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PubMed2001

Effect of glutamine supplementation of the diet on tissue protein synthesis rate of glucocorticoid-treated rats.

Although glutamine status in the critically ill patient can be improved by nutritional means, the most effective way of effecting such supplementation has received little attention. We evaluated two different ways of supplementing clinical nutrition products with glutamine, either with free glutamine or by providing a glutamine-rich protein source, in acute glucocorticoid-treated (intraperitoneal dexamethasone, 120 mg/kg) rats. During the recovery period, the animals received isonitrogenous and isoenergetic diets containing either casein, mixed whey proteins with or without glutamine, or carob protein plus essential amino acids. Plasma and tissue amino acids and glutathione as well as tissue protein synthesis were measured. Dexamethasone treatment lowered weight gain, muscle glutamine, and muscle and jejunal protein synthetic rate. Muscle protein synthesis was increased (from 15.9% to 24.2%/d) only when glutamine was included in the diet as a free amino acid. This increase paralleled a rise in plasma glutamine. We speculate that glutamine provided in dietary protein is extensively metabolized by the splanchnic tissues and does not influence peripheral glutamine status to the same extent as glutamine provided in a free amino acid form. However, both forms of glutamine supplementation were equally effective in increasing protein synthesis in the jejunum (by 25%). This is likely the main benefit of glutamine supplementation of enteral nutrition formulas.

Amino Acids↗

PubMed1986

Influence of reduced concentration of L-glutamine on growth and viability of cells in monolayer, in spheroids, and in experimental tumours.

L-Glutamine is a requirement for many cells in tissue culture, an intermediate in many metabolic pathways, and an alternative substrate to glucose for energy metabolism. These properties suggest that glutamine concentration might be a determinant of cell viability in tumours, especially in regions that are deficient in other metabolites. We have therefore studied the effects of glutamine depletion on single cells in culture, on spheroids and on experimental tumours. Absence of glutamine suppressed the growth rate of two cell lines, but cells cultured for up to 6 h in the absence of glutamine had no decrease in plating efficiency. There was little effect on growth of MGH-U1 (human bladder cancer) spheroids of varying the glutamine concentration in the range of 0.1 to 2 mM and spheroids exposed to these concentrations did not develop central necrosis. Lower concentration of glutamine suppressed the rate of spheroid growth, and spheroids did not grow in the absence of glutamine. Pseudomonas 7A glutaminase reduced the survival of cells in glutamine-free culture and prevented growth of spheroids. Glutaminase was injected into mice bearing experimental tumours to reduce blood levels of glutamine; some animals also received 15 Gy radiation to their tumours to assess the effects of glutamine levels on surviving nutrient-deprived (i.e. hypoxic) cells. Glutaminase had no effect on cell survival in the Lewis lung tumour or in MGH-U1 xenografts, with or without radiation; glutaminase caused dose-dependent growth delay of the KHT tumour, which was additive to that caused by radiation. The present results suggest that (i) short-term changes of glutamine concentration have small effects on cell viability; and (ii) depletion of glutamine levels in blood through the in vivo use of glutaminase is unlikely to produce major therapeutic effects against nutrient-deprived cells in solid tumours.

Animals↗

PubMed1983

Glutamine metabolism in lymphocytes of the rat.

The metabolism of glutamine in resting and concanavalin-A-stimulated lymphocytes was investigated. In incubated lymphocytes isolated from rat mesenteric lymph nodes, the rates of oxygen and glutamine utilization and that of aspartate production were approximately linear with respect to time for 60 min, and the concentrations of adenine nucleotides plus the ATP/ADP or ATP/AMP concentration ratios remained approximately constant for 90 min. The major end products of glutamine metabolism were glutamate, aspartate and ammonia: the carbon from glutamine may contribute about 30% to respiration. When both glucose and glutamine were presented to the cells, the rates of utilization of both substances increased. Evidence was obtained that the stimulation of glycolysis by glutamine could be due, in part, to an activation of 6-phosphofructokinase. Starvation of the donor animal increased the rate of glutamine utilization. The phosphoenolpyruvate carboxykinase inhibitor mercaptopicolinate decreased the rate of glutamine utilization by 28%; the rates of accumulation of glutamate and ammonia were decreased, whereas those of lactate, aspartate and malate were increased. The mitogen concanavalin A increased the rate of glutamine utilization (by about 51%). The rate of [3H]thymidine incorporation into DNA caused by concanavalin A in cultured lymphocytes was very low in the absence of glutamine; it was increased about 4-fold at 1 microM-glutamine and was maximal at 0.3 mM-glutamine; neither other amino acids nor ammonia could replace glutamine.

