Lung glutamine metabolism: effects of starvation,parenteral and enteral nutrition. A study in man.
Explore the source record for details and available documents.
Journal Article↗
Biomedical subjects
C H Dejong
Publications and source records attributed to C H Dejong.
Remote injury during glutamine supplementation.
Explore the source record for details and available documents.
Comment↗
Decreased plasma isoleucine concentrations after upper gastrointestinal haemorrhage in humans.
BACKGROUND: A decrease in arterial isoleucine values after intragastric blood administration in pigs has been observed. This contrasted with increased values of most other amino acids, ammonia, and urea. After an isonitrogenous control meal in these pigs all amino acids including isoleucine increased, and urea increased to a lesser extent, suggesting a relation between the arterial isoleucine decrease and uraemia after gastrointestinal haemorrhage. METHODS: To extend these findings to humans, plasma amino acids were determined after gastrointestinal haemorrhage in patients with peptic ulcers (n = 9) or oesophageal varices induced by liver cirrhosis (n = 4) and compared with preoperative patients (n = 106). RESULTS: After gastrointestinal haemorrhage, isoleucine decreased in all patients by more than 60% and normalised within 48 hours. Most other amino acids increased and also normalised within 48 hours. Uraemia occurred in both groups, hyperammonaemia was seen in patients with liver cirrhosis. CONCLUSIONS: These results confirm previous findings in animals and healthy volunteers that plasma isoleucine decreases after simulated upper gastrointestinal haemorrhage. This supports the hypothesis that the absence of isoleucine in blood protein causes decreased plasma isoleucine values after gastrointestinal haemorrhage, and may be a contributory factor to uraemia and hyperammonaemia in patients with normal and impaired liver function, respectively. Intravenous isoleucine administration after gastrointestinal haemorrhage could be beneficial and will be the subject of further research.
Adult↗
Ammonia and glutamine metabolism during liver insufficiency: the role of kidney and brain in interorgan nitrogen exchange.
BACKGROUND: During liver failure, urea synthesis capacity is impaired. In this situation the most important alternative pathway for ammonia detoxification is the formation of glutamine from ammonia and glutamate. Information is lacking about the quantitative and qualitative role of kidney and brain in ammonia detoxification during liver failure. METHODS: This review is based on own experiments considered against literature data. RESULTS AND CONCLUSIONS: Brain detoxifies ammonia during liver failure by ammonia uptake from the blood, glutamine synthesis and subsequent glutamine release into the blood. Although quantitatively unimportant, this may be qualitatively important, because it may influence metabolic and/or neurotransmitter glutamate concentrations. The kidney plays an important role in adaptation to hyperammonaemia by reversing the ratio of ammonia excreted in the urine versus ammonia released into the blood from 0.5 to 2. Thus, the kidney changes into an organ that netto removes ammonia from the body as opposed to the normal situation in which it adds ammonia to the body pools.
Ammonia↗
Effects of methionine sulphoximine treatment on renal amino acid and ammonia metabolism in rats.
Renal glutamine metabolism in relation to ammoniagenesis has been extensively studied during chronic metabolic acidosis, when arterial glutamine levels are reduced. However, little is known about the effects of reduced glutamine delivery on renal glutamine and ammonia metabolism at physiological systemic pH values. Therefore, a model of decreased arterial glutamine concentrations at normal pH values was developed using methionine sulphoximine (MSO). Renal glutamine and ammonia metabolism was measured by determining fluxes and intracellular concentrations after an overnight fast in ether anaesthetized normal rats, MSO-treated rats and their pair-fed controls. Moreover, fluxes and intracellular concentrations of several other amino acids were determined concomitantly. After 2 and 4 days of MSO treatment, arterial glutamine concentrations were reduced to 55%, while arterial ammonia concentrations increased by 70%. Kidney glutamine uptake reduced, but systemic pH was unchanged. Fractional extraction of glutamine remained unchanged, suggesting that also in vivo net uptake of glutamine by the kidney at subnormal levels is related to arterial glutamine concentrations. As a result, at day 2 but not at day 4, the kidney reduced the net release of ammonia into the renal vein and thus reduced net renal ammonia addition to body ammonia pools. Therefore at day 2, the kidney seems to play an important role in adaptation to both hyperammonaemia and hypoglutaminaemia.
