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PubMed1975

Quantification of the capacity of the liver to remove ammonia from the circulation of dogs with portacaval transposition.

To quantitate the ammonia that the liver removes from the circulation and to investigate the distribution of this substance during and after an exogenous ammonia load, ten dogs with portacaval transposition were studied by placing catheters in the hepatic and portal veins through the external jugular vein, in the portal vein going to the liver and in the infrarenal vena cava through the femoral vein. A catheter also was inserted into the femoral artery. Blood ammonia levels were measured in each catheter, then an infusion of ammonium sulfate, 0.7 milligram per minute per kilogram for 45 minutes through the infrarenal vena cava, was given continuously. All other catheters were simultaneously sampled at 15 minute intervals during the infusion and for a 45 minute period after it was stopped. By using a continuous infusion of indocyanine green and Fick's formula, the total hepatic blood flow was estimated in five of the ten dogs. Thus, knowing the amounts of ammonia in the hepatic inflow and outflow tracts and relating them to the estimated hepatic blood flow, the hepatic extraction ratios of ammonia were calculated. The estimated hepatic blood flow changed minimally before and after portacaval transposition. The blood ammonia levels in all sites where samples were obtained, except for the hepatic vein, followed uniform patterns. In the femoral artery, the portal vein and liver-portal vein now anastomosed to the infrahepatic infrarenal vana cava-the blood ammonia levels during the period of infusion increased by at least 90 per cent. When the infusion was discontinued, the blood ammonia levels decreased but remained elevated, from 30 to 60 per cent of the preinfusion blood ammonia levels. Blood ammonia levels in the hepatic veins increased some but never exceeded 56 micrograms per 100 milliliters. It also was found that the liver removes 80 to 87 per cent of the ammonia reaching it by means of the urea cycle; the other 13 to 19 per cent of the ammonia returns to the circulation through the hepatic veins and is distributed into the circulation, causing the blood ammonia levels to remain higher for at least 45 minutes after the ammonia infusion load was discontinued than the preinfusion control levels in all the sites where samples were obtained.

Amino Acids↗
PubMed1994

Splanchnic ammonia management in genetic and dietary obesity in the rat.

Three groups of 60-day-old Zucker rats: lean (Fa/Fa), obese by diet (Fa/Fa diet-obese) and genetically-obese (fa/fa) were fed ad libitum in order to study their splanchnic ammonia management. The study was also performed in 12 h food-deprived diet-obese and lean rats, to exclude a possible effect of diet composition on the parameters studied. Ammonia concentration was higher in the hepatic, portal and arterial plasma of diet-obese rats. The intestine did not contribute to a rise in the blood ammonia levels. This increase of ammonia in the blood of diet-obese rats coincides with higher alanine levels in plasma and a net glutamine production by liver. In fa/fa rats, ammonia levels were similar to those of lean rats, except for portal ammonia, which was lower. Hepatic availability of ammonia increased dramatically in diet-obese rats, but ammonia uptake by the liver was similar to that of lean rats. Conversely, hepatic availability of ammonia in fa/fa rats was similar to that of lean animals, whereas ammonia uptake by the liver was reduced to 50% of either lean or diet-obese values. Fasting for 12 h reduced plasma ammonia concentration in diet-obese rats: ammonia levels in the hepatic vein and aorta were similar to those of lean rats fasted for 12 h, whereas they were lower in the portal vein. Furthermore, ammonia hepatic availability was in the same range as that of lean animals, whereas ammonia uptake by the liver was reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed2002

Ammonia-induced heme oxygenase-1 expression in cultured rat astrocytes and rat brain in vivo.