Adenine Nucleotides↗

PubMed1991

Substrate-specificity of glutamine transporters in membrane vesicles from rat liver and skeletal muscle investigated using amino acid analogues.

We investigated the effects of glutamine and histidine analogues on glutamine transport processes in membrane vesicles prepared from rat liver (sinusoidal membrane) and skeletal muscle (sarcolemma). L-[14C]Glutamine is transported in these membranes predominantly by Systems N/Nm (liver and muscle respectively), and to a lesser extent by Systems A and L (e.g. about 60, 20 and 20% of total flux respectively via Systems N, A and L at 0.05 mM-glutamine in liver membrane vesicles). The glutamine anti-metabolites 6-diazo-5-oxo-L-norleucine and acivicin were relatively poor inhibitors of glutamine uptake into liver membrane vesicles (less than 25% inhibition at 20-fold excess) and appeared primarily to inhibit System A activity (i.e. N-methylaminoisobutyric acid-inhibitable glutamine uptake). In similar experiments azaserine (also a glutamine anti-metabolite) inhibited approx. 50% of glutamine uptake, apparently by inhibition of System A and also of System L (i.e. 2-amino-2-carboxybicyclo[2,2,1]heptane-inhibitable glutamine uptake). Glutamate gamma-hydroxamate, aspartate beta-hydroxamate, histidine and N'-methylhistidine were all strong inhibitors of glutamine uptake into liver membrane vesicles (greater than 65% inhibition at 20-fold excess), but neither homoglutamine nor N'-methylhistidine produced inhibition. L-Glutamate-gamma-hydroxamate was shown to be a competitive inhibitor of glutamine transport via System N (Ki approximately 0.6 mM). Glutamine uptake in sarcolemmal vesicles showed a similar general pattern of inhibition as in liver membrane vesicles. The results highlight limits on the substrate tolerance of System N; we suggest that the presence of both an L-alpha-amino acid group and a nitrogen group with a delocalized lone-pair of electrons (amide or pyrrole type), separated by a specific intramolecular distance (C2-C4 chain equivalent), is important for substrate recognition by this transporter.

Amino Acids↗

PubMed1998

Distribution of glutaminase and glutamine synthetase activities in the human gastrointestinal tract.

1. The activities of the two key enzymes involved in glutamine metabolism, glutaminase and glutamine synthetase, were measured in mucosal biopsies taken from different sites throughout the human gastrointestinal tract, from oesophagus to rectum. 2. The specific activity of glutamine synthetase was highest in the stomach (4.5 nmol glutamine formed per minute per mg of protein), but both small and large intestine and the oesophagus had little synthesizing capacity (less than 0.3 nmol of glutamine formed per minute per mg of protein). 3. Glutaminase specific activity was highest in the small intestine (53 nmol glutamate formed per minute per mg of protein by duodenal mucosa), intermediate in the large intestine and lowest in the oesophagus and stomach (less than 13 nmol of glutamate formed per minute per mg of protein). 4. The glutamine concentration in the mucosa was lower in the duodenum than in the colon (0.62 and 0.95 mmol/kg wet weight respectively), but both were much lower than the measured K(m) values of glutaminases obtained from these sites (3.8 and 4.0 nmol/kg wet weight respectively). 5. The concentration of glutamine in saliva, stomach juice, bile and duodenal juice suggests that very little glutamine passes into the gastrointestinal tract via these secretions. 6. The study provides the most complete information on the distribution of glutamine synthetase and glutaminase along the human gastrointestinal tract, and suggests that (i) both the small and large intestines have a high potential for glutamine metabolism, but little synthesizing capacity, thus both must derive their glutamine from other sources, and (ii) neither the stomach nor the oesophagus have a high glutaminase activity, although the stomach has substantial capacity to synthesize glutamine. The distribution of the enzymes along the gastrointestinal tract may help rationalize the use of glutamine for treating diseases that affect different parts of the gastrointestinal tract.

