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Normal volunteers infused with ammonium acetate for 3 hours developed a characteristic behavior pattern resembling that of prehepatic coma. They demonstrated certain specific defects in motor performance and recognition aswell as significant lowering of critical flicker fusion. These findings arecorrelated with the concentration of ammonia in arterial blood.
Sequencing the glnA genes of two chemically induced Azospirillum brasilense glutamine synthetase mutants revealed an Arg-->Cys mutation, corresponding to the glutamate binding site, in one mutant and an Asp-->Asn mutation, corresponding to the ammonium binding site, in the second mutant. The phenotypic changes in these mutants are discussed in relation to their genotypes.
To be appropriately excreted in urine, NH4+, the major component of urinary acid excretion, must be synthesized by proximal tubular cells, secreted into the proximal tubular fluid, reabsorbed by the medullary thick ascending limb (MTAL) to be accumulated in the medullary interstitium, and finally secreted in medullary collecting ducts. Several targets have been identified to account at the gene expression level for the adaptation of renal NH4+ synthesis and transport in response to a chronic acid load. These targets are the key enzymes of ammoniagenesis (mitochondrial glutaminase and glutamate dehydrogenase) and gluconeogenesis (phosphoenolpyruvate carboxykinase) and the Na+/H+(NH4+) exchanger NHE3 in the proximal tubule, the apical Na+-K+(NH4+)-2Cl- cotransporter of the MTAL, the basolateral Na+-K+(NH4+)-2Cl- cotransporter, and likely the epithelial Rh B and C glycoproteins in the collecting ducts. An acid pH per se appears to be a major factor in the control of the expression of these genes during metabolic acidosis probably through activation of pH sensors. Glucocorticoids may also act in concert with an acid pH to coordinate the adaptation of various tubular cell types. The present review focuses on some new aspects of NH3/ NH4+ transport and of regulations of gene expression that have recently emerged.
BACKGROUND: Recent studies clearly demonstrate that Helicobacter pylori (H. pylori) infection of the stomach causes persistent elevation of ammonia (NH3) in gastric juice leading to hypergastrinemia and enhanced pancreatic enzyme secretion. METHODS: The aim of this study is to evaluate the influence of NH4OH on plasma gastrin level and exocrine pancreatic secretion in vivo in conscious dogs equipped with chronic pancreatic fistulas and on secretory activity of in vitro isolated acini obtained from the rat pancreas by collagenase digestion. The effects of NH4OH on amylase release from pancreatic acini were compared with those produced by simple alkalization of these acini with NaOH. RESULTS: NH4OH given intraduodenally (i.d.) in increasing concentrations (0.5, 1.0, 2.0, 4.0, or 8.0 mM/L) resulted in an increase of pancreatic protein output, reaching respectively 9%, 10%, 19%, 16% and 17% of caerulein maximum in these animals and in a marked increase in plasma gastrin level. NH4OH (8 x 0 mM/L, i.d.) given during intravenous (i.v.) infusion of secretin (50 pmol/kg-h) and cholecystokinin (50 pmol/kg-h) reduced the HCO3 and protein outputs by 35% and 37% respectively, as compared to control obtained with infusion of secretin plus cholecystokinin alone. When pancreatic secretion was stimulated by ordinary feeding the same amount of NH4OH administered i.d. decreased the HCO3- and protein responses by 78% and 47% respectively, and had no significant effect on postprandial plasma gastrin. In isolated pancreatic acini, increasing concentrations of NH4OH (10(-7)-10(-4) M) produced a concentration-dependent stimulation of amylase release, reaching about 43% of caerulein-induced maximum. When various concentrations of NH4OH were added to submaximal concentration of caerulein (10(-12) M) or urecholine (10(-5) M), the enzyme secretion was reduced at a dose 10(-5) M of NH4OH by 38% or 40%, respectively. Simple alkalization with NaOH of the incubation medium up to pH 8.5 markedly stimulated basal amylase secretion from isolated pancreatic acini, whereas the secretory response of these acini to pancreatic secretagogues was significantly diminished by about 30%. LDH release into the incubation medium was not significantly changed in all tests indicating that NH4OH did not produce any apparent damage of pancreatic acini and this was confirmed by histological examination of these acini. CONCLUSIONS: 1. NH4OH affects basal and stimulated pancreatic secretion. 2. The excessive release of gastrin may be responsible for the stimulation of basal pancreatic enzyme secretion in conscious animals, and 3. The inhibitory effects of NH4OH on stimulated secretion might be mediated, at least in part, by its direct action on the isolated pancreatic acini possibly due to the alkalization of these acini.
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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.