Ammonia is a key factor in the pathogenesis of hepatic encephalopathy (HE), which is a major complication in acute and chronic liver failure and other hyperammonemic states. The molecular mechanisms underlying ammonia neurotoxicity and the functional consequences of ammonia on gene expression in astrocytes are incompletely understood. Using cDNA array hybridization technique we identified ammonia as a trigger of heme oxygenase-1 (HO-1) mRNA levels in cultured rat astrocytes. As shown by Northern and Western blot analysis, HO-1 mRNA levels were upregulated by ammonia (0.1-5 mmol/L) after 24 h and protein expression after 72 h in astrocytes. These ammonia effects on HO-1 are probably triggered to a minor extent by ammonia-induced glutamine synthesis or by astrocyte swelling, because HO-1 expression was not inhibited by the glutamine synthetase inhibitor methionine sulfoximine (which abrogated ammonia-induced cell swelling in cultured astrocytes), and ammonia-induced HO-1 expression could only partly be mimicked by hypoosmotic astrocyte swelling. Hypoosmotic (205 mOsm/L) exposure of astrocytes led even to a decrease in HO-1 mRNA levels within 4 h, whereas hyperosmotic (405 mOsm/L) exposure increased HO-1 mRNA expression. After 24 h, hypoosmolarity slightly raised HO-1 mRNA expression. Taurine and melatonin diminished ammonia-induced HO-1 mRNA or protein expression, whereas other antioxidants (dimethylthiourea, butylated hydroxytoluene, N-acetylcysteine, and reduced glutathione) increased HO-1 mRNA levels under ammonia-free conditions. An in vivo relevance is suggested by the finding that increased HO-1 expression occurs in the brain cortex from acutely ammonia-intoxicated rats. It is concluded that ammonia-induced HO-1 expression may contribute to cerebral hyperemia in hyperammonic states.

Ammonia↗
PubMed1979

The metabolic fate of 13N-labeled ammonia in rat brain.

13N-labeled ammonia was used to study the cerebral uptake and metabolism of ammonia in conscious rats. After infusion of physiological concentrations of [13N]ammonia for 10 min via one internal carotid artery, the relative specific activities of glutamate, glutamine (alpha-amino), and glutamine (amide) in brain were approximately 1:5:400, respectively. The data are consistent with the concept that ammonia, entering the brain from the blood, is metabolized in a small pool of glutamate that is both rapidly turning over and distinct from a larger tissue glutamate pool (Berl, S., Takagaki, G., Clarke, D.D., and Waelsch, H. (1962) J. Biol. Chem. 237, 2562-2569). Analysis of 13N-metabolites, after infusion of [13N]ammonia into one lateral cerebral ventricle, indicated that ammonia entering the brain from the cerebrospinal fluid is also metabolized in a small glutamate pool. Pretreatment of rats with methionine sulfoximine led to a decrease in the label present in brain glutamine (amide) following carotid artery infusion of [13N]ammonia. On the other hand, 13N activity in brain glutamate was greater than that in the alpha-amino group of glutamine, i.e. following methionine sulfoximine treatment the expected precursor-product relationship was observed, indicating that the two pools of glutamate in the brain were no longer metabolically distinct. The amount of label recovered in the right cerebral hemisphere, 5 s after a rapid bolus injection of [13N]ammonia via the right common carotid artery, was found to be independent of ammonia concentration within the bolus over a 1000-fold range. This finding indicates that ammonia enters the brain from the blood largely by diffusion. In normal rats that were killed by a freeze-blowing technique 5 s after injection of an [13N]ammonia bolus, approximately 60% of the label recovered in brain had already been incorporated into glutamine, indicating that the t1/2 for conversion of ammonia to glutamine in the small pool is in the range of 1 to 3 s or less. The data emphasize the importance of the small pool glutamine synthetase as a metabolic trap for the detoxification of blood-borne and endogenously produced brain ammonia. The possibility that the astrocytes represent the anatomical site of the small pool is considered.

Ammonia↗
PubMed1990

Ammonia metabolism in normal and portacaval-shunted rats.

