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PubMed1987

Characteristics of L-glutamine transport in perfused rat skeletal muscle.

1. We have investigated glutamine transport in the perfused rat hindlimb using the paired-tracer isotope dilution technique. 2. Uptake of L-glutamine was stereospecific, saturable, sodium dependent, insulin sensitive and pH insensitive in the physiological range. The maximum capacity of transport (Vmax) under normal perfusate conditions at 37 degrees C, 145 mM-Na+ and in the absence of insulin was 1156 +/- 193 nmol min-1 g-1 with transport being half-maximal at a perfusate glutamine concentration of 9.25 +/- 1.15 mM. 3. The kinetics of Na+ dependence strongly suggested co-transport of Na+ and glutamine with a stoichiometry of 1:1; furthermore, Na+ activated the carrier without any change in the concentration of glutamine at which transport was half-maximal, i.e. a 'Vmax effect' rather than a 'Km effect'. 4. The characteristics of glutamine transport, especially its substrate specificity and the pattern of competitive and non-competitive inhibition of glutamine transport by other amino acids, suggest that it is mediated by a carrier or carriers for which asparagine and histidine are also suitable substrates. 5. The characteristics of muscle glutamine transport are related but distinct from those of system N identified in hepatocytes; we suggest that they are sufficiently distinct to justify the identification of a new variant of mammalian amino acid transport systems which may be identified by the symbol Nm. 6. The kinetic characteristics of system Nm are such that glutamine is likely to be the most rapidly exchanging amino acid across the muscle membrane at physiological intra- and extracellular glutamine concentrations. Its hormone and ion sensitivities are likely to be important in the physiological modulation of whole-body glutamine metabolism and also during derangements observed in disease and after injury.

Amino Acids↗
PubMed1978

Salmonella typhimurium LT-2 mutants with altered glutamine synthetase levels and amino acid uptake activities.

To determine whether Salmonella typhimurium has a nitrogen control response, we have examined the regulation of nitrogen utilization in two mutants with fivefold and threefold elevations in their glutamine synthetase activities. The mutants do not require glutamine for growth on glucose--ammonia medium but do have altered growth on other nitrogen sources. They grow better than an isogenic control on media containing arginine or asparate, but more slowly with proline or alanine as nitrogen sources. This unusual growth pattern is not due to altered regulation of the ammonia assimilatory enzymes, glutamate dehydrogenase and glutamate synthase, or to changes in the enzymes for aspartate degradation. However, transport for several amino acids may be affected. Measurement of amino acid uptake show that the mutants with high glutamine synthetase levels have increased rates for glutamine, arginine, aspartate, and lysine, but a decreased rate for proline. The relationship between glutamine synthetase levels and uptake was examined in two mutants with reduced, rather than increased, glutamine synthetase production. The uptake rates for glutamine and lysine were lower in these two glutamine auxotrophs than in the Gln+ controls. These results show a correlation between the glutamine synthetase levels and the uptake rates for several amino acids. In addition, the pleiotropic growth of the mutants with elevated glutamine synthetase activities suggests that a nitrogen control response exists for S. typhimurium and that it can be altered by mutations affecting glutamine synthetase regulation.

Amino Acids↗
PubMed1981

Effect of glutamine on enzymes of nitrogen metabolism in Bacillus subtilis.