The authors evaluate two quaternary ammonium compounds, first and second generation, using three methods: minimum bactericide concentration, the suspension test of the German Society for Hygiene and Microbiology and the agar gel diffusion test. The compounds were tested against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Enterococcus faecalis from sheep and pigs. The results show that quaternary ammonia compounds with dodecyl chains have greater efficacy than benzalconium chloride, and that quaternary ammonium compounds are more effective against gram-positive bacteria. No resistance linked to the strains used in the tests was detected. Finally, the authors demonstrate that all three techniques are valid for the evaluation of quaternary ammonium disinfectants.
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The effects of lactulose on blood ammonia and fecal pH in beagles with an end-to-side portacaval shunt were investigated. Concentrations of blood ammonia before and two weeks after the operation were 4.65 +/- 0.34 micrograms/ml (N = 12) and 8.66 +/- 0.60 micrograms/ml (N = 6), respectively (P less than 0.01), while there was no significant difference in fecal pH values before and after the operation. The blood ammonia concentrations in the control and lactulose-treated (2.1 g/kg, p.o.) groups after administration of meat were 12.65 +/- 1.64 micrograms/ml (N = 8) and 8.45 +/- 0.90 micrograms/ml (N = 8), respectively (P less than 0.05). The fecal pH values in the control and lactulose-treated (2.1 g/kg, p.o.) beagles were 6.24 +/- 0.09 (N = 8) and 5.58 +/- 0.08 (N = 8), respectively (P less than 0.01). The lowering effect of lactulose on the blood ammonia levels could not be ascribed to its laxative action alone, because the oral administration of lactulose at doses less than 2.1 g/kg induced no fluid evacuation. The present studies in the beagle suggest that the action of lactulose produce a lowering of fecal pH, causing an increase in the concentration of less absorbable ammonium ions and a decrease in the production of toxic nitrogenous compounds such as ammonia, resulting in a reduction in blood ammonia levels.
The independent and combined effects of L-arginine (840 mg/kg) and diazepam (0.75 mg/kg) pretreatment (30 min) were tested on ammonium chloride (400 mg/kg)-induced convulsions in rats. Ammonia concentrations were determined in blood and brain regions (cerebral cortex, brain stem and cerebellum) 30 min after L-arginine or diazepam treatment. Ammonia concentrations were measured at the time of induction of convulsions by ammonium chloride in L-arginine, diazepam or saline pretreated animals. L-arginine and not diazepam decreased ammonia concentrations in control as well as in ammonium chloride-treated animals. However, both the compounds suppressed convulsions elicited by ammonium chloride. Protection produced concurrently by these agents was much greater than that produced by them independently. It is concluded that convulsions caused by hyperammonemic condition can be suppressed either by preventing a rise in brain ammonia to toxic level or by anticonvulsant agents having a GABA potentiating action. A much greater protection can be achieved if agents having these properties are administered concurrently.
OBJECTIVE: To study the effect of exposure on bronchial responsiveness in pig farmers. METHOD: A group of 196 pig farmers were tested for lung function and bronchial responsiveness to histamine in the summer of 1992. To achieve sufficient contrast in respiratory morbidity and exposure, 96 of the farmers were selected because they had chronic respiratory symptoms and the remaining 100 because they were free from any respiratory symptoms. Personal exposure to dust, endotoxins and ammonia was measured during 1 working day in the summer of 1991 and 1 day in the winter of 1992. Data on farm characteristics were gathered in the same period. RESULTS: After adjusting for age and smoking behaviour, mild bronchial responsiveness, defined as PC10 < or = 16 mg/ml, was associated with the use of quaternary ammonium compounds as disinfectant [prevalence odds ratio (POR) 6.7, 95% confidence interval (CI) 1.4-32.8], use of wood-shavings as bedding (POR 13.3, CI 1.3-136.7), use of automated dry feeding (POR 2.8, CI 1.0-7.8), use of pellets as feeding material (POR 4.8, CI 1.1-21.1) and location of air exhaust via pit or roof in the confinement units (POR 2.7, CI 1.2-6.3). The association with the use of disinfectants other than quaternary ammonium compounds was not significant (POR 2.4, CI 0.7-8.4). No associations between bronchial responsiveness and measured exposure to dust, endotoxins or ammonia were discernible. CONCLUSION: Protective measures, designed to prevent airway disease in confinement farming, should be based on information about the operational and other characteristics of farms that are related to high exposure and health effects. Specifically, the use of quaternary ammonium compounds as disinfectant, the use of wood-shavings as bedding and the use of automated dry feeding should be discouraged.
