations showed that the rel+ strain had a ppGpp concentration about 9 times that of the relA mutant 5 min after the shift to minimal medium. These results are consistent with those for other biosynthetic enzymes and show that the ammonia assimilatory enzymes require a relA product for their synthesis during shift from rich to minimal media. In addition, we examined the response of these strains to a change in nitrogen source. The relA mutant again failed to resume growth after a shift from glucose-ammonia to glucose-arginine medium. Even though the ppGpp concentration did not increase, the rel+ strain grew and increased glutamine synthetase activities about 2-fold. These changes the absence of increased ppGpp levels suggest that some other relA-mediated function is important during this change in nitrogen source.

Ammonia↗

PubMed1990

The relationship of plasma ammonia and lactate concentrations to perceived exertion in trained and untrained women.

The purpose of this study was to investigate the covariance between perceived exertion (recorded using Borg's category-ratio scale CR-10) and the relative oxygen uptake, and lactate and ammonia concentrations in blood from a peripheral vein. Ratings of perceived exertion (RPE) at 25%, 50%, 75% and 90% maximal oxygen uptake and lactate and ammonia concentrations were compared in well-trained women distance runners (n = 22) and untrained women (n = 10). Ammonia concentrations in peripheral venous blood were significantly correlated with RPE (P less than 0.05), both in the trained and untrained women. Differences between the trained and untrained subjects occurred when the ammonia concentration increased to 148 mumol.l-1 in both groups investigated; similarly, the mean RPE correlated significantly with the lactate concentration (P less than 0.05), both in the trained and untrained women and there was a difference in RPE between groups when lactate concentration in the blood had risen to 4.4 mmol.l-1. It would seem that the correlation of blood ammonia and lactate concentrations with RPE during exercise could be a useful indicator of the development of fatigue.

Adolescent↗

PubMed1983

Changes in blood ammonia, lactate and amino acids in relation to workload during bicycle ergometer exercise in man.

Whole body exercise at intensities up top 50% VO2max has no effect on the concentration of blood ammonia but a threefold rise in blood ammonia is observed at workloads up to maximal. There is a linear relationship between blood ammonia and lactate production during exercise which suggests that the two processes may be linked to a common process of short-term energy provision. Blood glutamine and blood alanine both show rises linearly related to power output during exercise, suggesting that if these amino acids are sinks for ammonia then the process of ammonia incorporation is saturated at high workloads.

Adenine Nucleotides↗

PubMed1993

High ammonia diet: its effect on the glial fibrillary acidic protein (GFAP).

The effect of a recent hyperammonemic model, consisting of a high ammonia diet for 3, 7, 15, 45, and 90 days, on glial fibrillary acidic protein (GFAP) in the rat spinal cord and on blood ammonia levels has been studied. The high ammonia diet was prepared by mixing a standard diet with ammonium acetate (20% wt/wt); in addition, 5 mM of ammonium acetate was added to the water supply. GFAP contents were determined by means of immunoblotting analysis. The results demonstrated that this high ammonia diet model neither induces significant changes in GFAP immunoreactivity, nor modifies total protein concentration, and only induces significant blood hyperammonemic levels in the first days of treatment. An adaptive response to the diet is suggested and discussed to explain these results. A relation between ammonia and GFAP expression is suggested because transient hyperammonemia induces transient, although no significant, changes on GFAP expression.

Ammonia↗

PubMed1991

Chronic effect of intragastric ammonia on gastric mucosal structures in rats.

The prevalence of Helicobacter pylori (HP) in the gastric mucosa of patients with chronic atrophic gastritis has been reported to be significantly higher than in normal mucosa. To clarify the role of HP in the etiology of chronic atrophic gastritis, we assessed the effect of ammonia on the gastric mucosal structure in rats, since HP has a strong urease activity and produces abundant amounts of ammonia. Ammonia administered orally at 0.01% and 0.1% as drinking water for two to four weeks decreased the mucosal thickness and the parietal cell number and oxyntic gland number in a dose- and time-dependent manner. The decrease of mucosal thickness was significantly greater in the antral mucosa than in the body mucosa. The border between the antral and body mucosa shifted toward the cardia, reflecting the decrease in oxyntic gland numbers. Furthermore, intracellular mucin was also decreased in a dose- and time-dependent manner, especially in the antral mucosa. Thus, ammonia chronically administered orally in rats led to changes in gastric mucosal structures and functions. The results suggest that the ammonia produced by HP partly plays an etiologic role in chronic atrophic gastritis.

Administration, Oral↗

PubMed1989

Influence of peripheral arterial occlusive disease on muscular metabolism. Part 1: Changes in lactate, ammonia, and hypoxanthine concentration in femoral blood.