An earlier study of the regulation of glutamate synthase (GOGAT) in Bacillus subtilis (Deshpande et al., Bichem. Biophys. Res. Commun. 95:55--60, 1980) revealed an inverse relationship between the specific activity of this essential ammonia-assimilatory enzyme and the intracellular pool of glutamine: GOGAT activity decreased when the internal glutamine concentration reached or exceeded 2.5 mM. This finding prompted the present investigation of the intracellular events linking glutamine formation to the regulation of GOGAT. A growing culture of B. subtilis was shifted from glutamate plus NH+4 medium (high GOGAT activity) to glutamate medium (low GOGAT activity). At various times after the shift, the intracellular concentrations of aspartate, glutamate, glutamine, alanine, and NH+4 and the activities of GOGAT and glutamine synthetase (GS) were measured. After 30 min, the only significant pool level change was an eightfold increase in glutamine, which paralleled a 2- to 3-fold increase in GS activity. Approximately 15 min after the glutamine pool reached its peak, GOGAT activity began to decrease and eventually declined 2.5-fold. In contrast, when B. subtilis was shifted from glutamate medium to glutamate plus NH+4 medium, there was a 1- to 2-h lag before the glutamine pool and GS activity approached a steady state. As a result, GOGAT activity was low until the concentration of glutamine dropped below 2.5 mM. We propose that glutamine is an important regulatory element in the control of GOGAT activity and that one form of GOGAT regulation involves enzyme inactivation. In addition, these results indicate that glutamine is neither a corepressor nor a feedback inhibitor of GS.

Bacillus subtilis↗
PubMed1983

Neurospora crassa mutant impaired in glutamine regulation.

The final products of the catabolism of arginine that can be utilized as nitrogen sources by Neurospora crassa are ammonium, glutamic acid, and glutamine. Of these compounds, only glutamine represses arginase and glutamine synthetase. We report here the isolation and characterization of a mutant of N. crassa whose arginase, glutamine synthetase, and amino acid accumulations are resistant to glutamine repression (glnI). This mutant has a greater capacity than the wild type (glns) to accumulate most of the arginine and some of the glutamine in osmotically sensitive compartments while growing exponentially. Nonetheless, the major part of the glutamine remains soluble and metabolically available for repression. We propose that the lower repression of glutamine synthetase by glutamine in this mutant could be a necessary condition for sustaining the higher flow of nitrogen for the accumulation of amino acids observed in ammonium excess and that, if glutamine is the nitrogen signal that regulates the arginine accumulation of the vesicle, the glnr mutant has also escaped this control. Finally, in the glnr mutant, some glutamine resynthesis is necessary for arginine biosynthesis and accumulation.

Amino Acids↗
PubMed1984

Glutamine enhances glutamate release in preference to gamma-aminobutyrate release in hippocampal slices.

To see the effect of physiological concentrations of glutamine on glutamate and gamma-aminobutyrate (GABA) release, rat hippocampal slices were incubated and (or) superfused without or with 0.25 mM glutamine in the presence or absence of Ca2+. The spontaneous and high K+-evoked release of glutamine, glutamate, and GABA was measured by precolumn derivatization and reversed phase high performance liquid chromatography. The spontaneous release of glutamate was increased by superfusion with glutamine and this increase was three times greater in the absence than in the presence of Ca2+. Spontaneous GABA release was not increased by glutamine. While in the absence of glutamine, the release of glutamate and GABA evoked by 50 mM K+ was about equal, in the presence of glutamine the evoked release of glutamate was nearly three times greater than that of GABA. The large evoked release of glutamate in the presence of glutamine was Ca2+ dependent nearly to the same extent as the smaller evoked release in the absence of glutamine. Results suggest that the availability of extracellular glutamine regulates the release of glutamate but not of GABA. Extracellular Ca2+ controls the spontaneous conversion of glutamine to glutamate but the site and mechanism of this control is uncertain.

Amino Acids↗
PubMed1985

Renal extraction of glutamine from plasma and whole blood: studies in dogs and rats.

The change in plasma and blood cell pools of L-glutamine during a single pass through the kidney was studied in dogs and rats. It was shown that the glutamine content of blood cells does not change following one passage through the renal vascular bed in normal or acidotic dogs. Furthermore, an infusion of L-glutamine elevating by 10-fold the plasma concentration of this amino acid only minimally changed the blood cells' glutamine content. Therefore within the time frame of acute experiments, the dog blood cells can be assumed to be impermeable to glutamine in vivo. Accordingly, renal glutamine extraction can be measured using either whole blood or plasma arteriovenous difference in this species. However, the latter value is larger and therefore can be measured more accurately. In normal rats, no net renal glutamine extraction is measured. In contrast, a considerable renal glutamine uptake occurs in acidotic rats, 23% of the extracted glutamine coming from the blood cell pool. A load of glutamine in vivo significantly elevates both the plasma and the blood cell concentration. It is concluded (i) that the renal extraction of glutamine is best estimated using plasma arteriovenous difference in the dog, especially when the renal extraction is small; (ii) that whole blood measurements should be obtained in the rat.