Amino Acids↗
Influence of storage conditions on normal plasma amino-acid concentrations.
Conflicting information in the literature is given concerning the optimal preparation and storage conditions of plasma samples for amino-acid analysis. To assess the optimal pre-storage treatment, we compared several methods and studied their influence on plasma amino-acid levels of rats and humans, stored at different temperatures. In rat plasma, the frequently reported degradation of glutamine was not measurable at a storage temperature of -70 degrees C. However, storage of native, not deproteinised plasma at this temperature, resulted in a 32% decrease of arginine and a 30% increase in ornithine after 24 weeks. Deproteinisation prohibited this arginine decay. At -20 degrees C, arginine decay was even more pronounced, whereas glutamine decreased by 14% in untreated plasma, by 10% in sulfosalicylic acid deproteinised plasma and by 3% if the deproteinisation was followed by removal of the protein pellet and subsequent neutralisation. To confirm these unexpected results in humans, we repeated this experiment with plasma of 6 volunteers. In contrast to rat plasma, we did not observe any changes in arginine and ornithine concentrations in human plasma stored at -70 degrees C. At -20 degrees C the reduction in glutamine was only 4-5%. These results suggest that interspecies differences in enxymatic activity exist in plasma. Finally, having assessed the optimal treatment and storage conditions (deproteinisation followed by storage at -70 degrees C), samples were obtained from a total of 112 human volunteers, stratified for age and sex, and amino-acids were measured. In the female group, we found a tendency to a gradual increase in most amino-acid concentrations with advancing age, which however only reached significance for histidine, citrulline, alanine and leucine. These observations demonstrate that plasma samples for amino-acid analysis should be deproteinised and stored at -70 degrees C. Also important interspecies differences appear to exist in plasma enzymatic activity. Finally, control samples should be taken from an age and sex matched control group.
Journal Article↗
Muscle ammonia and glutamine exchange during chronic liver insufficiency in the rat.
The aim of this study was to investigate the role of skeletal muscle in ammonia and glutamine metabolism during chronic hyperammonemia induced by liver insufficiency. The hindquarter ammonia and amino acid fluxes and muscle tissue concentrations were studied in two rat models of chronic liver insufficiency, portacaval shunting and portacaval shunting plus bile-duct ligation, as well as in sham-operated animals, 7 and 14 days after surgery, and in normal, unoperated rats. To reduce nutritional influences, portacaval-shunted rats and sham-operated rats were pair-fed to portacaval shunt biliary obstruction rats. Arterial ammonia levels were elevated in both liver insufficiency groups. In the portacaval shunting plus bile-duct ligation group, arterial glutamine levels were elevated compared with sham-operated controls. No net hind-quarter ammonia uptake was observed in any of the groups, despite hyperammonemia in the chronic liver insufficiency groups. Hindquarter glutamine release was always increased in the liver insufficiency groups compared with sham-operated controls, despite similar muscle glutamine levels in the sham-operated and hyperammonemic groups, suggesting enhanced muscle glutamine synthesis in the latter groups. Muscle ammonia levels were always increased and muscle glutamate decreased in the hyperammonemic groups, probably indicating glutamate consumption by enhanced glutamine synthesis. The increased phenylalanine tissue concentrations and efflux in portacaval shunt/biliary obstruction rats suggest that enhanced net muscle protein breakdown, amino acid catabolism and transamination, rather than ammonia uptake from the blood furnish amino acids and ammonia for enhanced glutamine synthesis. These experiments suggest that nutritional factors are important in explaining altered muscle metabolism during chronic liver insufficiency.
Amino Acids↗
Metabolic adaptation of the kidney to hyperammonemia during chronic liver insufficiency in the rat.