Adult↗

PubMed2003

Nutritional benefits of enteral alanyl-glutamine supplementation on rat small intestinal damage induced by cyclophosphamide.

BACKGROUND: Glutamine is the principal fuel used by the small intestine. Although the parental administration of glutamine promotes intestinal mucosal growth, it is controversial whether enteral glutamine is effective against small intestinal damage caused by chemotherapy. To further evaluate the benefits of enteral supplementation, peptide and amino acid transporter functions must be considered. METHOD: Rats were given cyclophosphamide (CPM) intraperitoneally (300 mg/kg). Expression of the amino acid transporter, B0 and peptide transporter (PepT1) in the jejunal mucosa was initially examined by northern blot analysis. Rats received a bolus oral supplement of an alanine (1.22 g/kg/day) plus glutamine (2.0 g/kg/day) mixture, alanyl-glutamine (2.972 g/kg/day) or saline as a control, for 7 days after CPM administration. RESULTS: Levels of B0 mRNA remained unchanged at both 3 and 7 days after CPM administration. Conversely, PepT1 mRNA increased significantly after CPM administration, and reached 200% of the initial level 7 days later. In rats given alanyl-glutamine, the mucosal wet weight and protein content increased significantly with increasing villus height at 3 and 7 days, compared with the alanine plus glutamine mixture. The plasma glutamine concentration in the alanyl-glutamine group, but not the alanine plus glutamine mixture group, increased significantly compared with that in the saline group. CONCLUSION: Enteral supplementation with an alanyl-glutamine but not alanine plus glutamine mixture prevents intestinal damage, as demonstrated by increased peptide transport expression and an elevated plasma glutamine concentration after CPM administration.

Alanine↗

PubMed1994

Inhibition of astrocyte glutamine production by alpha-ketoisocaproic acid.

We have evaluated the effect of alpha-ketoisocaproic acid (KIC), the ketoacid of leucine, on the production of glutamine by cultured astrocytes. We used 15NH4Cl as a metabolic tracer to measure the production of both [5-15N]glutamine, reflecting amidation of glutamate via glutamine synthetase, and [2-15N]glutamine, representing the reductive amination of 2-oxoglutarate via glutamate dehydrogenase and subsequent conversion of [15N]glutamate to [2-15N]glutamine. Addition of KIC (1 mM) to the medium diminished the production of [5-15N]glutamine and stimulated the formation of [2-15N]glutamine with the overall result being a significant inhibition of net glutamine synthesis. An external KIC concentration as low as 0.06 mM inhibited synthesis of [5-15N]glutamine and a level as low as 0.13 mM enhanced labeling (atom% excess) of [2-15N]glutamine. Higher concentrations of KIC in the medium had correspondingly larger effects. The presence of KIC in the medium did not affect flux through glutaminase, which was measured using [2-15N]glutamine as a tracer. Nor did KIC inhibit the activity of glutamine synthetase that was purified from sheep brain. Addition of KIC to the medium caused no increased release of lactate dehydrogenase from the astrocytes, suggesting that the ketoacid was not toxic to the cells. KIC treatment was associated with an approximately twofold increase in the formation of 14CO2 from [U-14C]glutamate, indicating that transamination of glutamate with KIC increases intraastrocytic alpha-ketoglutarate, which is oxidized in the tricarboxylic acid cycle. KIC inhibited glutamine synthesis more than any other ketoacid tested, with the exception of hydroxypyruvate.(ABSTRACT TRUNCATED AT 250 WORDS)

Ammonium Chloride↗

PubMed2006

Total glutamine content in human milk is not influenced by gestational age.

BACKGROUND: Glutamine may be a conditionally indispensable amino acid in neonates and should be given in adequate amounts. Reliable information concerning the glutamine content of human milk is lacking. AIM: To assess total glutamine content in human milk using a novel analytical procedure, and to evaluate the potential influence of time of delivery and lactational stage. METHODS: The content of free and protein-bound glutamine was assessed in transitional (days 4-7 of lactation) and mature (days 29-34) human milk, after preterm (<35 wk of gestation, n=20) or term (>37 wk, n=20) delivery. Milk samples were obtained by manual expression and stored at <or=70 degrees C. Measurement of protein-bound glutamine was performed after stabilization by bis(1,1-trifluoroacetoxy)iodobenzene (BTI). Free glutamine was detected by HPLC. RESULTS: There was no difference concerning glutamine content in human milk after term or preterm delivery (median of 5000 vs 4960 micromol/l milk). The protein-bound glutamine content decreased with the duration of lactation (6230 vs 4540 micromol/l milk). Free glutamine accounted for only 3-10% of the protein-bound glutamine content. The free glutamine content showed a high variability after preterm and term delivery. CONCLUSION: This study presents for the first time data on glutamine intake in preterm and term neonates fed human milk. With these data, it is possible to formulate adequately composed nutritional therapy for infants at risk of glutamine imbalance.