Ammonia is generated from a large number of metabolically important reactions. Despite its central importance in whole body nitrogen homeostasis excess ammonia is neurotoxic and its concentration must be kept low. Ammonia generated in most extrahepatic tissues is detoxified by incorporation into glutamine (amide). This glutamine may be used in a number of biosynthetic reactions (e.g. in pyrimidine synthesis). Alternatively, as a means of maintaining nitrogen balance, glutamine may be released to the blood. Resting skeletal muscle is particularly important 1) as a "sink" for removal of blood ammonia, and 2) as a major source of circulating glutamine. However, during vigorous exercise skeletal muscle may become a net contributor of ammonia to the blood. A few tissues and cell types (e.g. lymphocytes, macrophages, enterocytes, colonocytes, thymocytes, fibroblasts, bone) and tumors exhibit marked rates of glutamine utilization. In the kidney, glutamine is an important source of urinary ammonia. Ammonia generated from 1) the breakdown of nitrogenous substances in the gut, and 2) from the use of glutamine as a metabolic fuel in the small intestine, is taken up by the liver wherein it is detoxified by conversion to urea and to a lesser extent, glutamine. Some portal vein glutamine acts as a source of urea nitrogen. Ultimately, however, most excess ammonia nitrogen is detoxified indirectly (via glutamine (blood)----glutamine (small intestine)----ammonia (portal vein) or directly in the liver as urea. Portal-systemic shunting of blood, as occurs in chronic cirrhosis of the liver or following the surgical construction of a portacaval shunt results in portal blood bypassing the normal ammonia detoxification machinery of the liver. Under this condition blood ammonia levels rise markedly, increasing the burden on extrahepatic tissues, such as skeletal muscle, brain, and kidney, in maintaining ammonia homeostasis. The most commonly employed animal model of human liver disease is the rat in which an end-to-side portacaval shunt (PCS) has been surgically constructed. Brain glutamine synthetase activity is not increased in PCS rats and in some areas of the brain there may even be a decrease in activity. The brain glutamine synthetase appears to be working at near maximal capacity. Thus, the PCS rats exhibit profound neurological dysfunction when administered ammonium salts in amounts easily tolerated by normal animals. Because of the limited capacity of brain to remove excess ammonia, a rational approach to the treatment of patients with liver disease should include a regimen directed toward lowering the associated hyperammonemia.

Ammonia↗
PubMed1986

Pancreatic and duodenal ammonia in dogs: lowering by glucose infusion.

Ammonia is produced by some organs and removed by others. Glucose may influence ammonia formation. The contribution of the pancreas to ammonia metabolism is unknown. This study compares pancreatic and duodenal venous ammonia to arterial ammonia in dogs. Pancreatic venous ammonia exceeds arterial ammonia by a factor of 2.8 (range 1.3-9.3); and duodenal ammonia by a factor of 1.1 (range 0.9-2.8). Duodenal venous exceeds arterial ammonia by a factor of 2.4 (range 0.8-5.8). High-dose glucose infusion decreased pancreatic venous ammonia by approximately one-third and duodenal venous ammonia by approximately one quarter, but left arterial ammonia virtually unaltered. The mechanism of pancreatic ammonia production is unknown. We postulate that it may be related to pancreatic bicarbonate synthesis, binding the hydrogen ions which are liberated during this process.

Ammonia↗
PubMedDate not supplied

Heterogeneity of regional nitrogen 13-labeled ammonia tracer distribution in the normal human heart: comparison with rubidium 82 and copper 62-labeled PTSM.