Acidosis↗
PubMed1985

Regulation of glutamine production by skeletal muscle cells in culture.

Cells of the L6 rat myogenic line consume glutamine in contrast to skeletal muscle in vivo, which produces glutamine. The basis of glutamine consumption in the cultured cells and the conditions under which net glutamine production occurs were investigated. After treating cultures with cytosine-1-beta-D-arabinofuranoside to eliminate replicating myoblasts remaining after differentiation, the L6 cells continued to consume glutamine from medium containing normal plasma levels (650 microM). Consumption declined when cells were incubated with 325 microM glutamine, and, at 0 microM, net production occurred. In addition to the tendency to consume glutamine, the cells rapidly consumed glutamic acid. When medium glutamic acid was increased from 70 to 150, 500, and 1,000 microM, glutamine production increased. Alterations in levels of NH3, the other substrate for glutamine synthesis, did not have this effect. The L6 cells were found to have glutamine synthetase activity similar to normal rat skeletal muscle but markedly increased glutaminase activity. In spite of the imbalance in synthetic and degradative activities, however, inhibitor studies with L-methionine sulfoximine and 6-diazo-5-oxo-L-norleucine showed that flux through both pathways influenced net glutamine production.

Animals↗
PubMed1987

Gut-liver interaction in glutamine homeostasis: portal ammonia role in uptake and metabolism.

The role of ammonia released by the gut on hepatic glutamine handling and metabolism was studied in postabsorptive anesthesized male Sprague-Dawley rats at spontaneous and elevated arterial glutamine concentrations. Glutamine handling and metabolite release across both organ beds were studied using arteriovenous concentration differences and simultaneously measured portal and hepatic venous plasma flows. At the spontaneous arterial glutamine load, fractional glutamine extraction, FE-Gln, by the gut and the liver was 24 and 10%, respectively. At the elevated glutamine load, gut glutamine uptake doubled, while FE-Gln remained at 24%; however, portal ammonia and alanine increased and decreased, respectively. In response, hepatic FE-Gln increased to 28% with a large release of glutamate and urea. The role of portal ammonia in modulating hepatic glutamine uptake was studied by infusing NH4HCO3 directly into the portal vein. Increasing the portal load promptly stimulated hepatic glutamine uptake and glutamate and urea release. Mitochondria isolated from these livers produced more glutamate from glutamine, suggesting ammonia activation of hepatic glutaminase flux; in addition, citrulline formation increased, suggesting a coupling of glutaminase flux to urea synthesis. The results are consistent with portal ammonia release acting as a key informational molecule in interorgan glutamine flow.

Acid-Base Equilibrium↗
PubMed1989

Transport of glutamine across blood-facing membranes of perfused rat jejunum.

Transport of glutamine and other neutral amino acids across the blood-facing membranes of isolated, dually perfused rat jejunum was measured using a paired-tracer isotope-dilution technique. Glutamine, asparagine, histidine, alanine, and leucine showed mutual inhibition of transport. The major component of physiological glutamine transport was saturable (Km = 0.88 +/- 0.15 mM, Vmax = 454 +/- 49 nmol.g-1.min-1; mean +/- SE), stereospecific and Na-independent and appeared to exhibit symmetry of glutamine transport; it most resembled system L. The minor Na-dependent component of glutamine transport resembled system A, i.e., it transported N-methylaminoisobutyric acid (Km approximately equal to 10 microM, Vmax approximately equal to 1.2 nmol.g-1.min-1). At 0.5 mM glutamine transport was insensitive to insulin and glucagon and was unaffected by perfusate pH (7.0-7.8). Glutamine extracted by the jejunum is rapidly utilized; at physiological blood glutamine concentrations the basolateral glutamine-transporter flux may thus not only restrict intestinal glutamine catabolism but also the consequent release of glutamine-derived ammonia (a substrate and stimulant of ureogenesis) into the portal circulation.