Adolescent↗

PubMed2004

Effect of enteral glutamine or glycine on whole-body nitrogen kinetics in very-low-birth-weight infants.

BACKGROUND: Glutamine is a critical amino acid for the metabolism of enterocytes, lymphocytes, and other proliferating cells. Although supplementation with glutamine has been suggested for growing infants, its effect on protein metabolism has not been examined. OBJECTIVE: The objective was to examine the effect of enteral glutamine or glycine on whole-body kinetics of glutamine, phenylalanine, leucine, and urea in preterm infants. DESIGN: Infants at <32 wk of gestation were given formula supplemented with either glutamine (0.6 g. kg(-1). d(-1); n = 9) or isonitrogenous amounts of glycine (n = 9) for 5 d. Eight infants fed unsupplemented formula served as control subjects. Glutamine, phenylalanine, leucine nitrogen flux, leucine carbon flux, and urea kinetics were quantified during a basal fasting period and in response to nutrient intake. RESULTS: Growing preterm infants had a high weight-specific rate of appearance of glutamine, phenylalanine, and leucine nitrogen flux. When compared with the control treatment, enteral glutamine resulted in a high rate of urea synthesis, no change in the plasma glutamine concentration, and no change in the rate of appearance of glutamine. Glycine supplementation resulted in similar changes in nitrogen metabolism, but the magnitude of change was less than that in the glutamine group. In the nonsupplemented infants, the rate of appearance of leucine nitrogen flux was negatively correlated (rho = -0.72) with urea synthesis. In contrast, the correlation (rho = 0.75) was positive in the glutamine group. CONCLUSION: Enterally administered glutamine in growing preterm infants is entirely metabolized in the gut and does not have a discernable effect on whole-body protein and nitrogen kinetics.

Blood Urea Nitrogen↗

PubMed2001

Glutamine in animal science and production.

With its many proposed metabolic roles, glutamine would seem to have major potential in normal animal production systems as well as during situations involving adverse challenges. In practice, however, responses to glutamine supplementation have been inconsistent. Thus, during lactation and growth studies in ruminants, both positive and null effects on production responses have been reported. Similarly, therapeutic responses to glutamine supplementation during various digestive tract disorders have been inconsistent in both pigs and ruminants. This is despite a proven involvement in the nucleic acid biosynthesis necessary to support cell proliferation. In sheep, at least, glutamine may exert a protective effect against hepatic amino acid (AA) oxidation, particularly for methionine. This may offer anabolic potential because methionine is the first limiting AA in a number of animal feedstuffs. Glutamine is also important in control of metabolic acidosis, but, in contrast to rodents, the main site of production seems to be extra-hepatic. In the immune system, while lymphocyte proliferation is glutamine-dependent, intracellular concentrations are low (in contrast to other tissues, such as muscle and liver). Instead, glutamate is accumulated, but the majority of this (approximately 65%) is derived in vivo from plasma glutamine. In sheep, endotoxin challenge elevates the plasma flux of glutamine, with a corresponding decrease in plasma concentration. At the same time, both the glutamate accumulation and fractional rate of protein synthesis within lymphocytes are enhanced. These lymphocyte responses, however, are not altered by an AA supplement that contains glutamine. Overall, although glutamine obviously plays important metabolic roles within the body, supplementation does not appear to provide consistent beneficial or therapeutic effects, except during certain catabolic situations. Glutamine availability, therefore, does not seem to be a limitation in many challenge situations. Rather, glutamine may signal alterations in nutrient demands among organs and a better understanding of this role may increase understanding of where modulation of glutamine status would be beneficial.