The concentrations of lactate, ammonia and hypoxanthine were determined in blood from the femoral artery, femoral vein and cubital vein under resting conditions in 23 patients with stage II, 10 patients and 20 diabetics with stage IV peripheral arterial occlusive disease (PAOD) and in 19 healthy subjects. The metabolite concentrations were also measured immediately and 20 min after calf exercise in the patients with stage II PAOD and in the controls. At rest, there was a negative arteriovenous difference in femoral lactate level and a positive arteriovenous difference in the ammonia level in all groups. After exercise to the claudication limit, the femoral venous concentration and arteriovenous difference for lactate increased in the patient group significantly higher than in the controls, who were exercised three times as heavily. Furthermore, there was a significant rise in femoral venous ammonia concentration with inversion of the arteriovenous difference into the negative range and an increase in femoral venous hypoxanthine concentration only in the patients with PAOD and not in the controls. A significant correlation was found between the exercise-induced increases in lactate and ammonia. The results indicate activation of the purine nucleotide cycle in the muscles of limbs with impaired circulation, even for a short duration of load. This can be explained by activation of the AMP-deaminase in type I and type IIa muscle fibres by anoxaemia. The purine nucleotide cycle has an emergency metabolic function in ischaemia to maintain muscle contractility. Ammonia determination in femoral blood permits, in association with lactate and hypoxanthine determination, a precise quantitative assessment of the metabolic effects of PAOD.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1985

Excitatory and inhibitory amino acid neurotransmitters and ammonia metabolism in hepatic failure rats.

The molar ratio of excitatory amino acid neurotransmitters (glutamate and aspartate) to inhibitory amino acid neurotransmitters (r-aminobutyric acid, GABA, and glycine) in the brain was diminished in acute hepatic failure rats with hyperammonemia, brain edema, and abnormal electroencephalograms. The ratio was further decreased with a marked elevation of arterial and brain ammonia levels 30 min after ammonium acetate was administered i.p. to hepatic failure rats. A continuous infusion of a branched chain amino acid (BCAA) solution before and after the ammonia loading effectively reversed the ammonia-induced lowering of this ratio; high ammonia contents in the brain were concomitantly decreased. Infusing glutamate instead of the BCAA solution failed to produce similar effects probably because of limited entry of glutamate into the brain. The above results suggest that excitatory and inhibitory amino acid neurotransmitter (glutamate, aspartate, and GABA) levels in the brain of hepatic failure rats might vary with abnormal cerebral ammonia metabolism.

Ammonia↗

PubMed1994

Protection against lethal ammonia intoxication: synergism between endogenous ornithine and L-carnitine.

The protective effects of combinations of 5-fluoromethylornithine (5FMOrn), a selective inhibitor of ornithine aminotransferase, and of compounds known to antagonize ammonia toxicity, were studied in acute, lethal ammonia intoxication in mice. Two test conditions were used: (a) Mice were pretreated with 5FMOrn at a dose (5 mumol.kg-1) which partially protects against 13 mmol.kg-1 ammonium acetate. (b) Mice were pretreated with a maximally protective dose of 5FMOrn (0.1 mmol.kg-1), however, 15 mmol.kg-1 ammonium acetate was used for intoxication. Under these conditions treatment with 5FMOrn alone protected only marginally. Under condition (a), administration of L-citrulline, L-carnitine, and L-acetylcarnitine improved the protective effect of 5FMOrn significantly, in an additive manner. N-acetyl-L-glutamate administration was ineffective. Under condition (b), ornithine, arginine and citrulline did not improve the protective effect of 5FMOrn, even when these amino acids were given at doses, which were effective in preventing ammonia toxicity induced with 13 mmol.kg-1 ammonium acetate. The inability to improve the effect of 5FMOrn by these compounds is most probably due to the fact that 5FMOrn and these amino acids enhance urea formation by the same mechanism, namely by increasing the concentration of substrates of the urea cycle. In contrast, L-carnitine and L-acetylcarnitine, which are assumed to stimulate urea production by different mechanisms, or compounds which antagonize ammonia toxicity by a urea cycle-independent mechanism, such as antagonists of the NMDA-type glutamate receptor (MK-801; MDL 100,453), potentiated the effects of 5FMOrn. The principle reason for the observed protective effects of the treatments described in this work seems to be the prevention of accumulation of lethal concentrations of ammonia in the brain. But other effects may also contribute.

Acetates↗

PubMed1995

Gastric juice ammonia vs CLO test for diagnosis of Helicobacter pylori infection.

The aim of the present study was to compare the gastric juice ammonia test to the CLO test for the diagnosis of H. pylori infection in culture-proven cases by receiver operating characteristic (ROC) curve analysis. We studied 75 subjects (44 with chronic gastritis, 10 with gastric ulcer, 6 with duodenal ulcer, 8 with gastric cancer, and 7 normal) by endoscopy with biopsy for tissue diagnosis, culture of H. pylori. CLO test, and by gastric juice ammonia determinations. The culture-positive group had significantly higher intragastric ammonia levels (13.7 +/- 5.8 mg/dl) than the negative group (4.9 +/- 2.4 mg/dl, P < 0.01). In ROC curve analysis, the gastric juice ammonia test showed higher true positive and lower false positive ratios than the CLO test (P < 0.05). In conclusion, the measurement of intragastric juice ammonia levels was considered to be simpler, quicker, and overall a more valuable method for diagnosing H. pylori infection.

Ammonia↗