Amino Acids↗
PubMed1993

Characteristics of glutamine transport in primary tissue culture of rat skeletal muscle.

Glutamine transport was studied in preconfluent monolayered, mononucleated myoblasts (4 days old) and in fused, multinucleated, differentiated myotubes (10 days old), both prepared from neonatal rat skeletal muscle. The initial (60 s) rate of 50 microM glutamine uptake in myoblasts and myotubes was stereospecific, saturable, and largely (80%) Na+ dependent. At glutamine concentrations of 0.01-1 mM, Na(+)-dependent uptake showed saturation kinetics: in myoblasts, the Michaelis constant (Km) was 197 +/- 38 microM, maximum velocity (Vmax) was 1,165 +/- 60 pmol.min-1.mg protein-1; in myotubes, Km was 174 +/- 51 microM and Vmax was 1,435 +/- 47 pmol.min-1.mg protein-1. The Na(+)-dependent glutamine uptake was Li+ tolerant in both myoblasts and myotubes. The Na(+)-dependent uptake of 50 microM L-[3H]glutamine was investigated in the presence of various amino acids at 0.01-10 mM. Histidine and asparagine competitively inhibited glutamine uptake, but inhibition by serine was noncompetitive; glutamate, arginine, leucine, and 2-aminobicyclo(2,2,1)heptane-2-carboxylate (BCH) had no significant inhibitory effects; 2-(methyl-amino)isobutyrate (MeAIB) caused a small but significant inhibition. In parallel with a stimulation of glucose transport, addition of insulin stimulated Na(+)-dependent glutamine uptake within 1 h by a maximum of 27% in myoblasts and 42% in myotubes (half-maximal stimulation at 0.3 nM insulin). Glucagon had no effect. Kinetic analysis revealed that the insulin-stimulated increase in glutamine transport was due to a Vmax effect, which was cycloheximide inhibitable. The insulin-stimulated increase was Li+ tolerant and not inhibited by MeAIB or cysteine at 1 mM. The results indicate that the predominant glutamine transporter of neonatal rat skeletal muscle cells in primary tissue culture in System Nm. System Nm also appears to be the major insulin-sensitive glutamine transport component in skeletal muscle. Primary muscle culture appears to be a useful preparation for studying glutamine transport and its regulation.

Amino Acids↗
PubMed1995

Stimulatory effect of glutamine on glycogen accumulation in human skeletal muscle.

To determine whether glutamine can stimulate human muscle glycogen synthesis, we studied in groups of six subjects the effect after exercise of infusion of glutamine, alanine+glycine, or saline. The subjects cycled for 90 min at 70-140% maximal oxygen consumption to deplete muscle glycogen; then primed constant infusions of glutamine (30 mg/kg; 50 mg.kg-1.h-1) or an isonitrogenous, isoenergetic mixture of alanine+glycine or NaCl (0.9%) were administered. Muscle glutamine remained constant during saline infusion, decreased 18% during alanine+glycine infusion (P < 0.001), but rose 16% during glutamine infusion (P < 0.001). By 2 h after exercise, muscle glycogen concentration had increased more in the glutamine-infused group than in the saline or alanine+glycine controls (+2.8 +/- 0.6, +0.8 +/- 0.4, and +0.9 +/- 0.4 mumol/g wet wt, respectively, P < 0.05, glutamine vs. saline or alanine+glycine). Labeling of glycogen by tracer [U-13C]glucose was similar in glutamine and saline groups, suggesting no effect of glutamine on the fractional rate of blood glucose incorporation into glycogen. The results suggest that, after exercise, increased availability of glutamine promotes muscle glycogen accumulation by mechanisms possibly including diversion of glutamine carbon to glycogen.