Acid-Base Equilibrium↗

PubMed1996

Glutamine as a regulator of DNA and protein biosynthesis in human solid tumor cell lines.

OBJECTIVE: The transport of glutamine by six different human solid tumor-derived cell lines (e.g., breast, colon, liver) was characterized and the impact of glutamine deprivation on rates of tumor cell proliferation and DNA and protein synthesis was assayed. SUMMARY BACKGROUND DATA: Glutamine is added routinely to cell culture media and its importance for cellular growth has been established. However, carrier-mediated glutamine transport by solid tumors has not been studied extensively, and the mechanisms by which glutamine contributes to cell growth regulation require further investigation. METHODS: In a panel of different human solid tumor-derived cells, sodium-dependent glutamine transport was characterized in vitro and rates of cell proliferation, protein and DNA synthesis, as well as thymidine transport, were correlated with glutamine concentrations in the culture media. RESULTS: In all cells, regardless of tissue origin, sodium-dependent glutamine transport was mediated almost exclusively by a single carrier. There was a range of Michaelis constants (Km) and maximal transport velocities (Vmax) for the glutamine transporter in each cell type, but the amino acid inhibition profiles were nearly identical, consistent with uptake by the System ASC family of transporters. Rates of cell growth, DNA and protein synthesis, and thymidine transport correlated with the glutamine concentration in the culture media, indicating the central role of this amino acid in regulating cellular proliferation. CONCLUSIONS: These data indicate that glutamine transport by all solid tumors is mediated by the System ASC family of transporters. The variation in Km values suggests that some cancers may be better suited to survive in a low glutamine environment than others. The mechanism by which glutamine supports cell proliferation and regulates cell cycle kinetics involves its modulation of DNA and protein biosynthetic rates.

Cell Division↗

PubMedDate not supplied

Deficiency in peripheral glutamine production in pediatric patients with burns.

Plasma glutamine levels decrease in association with severe injury, which suggests that the consumption of glutamine exceeds the production of glutamine or possibly represents a deficit in the release of glutamine from skeletal muscle. The goal of this study was to assess the peripheral glutamine kinetic response to prolonged stress in children with critical injuries. To accomplish this purpose, we quantitated peripheral glutamine kinetics in vivo with the use of 5N15 glutamine in 5 children with severe burns (total body surface area, 74%+/-14%; mean +/- SEM) and 3 children who underwent elective scar reconstruction. In the children with severe burns, leg blood flow was significantly elevated (16.2+/-2.1 vs 7.5 +/-0.3 mL/min/100 mL leg volume, P < .02) and the arterial concentration of glutamine was significantly reduced (0.31+/-0.04 vs 0.84+/-0.05 mmol/L, P < .001). The rate of glutamine turnover within the leg was significantly reduced in the patients with acute burns, whereas the net efflux of glutamine was similar between the 2 groups. These findings suggest that plasma glutamine concentrations decrease during severe stress as a result of a deficit in peripheral glutamine release in conjunction with an increased central consumption. This preliminary study supports the notion that exogenous glutamine supplementation in pediatric patients with severe injuries may be needed because of this inadequate skeletal muscle response.

Burns↗

PubMed1992

Adaptive regulation in skeletal muscle glutamine metabolism in endotoxin-treated rats.

The effects of a single dose of endotoxin (7.5 mg/kg BW) on skeletal muscle glutamine metabolism were studied in vivo in rats to gain further understanding of the altered glutamine metabolism that characterizes sepsis and other catabolic diseases. In endotoxin-treated animals the arterial glutamine concentration fell early initially and then increased compared with control values. Twelve hours after treatment, the arteriovenous concentration difference for glutamine across the hindquarter doubled, resulting in a significant increase in net muscle glutamine release in endotoxin-treated rats. As a consequence, the muscle glutamine concentration fell in the endotoxin-treated animals by 25%-40%, an event that was apparent as early as two hours after endotoxin treatment. Skeletal muscle glutaminase activity, the major enzyme of glutamine breakdown, was unchanged by endotoxemia, but expression of glutamine synthetase mRNA and glutamine synthetase specific activity increased in a time-dependent fashion. The glutamine depletion that develops in skeletal muscle during endotoxemia is caused by accelerated muscle glutamine release rather than an increase in intracellular degradation or a fall in intracellular biosynthesis. The adaptive increase in glutamine synthetase expression that occurs requires de novo RNA and protein synthesis and may be designed to prevent complete depletion of the intracellular glutamine pool.