The aim of this study was to evaluate the role of renal ammonia and glutamine metabolism in the metabolic adaptation to chronic liver insufficiency-induced hyperammonemia in the rat. To this purpose, urinary excretion, renal net exchange and tissue concentrations of ammonia and amino acids were measured in anesthetized, normal control rats that did not undergo surgery, in control rats that underwent sham surgery, in rats that underwent portacaval shunting and in rats that underwent both portacaval shunting and bile duct ligation. Rats that underwent sham surgery and portacaval shunting were pair-fed with rats that underwent portacaval shunting and biliary obstruction, to correct for anorexia in that group, and all rats that were operated on were studied 7 and 14 days after surgery. Arterial ammonia and glutamine levels were elevated in groups that underwent portacaval shunting and portacaval shunting plus biliary obstruction at all time points. At days 7 and 14, total renal ammonia production decreased in rats that underwent portacaval shunting and in rats that underwent portacaval shunting plus biliary obstruction, associated with a 50% decrease in net renal glutamine uptake and strongly diminished net ammonia release into the renal vein, which was most prominent in the group that underwent portacaval shunting plus biliary obstruction. Urinary ammonia excretion was similar in rats that underwent portacaval shunting and in those that underwent sham surgery but was increased more than 200% at days 7 and 14 in rats that underwent portacaval shunting plus biliary obstruction. In this group, in contrast to portacaval-shunted rats, the kidney appeared to be an organ of net ammonia disposal from the body. In separate experiments in unanesthetized, unrestrained rats, similar changes in urinary ammonia excretion were observed without changes in arterial pH, excluding an effect of anesthesia or pH on the obtained results. These results indicate that the kidney plays an important role in the metabolic adaptation to hyperammonemia during chronic liver insufficiency in the rat.
Adaptation, Physiological↗
Cerebral cortex ammonia and glutamine metabolism in two rat models of chronic liver insufficiency-induced hyperammonemia: influence of pair-feeding.
Enhanced cerebral cortex ammonia uptake, subsequent glutamine synthesis, and glutamine release into the bloodstream have been hypothesized to deplete cerebral cortex glutamate pools. We investigated this hypothesis in rats with chronic liver insufficiency-induced hyperammonemia and in pair-fed controls to rule out effects of differences in food intake. Cerebral cortex plasma flow and venous-arterial concentration differences of ammonia and amino acids, as well as cerebral cortex tissue concentrations, were studied 7 and 14 days after surgery in portacaval-shunted/bile duct-ligated, portacaval-shunted, and sham-operated rats, while the latter two were pair-fed to the first group, and in normal unoperated ad libitum-fed control rats. At both time points, arterial ammonia was elevated in the chronic liver insufficiency groups and arterial glutamine was elevated in portacaval shunt/biliary obstruction rats compared to the other groups. In the chronic liver insufficiency groups net cerebral cortex ammonia uptake was observed at both time points and was accompanied by net glutamine release. Also in these groups, cerebral cortex tissue glutamine, many other amino acid, and ammonia levels were elevated. Tissue glutamate levels were decreased to a similar level in all operated groups compared with normal unoperated rats, irrespective of plasma and tissue ammonia and glutamine levels. These results demonstrate that during chronic liver insufficiency-induced hyperammonemia, the rat cerebral cortex enhances net ammonia uptake and glutamine release. However, the decrease in tissue glutamate concentrations in these chronic liver insufficiency models seems to be related primarily to nutritional status and/or surgical trauma.
Amino Acids↗
Intestinal glutamine and ammonia metabolism during chronic hyperammonaemia induced by liver insufficiency.