Adolescent↗
PubMed1997

Regulation of gluconeogenesis by glutamine in normal postabsorptive humans.

There is evidence that glutamine may act as a regulator of protein, free fatty acid, and glycogen metabolism. To test the hypothesis that glutamine may act as a physiological regulator of gluconeogenesis, we infused 16 normal postabsorptive volunteers with glutamine at a rate (11.4 micromol kg(-1) x min(-1)) estimated to approximate its appearance in plasma after a protein meal and assessed changes in production of glucose from glutamine, systemic glucose appearance and disposal, and uptake and release of glucose, glutamine, and alanine by forearm skeletal muscle. Although infusion of glutamine increased plasma glutamine concentration and turnover only threefold (from 0.63 +/- 0.03 to 1.95 +/- 0.10 mmol/l and from 5.43 +/- 0.24 to 14.85 +/- 0.66 micromol x kg(-1) x min(-1), respectively; P < 0.001), formation of glucose from glutamine increased sevenfold from 0.55 +/- 0.03 to 3.74 +/- 0.28 micromol x kg(-1) x min(-1) (P < 0.001). Formation of glucose from alanine was also stimulated (0.52 +/- 0.05 vs. 0.75 +/- 0.04 micromol x kg(-1) x min(-1); P < 0.001) in the absence of a change in plasma alanine concentration. Furthermore, glutamine infusion decreased its own de novo synthesis (4.55 +/- 0.22 vs. 2.81 +/- 0.62 micromol x kg(-1) x min(-1);P < 0.02) while increasing that of alanine (2.82 +/- 0.32 vs. 3.56 +/- 0.32 micromol x kg(-1) x min(-1); P < 0.002). Systemic glucose appearance, systemic glucose disposal, and forearm balance of glucose and alanine were not altered. Because the stimulatory effects of glutamine on gluconeogenesis occurred in the absence of changes in plasma insulin and glucagon levels, these results provide evidence that, in humans, glutamine may act both as a substrate and as a regulator of gluconeogenesis as well as a modulator of its own metabolism.

Alanine↗
PubMed2001

Free and protein-bound glutamine have identical splanchnic extraction in healthy human volunteers.

The objectives of the present study were to determine the splanchnic extraction of glutamine after ingestion of glutamine-rich protein ((15)N-labeled oat proteins) and to compare it with that of free glutamine and to determine de novo glutamine synthesis before and after glutamine consumption. Eight healthy adults were infused intravenously in the postabsorptive state with L-[1-(13)C]glutamine (3 micromol x kg(-1) x h(-1)) and L-[1-(13)C]lysine (1.5 micromol x kg(-1) x h(-1)) for 8 h. Four hours after the beginning of the infusion, subjects consumed (every 20 min) a liquid formula providing either 2.5 g of protein from (15)N-labeled oat proteins or a mixture of free amino acids that mimicked the oat-amino acid profile and contained L-[2,5-(15)N(2)]glutamine and L-[2-(15)N]lysine. Splanchnic extraction of glutamine reached 62.5 +/- 5.0% and 66.7 +/- 3.9% after administration of (15)N-labeled oat proteins and the mixture of free amino acids, respectively. Lysine splanchnic extraction was also not different (40.9 +/- 11.9% and 34.9 +/- 10.6% for (15)N-labeled oat proteins and free amino acids, respectively). The main conclusion of the present study is that glutamine is equally bioavailable when given enterally as a free amino acid and when protein bound. Therefore, and taking into consideration the drawbacks of free glutamine supplementation of ready-to-use formulas for enteral nutrition, protein sources naturally rich in this amino acid are the best option for providing stable glutamine.

Adult↗
PubMed2001

Glutamine protects mitochondrial structure and function in oxygen toxicity.