Adaptation, Physiological↗

PubMed2000

Relative effects of glucose and glutamine on reactive oxygen intermediate production by neutrophils.

The energy source for neutrophils (PMNs) has long been believed to be glucose. However, it has been shown recently that PMNs use glutamine as well as glucose. Nevertheless, the comparative effects of glucose and glutamine on PMN function remain to be clarified. This study investigated the relative effects of glucose and glutamine on reactive oxygen intermediate (ROI) production by PMNs. In experiment 1, PMNs (1 x 10(6)/mL) isolated from healthy volunteers were incubated in RPMI 1640 medium containing neither glucose nor glutamine for 4, 12, 18, and 24 h at 37 degrees C. The medium was supplemented with 0 or 200 mg/dL (0 or 11 mM, respectively) glucose and glutamine (0, 0.5, 1, or 2 mM). PMN cell death was assessed on the basis of hypodiploid DNA by flow cytometry using propidium iodide DNA staining. ROI production by PMNs was determined by flow cytometry using dihydrorhodamine 123. In experiment 2, isolated PMNs were cultured in RPMI 1640 medium containing neither glucose nor glutamine. The medium was supplemented with glucose (0 or 11 mM) and a competitive inhibitor of glycolysis, 2-deoxy-D-glucose (2-DG; 0 or 20 mM). Each medium was supplemented with glutamine (0, 0.5, 1, or 2 mM) and incubated for 12 h at 37 degrees C. Then, ROI production by PMNs was measured. PMN cell death was not affected by glucose or glutamine in this experiment. In contrast, ROI production by PMNs was greater at 11 mM glucose than at 0 mM glucose at all incubation times studied. At 11 mM glucose, supplemental glutamine enhanced PMN ROI production after 18 and 24 h culture. In contrast, at 0 mM glucose, glutamine augmented ROI production by PMNs after 12 h as well as with 18 and 24 h incubations. PMN ROI production after 12 h culture was significantly greater at 11 mM glucose without 2-DG than at both 11 and 0 mM glucose with addition of 2-DG. In addition, supplemental glutamine enhanced ROI production by PMNs when 2-DG was added at 11 and 0 mM glucose. Glucose is essential for PMN ROI production. Under conditions of glucose depletion in vitro, glutamine is of importance in ROI production by PMNs, whereas the enhancing effect of glutamine on PMN ROI production is minor compared to that of glucose.

Cells, Cultured↗

PubMed2003

Regulative capacity of glutamine.

PURPOSE OF REVIEW: The amino acid glutamine plays a central role in nitrogen transport within the body and is a fuel for rapidly dividing cells, such as in the gut and the immune system. Plasma glutamine levels decline during critical illness, and therefore these cells suffer from glutamine starvation under these conditions. The present review summarizes data on the specific effect of extracellular glutamine on metabolism, function, stress response, and apoptosis of glutamine-utilizing cells. RECENT FINDINGS: Glutamine starvation leads to an energy depletion that is associated with a reduced responsiveness to exogenous stimuli. In addition, glutamine-starving cells show a reduced expression of the 70000 M(r) heat shock protein, which is an important factor for cell survival, and contain a reduced level of the antioxidant glutathione. Recent findings show that the extracellular glutamine level affects the susceptibility of cells to different apoptosis triggers: whereas glutamine-starving cells are more sensitive to Fas ligand-mediated apoptosis, they are desensitized against the cytotoxic effects of TNF-alpha. In addition, this review summarizes current knowledge on the molecular mechanisms of glutamine sensing. It discusses the role of AMP-activated protein kinase, the cellular redox state, osmosignalling, the regulation of translation, and amino acyl transfer RNA synthetases. SUMMARY: These data show that glutamine-utilizing cells possess molecular mechanisms to detect the availability of glutamine and to respond specifically to changes in the extracellular glutamine concentration.

Adenosine Monophosphate↗

PubMed1995

Comparison of glutamine-enhanced glutamate release from slices and primary cultures of rat brain.