BACKGROUND: Recent reports on 13N-labeled ammonia (13N-ammonia) positron emission tomographic (PET) imaging have suggested a relative reduction of measured tracer activity in the posterolateral wall. Such inhomogeneity of tracer distribution could potentially affect accuracy for detection of disease. The aim of this study was to compare the regional distribution of 13N-ammonia with 82Rb and 62Cu-labeled PTSM (62Cu-PTSM) to identify tracer-specific patterns that may be important in the clinical interpretation of cardiac flow studies. METHODS AND RESULTS: Twenty-eight healthy volunteers underwent PET imaging at rest with either 13N-ammonia (n = 14), 82Rb (n = 8), or 62Cu-PTSM (n = 6). Eight subjects given 13N-ammonia also underwent imaging after adenosine. Activity measured in the posterolateral wall on transaxial images was significantly lower than in the septum for 13N-ammonia, both at rest (p < 0.005) and after adenosine (p < 0.05). No differences were detected for 82Rb or 62Cu-PTSM. The septum/posterolateral wall activity ratios for 13N-ammonia, 82Rb, and 62Cu-PTSM were 1.15 +/- 0.07, 1.00 +/- 0.06, and 0.97 +/- 0.08, respectively (p < 0.001). Regional analysis of image data showed the percent of maximal activity data for 13N-ammonia in the lateral wall to be less than that of other regions (p < 0.001) and in the inferior wall to be greater than in the anterior and lateral walls (p < 0.001). For 62Cu-PTSM, activity in the inferior wall was greater than that in other regions (p < 0.005). No regional differences were detected for 82Rb. CONCLUSIONS: The relatively increased wall activity with 13N-ammonia and 62Cu-PTSM is most likely due to cross-contamination of activity from the liver. The significant reduction in activity in the lateral wall with 13N-ammonia, which persists after adenosine, is most likely related to regional heterogeneity in 13N-ammonia retention and may reflect regional differences in metabolic-trapping mechanisms for 13N-ammonia. Further investigation is required to elucidate the underlying mechanism of this phenomenon. Reduced tracer retention in the lateral wall segment as a normal variant must be considered when evaluating clinical 13N-ammonia PET studies.

Adult↗
PubMed2003

Correlation between ammonia levels and the severity of hepatic encephalopathy.

PURPOSE: Because the correlation between ammonia levels and the severity of hepatic encephalopathy remains controversial, we prospectively evaluated the correlation in 121 consecutive patients with cirrhosis. METHODS: The diagnosis of hepatic encephalopathy was based on clinical criteria, and the severity of hepatic encephalopathy was based on the West Haven Criteria for grading of mental status. Arterial and venous blood samples were obtained from each patient. Four types of ammonia measurements were analyzed: arterial and venous total ammonia, and arterial and venous partial pressure of ammonia. Spearman rank correlations (r(s)) were calculated. RESULTS: Of the 121 patients, 30 (25%) had grade 0 encephalopathy (no signs or symptoms), 27 (22%) had grade 1, 23 (19%) had grade 2, 28 (23%) had grade 3, and 13 (11%) had grade 4 (the most severe signs and symptoms). Each of the four measures of ammonia increased with the severity of hepatic encephalopathy: arterial total ammonia (r(s) = 0.61, P < or = 0.001), venous total ammonia (r(s) = 0.56, P < or = 0.001), arterial partial pressure of ammonia (r(s) = 0.55, P < or = 0.001), and venous partial pressure of ammonia (r(s) = 0.52, P < or = 0.001). CONCLUSION: Ammonia levels correlate with the severity of hepatic encephalopathy. Venous sampling is adequate for ammonia measurement. There appears to be no additional advantage of measuring the partial pressure of ammonia compared with total ammonia levels.

Adult↗
PubMed2002

Ammonia toxicity in fish.

Ammonia is present in the aquatic environment due to agricultural run-off and decomposition of biological waste. Ammonia is toxic to all vertebrates causing convulsions, coma and death, probably because elevated NH4+ displaces K+ and depolarizes neurons, causing activation of NMDA type glutamate receptor, which leads to an influx of excessive Ca2+ and subsequent cell death in the central nervous system. Present ammonia criteria for aquatic systems are based on toxicity tests carried out on, starved, resting, non-stressed fish. This is doubly inappropriate. During exhaustive exercise and stress, fish increase ammonia production and are more sensitive to external ammonia. Present criteria do not protect swimming fish. Fish have strategies to protect them from the ammonia pulse following feeding, and this also protects them from increases in external ammonia, as a result starved fish are more sensitive to external ammonia than fed fish. There are a number of fish species that can tolerate high environmental ammonia. Glutamine formation is an important ammonia detoxification strategy in the brain of fish, especially after feeding. Detoxification of ammonia to urea has also been observed in elasmobranches and some teleosts. Reduction in the rate of proteolysis and the rate of amino acid catabolism, which results in a decrease in ammonia production, may be another strategy to reduce ammonia toxicity. The weather loach volatilizes NH3, and the mudskipper, P. schlosseri, utilizes yet another unique strategy, it actively pumps NH4+ out of the body.