Glutamine is an important mitochondrial substrate implicated in the protection of cells from oxidant injury, but the mechanisms of its action are incompletely understood. Human pulmonary epithelial-like (A549) cells were exposed to 95% O2 for 4 days in the absence and presence of glutamine. Cell proliferation in normoxia was dependent on glutamine, and glutamine deprivation markedly accelerated cell death in hyperoxia. Glutamine significantly increased cellular ATP levels in normoxia and prevented the loss of ATP in hyperoxia seen in glutamine-deprived cells. Mitochondrial membrane potential as assessed by flow cytometry with chloromethyltetramethylrosamine was increased by glutamine in hyperoxia-exposed A549 cells, and a glutamine dose-dependent increase in mitochondrial membrane potential was detected. Glutamine-supplemented, hyperoxia-exposed cells had a higher O2 consumption rate and GSH content. Electron and fluorescence microscopy revealed that, in hyperoxia, glutamine protected cellular structures, especially mitochondria, from damage. In hyperoxia, activity of the tricarboxylic acid cycle enzyme alpha-ketoglutarate dehydrogenase was partially protected by its indirect substrate, glutamine, indicating a mechanism of mitochondrial protection.

Adenosine Triphosphate↗
PubMed1990

Effect of acute pH change on mitochondrial glutamine transport.

The uptake of [3H]glutamine in submitochondrial particles (SMP) was measured at varying medium pH. Glutamine transport, but not glutamine binding, was inversely related to medium pH (range 6.5-8.5). Glutamine uptake was highest at medium pH of 6.5 (4.59 +/- 0.4 pmol.mg-1.30 s-1) and lowest at medium pH of 8.0 (1.99 +/- 0.3 pmol.mg-1.30 s-1). The effect of medium pH on glutamine transport was rapidly reversible. Changes in pH gradient (delta pH) had no influence on the rate of glutamine transport. Kinetics of mitochondrial glutamine transport was studied at pH 6.5 and 8.5 to further elucidate the mechanism by which pH alters glutamine transport. Glutamine concentration at half-maximal velocity ([S]0.5) was 9.07 and 13.32 mM at pH 6.5 and 8.5, respectively (P less than 0.02). The maximal velocity (Vmax) was 1,417.72 +/- 185.69 pmol.mg-1.15 s-1 at pH 6.5 and 910.95 +/- 192.85 pmol.mg-1.15 s-1 at pH 8.5 (P less than 0.01). Thus both the affinity and the Vmax of the transport system were enhanced in acidic pH. These data imply that intracellular pH has influence over glutamine transport into the mitochondrial matrix and, consequently, renal NH3 production. Glutamine delivery to the matrix via changes in cytosolic pH may be one of the regulators for ammoniagenesis during acute acid-base disorders.

Acid-Base Imbalance↗
PubMed1994

Effect of l-glutamine on pulmonary hypertension in the perfused rabbit lung.

The effects of l-glutamine on pulmonary hypertension in the isolated perfused rabbit lung were investigated. Pulmonary hypertension was produced by the thromboxane-A2 mimetic U46619. l-Glutamine at a dose of 0.04 mM produced a sustained increase in pulmonary artery pressure (PAP) and subsequent administration of an equimolar dose of l-arginine did not affect PAP. l-Glutamine at a dose of 0.5 mM transiently increased PAP, which then decreased to baseline (pre-glutamine) values. When endogenous nitric oxide (NO) synthesis was inhibited with NG-nitro-l-arginine methylester, l-glutamine at a dose of 0.04 mM decreased PAP. These results demonstrate that the effect of l-glutamine on PAP during pulmonary hypertension depends upon dose, time and the presence of endogenous NO synthesis. We believe that the results can be explained by two different effects of l-glutamine, namely a direct inhibition of NO release by glutamine and the donation of nitrogen atoms by glutamine for additional NO or other vasodilator synthesis. Since plasma glutamine levels are 0.4-0.7 mM, endogenous l-glutamine may play a modulatory role during pulmonary hypertension.