During liver insufficiency, besides portasystemic shunting, high arterial glutamine concentrations could enhance intestinal glutamine consumption and ammonia generation, thereby aggravating hyperammonaemia. To investigate this hypothesis, portal drained viscera (intestines) fluxes and jejunal tissue concentrations of ammonia and glutamine were measured in portacaval shunted rats with a ligated bile duct, portacaval shunted, and sham operated rats, seven and 14 days after surgery, and in normal unoperated controls. Effects of differences in food intake were minimised by pair feeding portacaval shunted and sham operated with portacaval shunted rats with biliary obstruction. At both time points, arterial ammonia was increased in the groups with liver insufficiency. Also, arterial glutamine concentration was raised in all operated groups compared with normal unoperated controls. At both time points, ammonia production by portal drained viscera was reduced in portacaval shunted rats with biliary obstruction, portacaval shunted, and sham operated rats compared with normal unoperated controls, and no major differences were found between these operated groups. At day 7 in all operated groups glutamine uptake by portal drained viscera was lower than in normal unoperated controls, but no major differences were found at day 14. These experiments show that ammonia generation by portal drained viscera remains unchanged in rats with chronic liver insufficiency despite alterations in arterial glutamine concentrations and intestinal glutamine uptake. The hyperammonaemia seems to be mainly determined by the portasystemic shunting.
Alanine↗
Renal ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat.
Renal glutamine uptake and subsequent urinary ammonia excretion could be an important alternative pathway of ammonia disposal from the body during liver failure (diminished urea synthesis), but this pathway has received little attention. Therefore, we investigated renal glutamine and ammonia metabolism in midly hyperammonemic, portacaval shunted rats and severely hyperammonemic rats with acute liver ischemia compared to their respective controls, to investigate whether renal ammonia disposal from the body is enhanced during hyperammonemia and to explore the limits of the pathway. Renal fluxes, urinary excretion, and renal tissue concentrations of amino acids and ammonia were measured 24 h after portacaval shunting, and 2, 4, and 6 h after liver ischemia induction and in the appropriate controls. Arterial ammonia increased to 247 +/- 22 microM after portacaval shunting compared to controls (51 +/- 8 microM) (P < 0.001) and increased to 934 +/- 54 microM during liver ischemia (P < 0.001). Arterial glutamine increased to 697 +/- 93 microM after portacaval shunting compared to controls (513 +/- 40 microM) (P < 0.01) and further increased to 3781 +/- 248 microM during liver ischemia (P < 0.001). In contrast to controls, in portacaval shunted rats the kidney net disposed ammonia from the body by diminishing renal venous ammonia release (from 267 +/- 33 to -49 +/- 59 nmol/100 g body wt per min) and enhancing urinary ammonia excretion from 113 +/- 24 to 305 +/- 52 nmol/100 g body wt per min (both P < 0.01). Renal glutamine uptake diminished in portacaval shunted rats compared to controls (-107 +/- 33 vs. -322 +/- 41 nmol/100 g body wt per min) (P < 0.01). However, during liver ischemia, net renal ammonia disposal from the body did not further increase (294 +/- 88 vs. 144 +/- 101 nmol/100 g body wt per min during portacaval shunting versus liver ischemia). Renal glutamine uptake was comparable in both hyperammonemic models. These results indicate that the rat kidney plays an important role in ammonia disposal during mild hyperammonemia. However, during severe liver insufficiency induced-hyperammonemia, ammonia disposal capacity appears to be exceeded.
Ammonia↗
Selective uptake of glutamine in the gastrointestinal tract.
Explore the source record for details and available documents.
Digestive System↗
Altered glutamine metabolism in rat portal drained viscera and hindquarter during hyperammonemia.
In normal rats, muscle is the major glutamine releasing organ and gut is the major glutamine consuming organ. It has been suggested that enhanced muscle ammonia detoxification and gut ammonia production occurs during liver insufficiency-induced hyperammonemia. Therefore, ammonia and amino acid fluxes across portal-drained viscera and hindquarter, and muscle concentrations were measured in portacaval shunted and acute liver ischemia rats. Arterial ammonia and most amino acids were increased after portacaval shunting and increased progressively during liver ischemia, but net hindquarter ammonia uptake was not observed. Net hindquarter glutamine efflux was increased during portacaval shunting, but it decreased during liver ischemia, while muscle glutamine concentrations increased. The comparable net portal drained viscera glutamine uptake in normal and portacaval shunted rats changed during liver ischemia from net uptake to release, coinciding with release of most other amino acids. These results cast doubt on the ammonia detoxifying role of muscle during acute liver ischemia-induced hyperammonemia in the rat. The portal drained viscera glutamine release during severe hyperammonemia could be due to intestinal damage.