Adaptation, Physiological↗
PubMed2003

Monitoring and kinetic study of ammonia oxidation using dissolved oxygen electrode and NAD(P) H fluorometer.

The ammonia oxidation of a mixed culture enriched from a wastewater treatment plant sludge was monitored by a DO probe and a nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) fluorometer. Under fixed aeration, DO reflected ammonia oxidation effectively. According to the DO profiles and the total ammonia concentrations analyzed experimentally, the ammonia oxidation kinetics of the enriched culture was determined. The ammonia oxidation rate was found sensitive to pH, especially at low total ammonia concentrations. At high concentrations of total ammonia, the maximum ammonia oxidation rate occurred at pH 7.6+/-0.1. At low concentrations, the pH sensitivity intensified significantly and the apparent optimal pH shifted higher with decreasing total ammonia concentrations, because NH3 molecules were the true substrate for ammonia oxidation and more NH4+ ions were converted to NH3 molecules at higher pH. The ammonia oxidation kinetics was therefore developed according to the concentration of NH3 molecules, instead of the commonly used total ammonia concentration. The kinetics followed Michaelis-Menten behavior for both DO and NH3 concentration: the maximum rate was 16.7+/-0.7 mg NH3-N/(g TSS-h) and the Michaelis constants for DO and NH3 were (14+/-2)% air saturation and (4.4+/-0.4) x 10(-2) (mg NH3-N/L), respectively. It was also concluded from the study that with or without exogenous organic substances, the NAD(P)H fluorescence of the enriched nitrifying culture was undetectable. The fluorescence did not respond to addition or depletion of substrate (ammonia, glucose, or acetate), change between aerobic and anaerobic conditions, or even KCN addition to kill the culture.

Ammonia↗
PubMed1999

Enhanced renal vein ammonia efflux after a protein meal in the pig.

BACKGROUND/AIMS: The intake of dietary protein has been associated with increased arterial ammonia levels. However, the origin of this rise in ammonia levels is unknown. This study was designed to examine whether this increase is caused by ammonia formed by the gut escaping hepatic clearance, or ammonia formed by the kidney and subsequently released into the circulation. METHODS: Splanchnic and renal fluxes of ammonia and amino acids were studied in 10 pigs that were fed in a randomized cross-over design with a protein meal (n = 8), a meal with an equimolar amount of free amino acids (n = 8) or an iso-osmolar NaCl solution (n = 6). RESULTS: After the protein meal, and less pronounced after the amino acid meal, arterial ammonia levels increased from approximately 25 to 75 micromol/l. Arterial pH changes and splanchnic ammonia release were negligible. The renal vein ammonia efflux increased after the protein meal (0.67+/-0.10 to 1.94+/-0.35 micromol/kg bw/min) and to a lesser degree after the amino acid meal (to 1.20+/-0.39 micromol/kg bw/ min). Renal uptake of alanine, and not glutamine, increased stoichiometrically, paralleling the enhanced renal vein ammonia efflux. CONCLUSIONS: Arterial ammonia increases after a meal in pigs, coinciding with a negligible splanchnic ammonia release, but increased renal vein ammonia efflux. Thus, post-prandial plasma ammonia levels appear to be mainly related to renal ammoniagenesis. Alanine appears to be the main precursor for this renal ammoniagenesis in the pig.

Ammonia↗
PubMed2005

Inactivation of Ascaris suum eggs by ammonia.