Animals↗
PubMed1969

Regulation of glutamine metabolism in vitro by bicarbonate ion and pH.

The effect of variations of medium pH and bicarbonate concentration on glutamine oxidation was studied in slices and mitochondria from dog renal cortex. Decreasing pH and bicarbonate concentration increased the rate of oxidation of glutamine-U-(14)C to (14)CO(2) in both slices and mitochondria, an effect comparable to the acute stimulation of glutamine utilization produced by metabolic acidosis. Decreases in the concentration of glutamate and alpha-ketoglutarate, which accompany metabolic acidosis in the intact animal, also occurred in tissue slices when pH and [HCO(3) (-)] were lowered; decrease in alpha-ketoglutarate but not in glutamate content occurred in mitochondria under these conditions. Study of independent variations of medium pH and [HCO(3) (-)] showed that simultaneous changes in both pH and [HCO(3) (-)] produced a greater effect on glutamine metabolism than did change in either of these parameters alone. The rate of glutamine oxidation was also compared in tissue preparations from pairs of litter-mate dogs with chronic metabolic acidosis and alkalosis. No significant difference in the rate of glutamine oxidation was present in mitochondria from the two sets of animals. Slices from animals with chronic metabolic acidosis consistently oxidized glutamine at a more rapid rate than slices from alkalotic dogs both at high and at low concentrations of bicarbonate in the medium. We believe this difference is a result of the same mechanism which leads to the delayed increase in ammonium excretion during induction of metabolic acidosis. The close parallel between the effects demonstrated here and the changes in ammonium production and glutamine utilization in the intact animal with metabolic acidosis suggest that the observed in vitro changes accurately represent the operation of the physiologic mechanism by which acid-base changes regulate ammonium excretion. The similarity between the changes in glutamine oxidation observed in this study and those described previously for citrate suggests that one control mechanism affects the metabolism of both citrate and glutamine. Thus, we believe that the increase in citrate clearance in metabolic alkalosis and the increase in glutamine utilization and ammonium production in metabolic acidosis reflect the operation of the same underlying biochemical mechanism. This mechanism permits changes in pH and [HCO(3) (-)] in the cellular environment to regulate the rate of mitochondrial uptake and oxidation of several physiologically important substrates.

Acidosis↗
PubMed1995

Interactions between L-arginine and L-glutamine change endothelial NO production. An effect independent of NO synthase substrate availability.

The effect of extracellular L-arginine and L-glutamine on nitric oxide (NO) release was studied in cultured bovine aortic endothelial cells and in rabbit aortic rings. Increasing L-arginine (0.01 to 10 mM) did not alter NO release from cultured endothelial cells or modify endothelium-dependent relaxation to acetylcholine in isolated vessels. L-Glutamine (0.6 and 2 mM) inhibited NO release from cultured cells (in response to bradykinin) and from aortic rings (in response to acetylcholine or ADP). L-Arginine (0.1-10 mM) dose-dependently reversed the L-glutamine inhibition of receptor-stimulated NO release in both models. In contrast to its inhibitory response to receptor-mediated stimuli, glutamine alone slightly potentiated NO release in both models when the calcium ionophore, A23187, was added. Furthermore, cultured cells incubated with L-arginine (0.01-10 mM), in the presence or absence of glutamine, released similar amounts of NO in response to A23187. L-Glutamine did not affect intracellular L-arginine levels. Neither D-glutamine nor D-arginine affected NO release or endothelium-dependent vascular relaxation. L-Glutamine had no effect on the activity of endothelial NOS assessed by L-arginine to L-citrulline conversion. These findings show that in the absence of L-glutamine, manipulating intracellular L-arginine levels over a wide range does not affect NO release. L-Glutamine in concentrations circulating in vivo may tonically inhibit receptor-mediated NO release by interfering with signal transduction. One mechanism by which L-arginine may enhance NO release is via reversal of the inhibitory effect of L-glutamine, but apparently independently of enhancing NO synthase substrate.

Acetylcholine↗