Amino Acids↗
Partial enterectomy in the rat does not diminish muscle glutamine production.
The hypothesis was posed that consumption of the amino acid glutamine by the splanchnic tissues is an important regulating mechanism for its production in muscle. Therefore, glutamine consumption or production in portal-drained viscera (PDV), liver, and hindquarter was measured by determining fluxes and intracellular concentrations after 80% enterectomy or SHAM operation in rats. Moreover, fluxes and intracellular concentrations of several other amino acids, ammonia, and liver urea production were determined concomitantly. After enterectomy, arterial glutamine concentration was increased, PDV glutamine consumption was decreased by 77%, and liver glutamine consumption was unchanged compared with values in SHAM-operated rats. Although hindquarter glutamine production remained unchanged after enterectomy, intracellular glutamate concentration (glutamine precursor) was lower, suggesting that enterectomy induces changes in muscle metabolism without changing the flux of glutamine. For the remaining gut, it was calculated that after enterectomy glutamine consumption per gram remaining gut tissue increased. These results cast doubt on the hypothesis that diminished splanchnic glutamine uptake can reduce muscle glutamine production.
Alanine↗
Cerebral cortex ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat.
Hyperammonemia has been suggested to induce enhanced cerebral cortex ammonia uptake, subsequent glutamine synthesis and accumulation, and finally net glutamine release into the blood stream, but this has never been confirmed in liver insufficiency models. Therefore, cerebral cortex ammonia- and glutamine-related metabolism was studied during liver insufficiency-induced hyperammonemia by measuring plasma flow and venous-arterial concentration differences of ammonia and amino acids across the cerebral cortex (enabling estimation of net metabolite exchange), 1 day after portacaval shunting and 2, 4, and 6 h after hepatic artery ligation (or in controls). The intra-organ effects were investigated by measuring cerebral cortex tissue ammonia and amino acids 6 h after liver ischemia induction or in controls. Arterial ammonia and glutamine increased in portacaval-shunted rats versus controls, and further increased during liver ischemia. Cerebral cortex net ammonia uptake, observed in portacaval-shunted rats, increased progressively during liver ischemia, but net glutamine release was only observed after 6 h of liver ischemia. Cerebral cortex tissue glutamine, gamma-aminobutyric acid, most other amino acids, and ammonia levels were increased during liver ischemia. Glutamate was equally decreased in portacaval-shunted and liver-ischemia rats. The observed net cerebral cortex ammonia uptake, cerebral cortex tissue ammonia and glutamine accumulation, and finally glutamine release into the blood suggest that the rat cerebral cortex initially contributes to net ammonia removal from the blood during liver insufficiency-induced hyperammonemia by augmenting tissue glutamine and ammonia pools, and later by net glutamine release into the blood. The changes in cerebral cortex glutamate and gamma-aminobutyric acid could be related to altered ammonia metabolism.
Ammonia↗
A simple new method for repeated in vivo cerebral cortex flux measurement in rats.
A new application of an indicator dilution technique, using nonradioactive para-aminohippuric acid, is described for superior sagittal sinus blood flow determination in rats. Superior sagittal sinus blood flow, mainly representing cerebral cortex blood flow, amounted to 541 +/- 49 microliters/min in ketamine-anesthetized, but otherwise normal, rats breathing room air. Increasing arterial pCO2 enhanced superior sagittal sinus blood flow (P less than 0.01), providing evidence that this method correctly measures cerebral blood flow. The respiratory quotient was 1.1 and the cerebral cortex metabolic rate of oxygen consumption was +/- 1.45 mumol/min. Cerebral cortex ammonia uptake was not significantly different from zero and of the amino acid fluxes, only alanine differed from zero (P less than 0.05). Flux measurements are crucial in studies of healthy or altered organ metabolism in both experimental animals and postoperative surgical patients. We devised a simple and economical method of repeated cerebral cortex flux measurement in rats that is a potentially valuable tool in metabolic studies of the cerebral cortex.
Animals↗
[Ruptures of the patellar ligament].
Explore the source record for details and available documents.
Humans↗