Tyramine oxidase in Klebsiella aerogenes is highly specific for tyramine, dopamine, octopamine, and norepinephrine, and its synthesis is induced specifically by these compounds. The enzyme is present in a membrane-bound form. The Km value for tyramine is 9 X 10(-4) M. Tyramine oxidase synthesis was subjected to catabolite repression by glucose in the presence of ammonium salts. Addition of cyclic adenosine 3',5'-monophosphate (cAMP) overcame the catabolite repression. A mutant strain, K711, which can produce a high level of beta-galactosidase in the presence of glucose and ammonium chloride, can also synthesize tyramine oxidase and histidase in the presence of inducer in glucose ammonium medium. Catabolite repression of tyramine oxidase synthesis was relieved when the cells were grown under conditions of nitrogen limitation, whereas beta-galactosidase was strongly repressed under these conditions. A cAMP-requiring mutant, MK54, synthesized tyramine oxidase rapidly when tyramine was used as the sole source of nitrogen in the absence of cAMP. However, a glutamine synthetase-constitutive mutant, MK94, failed to synthesize tyramine oxidase in the presence of glucose and ammonium chloride, although it synthesized histidase rapidly under these conditions. These results suggest that catabolite repression of tyramine oxidase synthesis in K. aerogenes is regulated by the intracellular level of cAMP and an unknown cytoplasmic factor that acts independently of cAMP and is formed under conditions of nitrogen limitation.
Degradation of nitrogen containing organic compounds often leads to formation of ammonium and some low molecular weight organic compounds. The study is focused on degradation of acetonitrile in a sequence of stirred biofilm reactors, where the degradation of acetonitrile into acetic acid and ammonia takes place in the first two reactors. A large fraction of the acetic acid is also degraded in these reactors. The subsequent two reactors were introduced in order to take care of the ammonia, while a fifth reactor was a polishing step before the water was released to the recipient. From earlier studies it is known that the rate of acetonitrile degradation is approximately 80 g acetonitrile/ (m3 reactor h). In the present study nitrification proceeded with 10 g NH4(+)-N/(m3 reactor h) and the denitrification by 35 g NOx(-)-N/ (m3 reactor h). This means that the reactors involved in removal of the nitrogen component needs to be far larger than those dealing with degradation of the more complex molecules.
Intraperitoneal administration of L-carnitine (16 mmol/kg) was reported by O'Connor et al. (FEBS Lett 166: 331-334, 1984) to fully protect mice from ammonium acetate given at a dose that kills 100% of untreated controls. Other investigators either have failed to observe protection by L-carnitine or have attributed the increased survival to a nonspecific "osmoprotective effect" of quaternary ammonium compounds. In the present studies we have confirmed the protective effect of L-carnitine in acute ammonia intoxication and have shown that D-carnitine and deoxycarnitine, close structural analogs of L-carnitine, are without protective effect. Although D-carnitine and deoxycarnitine do not support L-carnitine-dependent metabolisms, they are transported into tissues and their solutions are osmotically identical to those of L-carnitine; lack of protection by D-carnitine and deoxycarnitine suggests that metabolic rather than nonspecific osmotic effects account for L-carnitine-mediated protection. Further supporting the importance of L-carnitine-dependent metabolisms, we found that mice exhibited increased sensitivity to ammonium acetate when pretreated with DL-aminocarnitine, acetyl-DL-aminocarnitine or palmitoyl-DL-aminocarnitine, potent inhibitors of the carnitine acyltransferases. Interestingly, intraperitoneal injection of hyperosmotic solutions of sodium chloride or sucrose did afford significant protection against subsequently administered ammonium acetate. This phenomenon, which may be due to interference with ammonium acetate uptake from the peritoneal cavity or to reduction of cerebral edema by increased plasma osmolarity, apparently does not play a major role in L-carnitine-mediated protection since, as noted, hyperosmotic D-carnitine and deoxycarnitine solutions were not protective.
Biological treatment of landfill leachate usually results in low COD removals because of high chemical oxygen demand (COD), high ammonium-N content and presence of toxic compounds. Coagulation-flocculation with lime addition and air stripping of ammonia were used as pre-treatment in this study in order to improve biological treatability of the leachate. Pre-treated leachate was subjected to adsorbent supplemented biological treatment in an aeration tank operated in fed-batch mode. COD and NH(4)-N removal performances of powdered activated carbon (PAC) and powdered zeolite (PZ) were compared during biological treatment. Adsorbent concentrations varied between 0 and 5 gl(-1). Percent COD and ammonium-N removals increased with increasing adsorbent concentrations. Percent COD removals with PAC addition were significantly higher than those obtained with the zeolite. However, zeolite performed better than the PAC in ammonium-N removal from the leachate. Nearly 87% and 77% COD removals were achieved with PAC and zeolite concentrations of 2 gl(-1), respectively. Ammonium-N removals were 30% and 40% with PAC and zeolite concentrations of 5 gl(-1), respectively at the end of 30 h of fed-batch operation.
The possible involvement of the glutamine synthetase/glutamate synthase pathway in ammonia assimilation is reported in a monokaryon of Coprinus cinereus.