Uncharged ammonia is known to cause inactivation of a number of wastewater pathogens, but its effect on Ascaris eggs has never been isolated or quantified. The objectives of this research were to determine the conditions under which ammonia inactivates eggs of the swine Ascaris species, Ascaris suum, and to quantify the impact of ammonia on the U.S. EPA's requirements for alkaline treatment to produce Class A sludge. Eggs were incubated in controlled, laboratory solutions such that the effects of ammonia concentration and speciation, pH, and temperature could be separated. With a 24-h incubation, the inactivation at all pH levels (range 7-11) was not statistically different in the absence of ammonia. The presence of ammonia (0-1000 ppm as N) significantly increased Ascaris egg inactivation at pH 9 and 11, and the ovicidal effect was directly related to the concentration of the uncharged NH3 species. Increasing temperatures (32-52 degrees C) caused increased inactivation at all pH levels and ammonia concentrations. The current EPA treatment requirements to produce Class A biosolids by alkaline treatment have temperature, pH, and time requirements, but do not account for the effectof differences in ammonia concentration on inactivation. To illustrate the potential savings in temperature and pH that could be achieved when accounting for ammonia inactivation, the combinations of ammonia concentration, temperature, and pH neededto achieve 99% inactivation after 72 h were determined. The presence of ammonia at concentrations encountered in sludges and feces (up to 8000 ppm as N) allowed for 99% egg inactivation to be achieved at temperatures up to 14 degrees C lower than ammonia-free controls. Thus, environmentally relevant concentrations of ammonia may significantly increase the rate of Ascaris egg inactivation during alkaline stabilization.

Ammonia↗
PubMedDate not supplied

Five tropical air-breathing fishes, six different strategies to defend against ammonia toxicity on land.

Most tropical fishes are ammonotelic, producing ammonia and excreting it as NH3 by diffusion across the branchial epithelia. Hence, those air-breathing tropical fishes that survive on land briefly or for an extended period would have difficulties in excreting ammonia when out of water. Ammonia is toxic, but some of these air-breathing fishes adopt special biochemical adaptations to ameliorate the toxicity of endogenous ammonia accumulating in the body. The amphibious mudskipper Periophthalmodon schlosseri, which is very active on land, reduces ammonia production by suppressing amino acid catabolism (strategy 1) during aerial exposure. It can also undergo partial amino acid catabolism, leading to the accumulation of alanine (strategy 2) to support locomotory activities on land. In this case, alanine formation is not an ammonia detoxification process but reduces the production of endogenous ammonia. The snakehead Channa asiatica, which exhibits moderate activities on land although not truly amphibious, accumulates both alanine and glutamine in the muscle, with alanine accounting for 80% of the deficit in reduction in ammonia excretion during air exposure. Unlike P. schlosseri, C. asiatica apparently cannot reduce the rates of protein and amino acid catabolism and is incapable of utilizing partial amino acid catabolism to support locomotory activities on land. Unlike alanine formation, glutamine synthesis (strategy 3) represents an ammonia detoxification mechanism that, in effect, removes the accumulating ammonia. The four-eyed sleeper Bostrichyths sinensis, which remains motionless during aerial exposure, detoxifies endogenous ammonia to glutamine for storage. The slender African lungfish Protopterus dolloi, which can aestivate on land on a mucus cocoon, has an active ornithine-urea cycle and converts endogenous ammonia to urea (strategy 4) for both storage and subsequent excretion. Production of urea and glutamine are energetically expensive and appear to be adopted by fishes that remain relatively inactive on land. The Oriental weatherloach Misgurnus anguillicaudatus, which actively burrows into soft mud during drought, manipulates the pH of the body surface to facilitate NH3 volatilization (strategy 5) and develops high ammonia tolerance at the cellular and subcellular levels (strategy 6) during aerial exposure. Hence, with regard to excretory nitrogen metabolism, modern tropical air-breathing fishes exhibit a variety of strategies to survive on land, and they represent a spectrum of specimens through which we may examine various biochemical adaptations that would have facilitated the invasion of the terrestrial habitat by fishes during evolution.

Adaptation, Physiological↗
PubMed2005

Predictive value of arterial ammonia for complications and outcome in acute liver failure.