Increased extracellular glutamate has been associated with a wide range of effects including production of neurotoxicity. Glutamine has previously been shown to cause increased release of glutamate from a variety of preparations. Extracellular central nervous system (CNS) glutamine levels are known to increase with neurotoxin exposures, hepatic failure, renal failure, head trauma or stroke. However, the action of glutamine to enhance the release of glutamate under nondepolarizing conditions has not been well studied. Since glutamine-mediated increases in extracellular glutamate are potentially of significance in cellular damage as a result of CNS insult, further examination of this phenomenon is important. Striatal and hippocampal slices or virtually neuron-free primary striatal glial cultures were employed in studies to further elucidate the mechanism(s) of glutamine-enhanced glutamate release. Elevated extracellular glutamine caused increased glutamate release in all three preparations. In hippocampal and striatal slices elevated glutamine caused an enhancement of N-methyl-D-aspartate (NMDA) receptor-mediated [3H]catecholamine release equivalent to that produced by high concentrations (up to 100 microM) of exogenous glutamate. In both striatal slices and primary cultures kynurenate increased glutamate release in the presence of 500 microM glutamine, while kainate either had no effect or decreased glutamate levels in the presence of glutamine. Since several presynaptic modulators of release did not affect the glutamate release produced by glutamine in slices, vesicular release of glutamate from nerve terminals was probably not involved in the effects of the exogenous glutamine. The similarities between striatal slices and primary striatal cultures indicate that enzymatic conversion of glutamine to glutamate within glia may be an important factor in the glutamine-mediated elevation of extracellular glutamate levels.

Analysis of Variance↗

PubMed1978

Glutamine metabolism, interorgan transport and glucogenicity in the sheep.

[U-14C]glutamine and [6-3H]glucose were infused into four groups of sheep: fed, NH4Cl acidotic, fasted, and dexamethasone treated. Net and unidirectional plasma glutamine fluxes in the portal-drained viscera (PDV), liver, kidneys, and hindquarters were measured by multiplying venoarterial concentration differences and 14C extraction ratios by the rate of blood flow. In fed sheep, glutamine was released by kidneys and muscle but removed by PDV and liver. In all other sheep, renal glutamine release either decreased or switched over to net removal largely due to increased unidirectional renal utilization. This increased renal glutamine demand was compensated for, during acidosis, by a decreased net hepatic glutamine removal but, during fasting and dexamethasone treatment, by an increased muscle glutamine release. Plasma glutamine and glucose turnover rates averaged 11-12 and 19-24 mmol/h but the percentage of glutamine converted to glucose was higher during fasting and dexamethasone treatment (21%) than in normal fed sheep (17%) perhaps reflecting the increased glutamine removal by the kidneys. Since renal glutamine utilization increases with acidosis and fasting and, since glutamine turnover remains unchanged, glutamine metabolism by other body tissues must be altered to compensate for renal changes.

Acidosis↗

PubMed1986

Characterization of glutamine transport by liver plasma membrane vesicles.

Plasma membrane vesicles were prepared from livers of fed normal and diabetic rats and used to characterize the membrane transport process responsible for glutamine uptake by the liver cell. In vesicles from normal rats the initial velocity of glutamine uptake was fourfold more rapid (0.20 +/- 0.02 vs. 0.05 +/- 0.02 nmol X mg protein-1 X 10 s-1) when Na+ replaced K+ in the extravesicular buffer. In the presence of a Na+-gradient glutamine uptake by vesicles was saturable, with a Km of 1.3 +/- 0.5 mM and a Vmax of 10 +/- 2.3 nmol X mg-1 X min-1. Lithium could fully substitute for Na+ in stimulating glutamine entry. In the presence of an imposed K+-gradient glutamine uptake was a linear function of its extravesicular concentration. In accord with the sodium-stimulated uptake of glutamine occurring via a sodium symport process, we observed that glutamine stimulated the initial rate of 22Na+ entry into vesicles by four- to fivefold. We further observed that glutamine entry was more rapid when lipophilic anions accompanied sodium in the incubation buffer, suggesting that Na+-glutamine flux is electrogenic. Preloading of vesicles with glutamine did not effect subsequent entry of labeled glutamine (no transstimulation), whereas intravesicular alanine did enhance alanine but not glutamine entry. Alloxan diabetes, which is known to stimulate the Na+-alanine cotransporter in these vesicles did not increase glutamine entry at any concentration tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