BACKGROUND AND AIMS: In acute liver failure (ALF), the brain is exposed to high levels of ammonia. Human studies defining the clinical significance of ammonia in ALF are lacking. This prospective study evaluated the relationship of arterial ammonia levels at admission to complications and survival among patients with ALF. METHODS: Eighty consecutive ALF patients admitted from March 2001 to December 2003 were followed up until death or complete recovery. All had arterial ammonia estimation at admission (enzymatic method). Logistic regression analysis was performed to identify independent predictors of mortality. RESULTS: Forty two (52.5%) patients died. Non-survivors had significantly higher median ammonia levels than survivors (174.7 v 105.0 micromol/l; p<0.001). An arterial ammonia level of > or = 124 micromol/l was found to predict mortality with 78.6% sensitivity and 76.3% specificity, and had 77.5% diagnostic accuracy. Patients with higher ammonia levels also developed more complications, including deeper encephalopathy (p = 0.055), cerebral oedema (p = 0.020), need for ventilation (p<0.001), and seizures (p = 0.006). Logistic regression analysis showed that pH, presence of cerebral oedema, and arterial ammonia at admission were independent predictors of mortality (odds ratios 6.6, 12.6, and 10.9, respectively). Incorporating these variables, a score predicting mortality risk at admission was derived: 2.53 + 2.91 ammonia + 2.41 oedema + 1.40 pH, where ammonia is scored as 0 (if <124 micromol/l) or 1 (if > or =124 micromol/l); oedema is scored as 0 (absent) or 1(present); and pH is scored as 1 (if < or =7.40) or 0 (if >7.40). Levels of partial pressure of ammonia were equally correlated with outcome. CONCLUSION: Arterial ammonia at presentation is predictive of outcome and can be used for risk stratification. Ammonia lowering therapies in patients with ALF should be evaluated.

Adolescent↗
PubMed2006

Kidney plays a major role in ammonia homeostasis after portasystemic shunting in patients with cirrhosis.

The kidney plays an important role in ammonia metabolism. In this study the hypothesis was tested that the kidney can acutely diminish ammonia release after portacaval shunting. Thirteen patients with cirrhosis (6 female/7 male, age 54.4 +/- 3.3 yr) were studied. Blood was sampled prior to and 1 h after transjugular intrahepatic stent-shunt (TIPSS) insertion from the portal vein, a hepatic vein, the right renal vein, and the femoral vein, and renal and liver plasma flow were measured. Prior to TIPSS, renal ammonia release was significantly higher than ammonia release from the splanchnic region, which was not significantly different from zero. TIPSS insertion did not change arterial ammonia concentration or ammonia release from the splanchnic region but reduced renal ammonia release into the circulation (P < 0.05) to values that were not different from zero. TIPSS resulted in a tendency toward increased venous-arterial ammonia concentration differences across leg muscle. Post-TIPSS ammonia efflux via portasystemic shunts was estimated to be seven times higher than renal efflux. Kidneys have the ability to acutely diminish systemic ammonia release after portacaval shunting. Diminished renal ammonia release and enhanced muscle ammonia uptake are important mechanisms by which the cirrhotic patient maintains ammonia homeostasis after portasystemic shunting.

Adaptation, Physiological↗
PubMed1989

Determinants of ammonia entry along the rat proximal tubule during chronic metabolic acidosis.

The technique of in vivo microperfusion was used to examine the determinants of ammonia entry along the rat proximal tubule under conditions of chronic metabolic acidosis (CMA). When perfused with a 5 mM bicarbonate-containing perfusate, collected fluid ammonia concentrations remained constant with increasing flow rate and thus ammonia entry was highly flow-rate dependent. Ammonia entry was also flow-rate dependent using a 25 mM bicarbonate perfusate but entry reached a plateau as perfusion rate increased. Also, ammonia entry tended to be lower at all perfusion rates with the 25 mM perfusate compared with the 5 mM bicarbonate perfusate, but this was most evident at the highest perfusion rate (45 nl/min). The decline in ammonia entry was associated with increasing collected fluid bicarbonate concentrations, suggesting that there was inhibition of diffusion trapping of ammonia. The effects of Na+-H+ exchange inhibition on ammonia entry were examined using the amiloride analogue, 5-(N-ethyl-N-isopropyl)amiloride. With a 25 mM bicarbonate-containing perfusate, the amiloride analogue caused a significant decrease in bicarbonate reabsorption but a nonsignificant decrease in ammonia entry associated with a significant rise in collected fluid bicarbonate concentration. When the potential effects of decreased diffusion trapping of ammonia were eliminated with 12 and 5 mM bicarbonate-containing perfusates, the analogue had no effect on ammonia entry despite significant inhibition of bicarbonate reabsorption. Thus ammonia entry in CMA is moderately affected by tubule fluid pH but is highly flow-rate dependent. There were no effects of inhibition of Na+-H+ exchange above those expected from inhibition of diffusion trapping of ammonia.

Acidosis↗
PubMed1967

Diffusion equilibrium for ammonia in the kidney of the acidotic dog.

Inflow of preformed ammonia in arterial blood, renal production of ammonia, outflow of ammonia in renal venous blood, and urinary excretion of ammonia were measured during the infusion of (15)NH(4)Cl into one renal artery of dogs with chronic metabolic acidosis. Our results show that the specific activity of ammonia measured in the urine and that calculated in the renal pool agree within 95%. Pool specific activity is obtained by dividing the rate of infusion of isotope by the pool turnover rate, i.e., the sum of the rate of ammonia output in the urine and that in renal venous blood. An average of 35% of urinary ammonia is derived from arterial ammonia in these experiments. We conclude that ammonia is distributed evenly throughout all phases of the kidney within a period less than the transit time of blood through the kidney. Furthermore, from the proportion of urinary ammonia we found to be derived from preformed arterial ammonia (35%), and from our previous demonstration that 73% of urinary ammonia derives from deamidation and/or deamination of plasma glutamine, alanine, glycine, and glutamate, we can account for all of the ammonia that leaves the kidney in renal venous blood and in urine.

Acidosis↗
PubMed1979

The dynamics of ammonia metabolism in man. Effects of liver disease and hyperammonemia.

The cyclotron-produced radionuclide, 13N, was used to label ammonia and to study its metabolism in a group of 5 normal subjects and 17 patients with liver disease, including 5 with portacaval shunts and 11 with encephalopathy. Arterial ammonia levels were 52-264 micron. The rate of ammonia clearance from the vascular compartment (metabolism) was a linear function of its arterial concentration: mumol/min = 4.71 [NH3]a + 3.76, r = +0.85, P less than 0.005. Quantitative body scans showed that 7.4 +/- 0.3% of the isotope was metabolized by the brain. The brain ammonia utilization rate, calculated from brain and blood activities, was a function of the arterial ammonia concentration: mumol/min per whole brain = 0.375 [NH3]a - 3.6, r = +0.93, P less than 0.005. Assuming that cerebral blood flow and brain weights were normal, 47 +/- 3% of the ammonia was extracted from arterial blood during a single pass through the normal brains. Ammonia uptake was greatest in gray matter. The ammonia utilization reaction(s) appears to take place in a compartment, perhaps in astrocytes, that includes less than 20% of all brain ammonia. In the 11 nonencephalopathic subjects the [NH3]a was 100 +/- 8 micron and the brain ammonia utilization rate was 32 +/- 3 mumol/min per whole brain; in the 11 encephalopathic subjects these were respectively elevated to 149 +/- 18 micron (P less than 0.01), and 53 +/- 7 mumol/min per whole brain (P less than 0.01). In normal subjects, approximately equal to 50% of the arterial ammonia was metabolized by skeletal muscle. In patients with portal-systemic shunting, muscle may become the most important organ for ammonia detoxification. Muscle atrophy may thereby contribute to the development of hyperammonemic encephalopathy with an associated increase in the brain ammonia utilization rate.

Adolescent↗