Arterial Glutamine Concentration Research Articles

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.

The regulation of glutamine and ketone-body metabolism in the small intestine of the long-term (40-day) streptozotocin-diabetic rat.

The small intestine is the major site of glutamine utilization in the mammalian body. During prolonged (40-day) streptozotocin-diabetes in the rat there is a marked increase in both the size and the phosphate-activated glutaminase activity of the small intestine. Despite this increased capacity, intestinal glutamine utilization ceases in diabetic rats. Mean arterial glutamine concentration fell by more than 50% in diabetic rats, suggesting that substrate availability is responsible for the decrease in intestinal glutamine use. When arterial glutamine concentrations in diabetic rats were elevated by infusion of glutamine solutions, glutamine uptake across the portal-drained viscera was observed. The effect of other respiratory fuels on intestinal glutamine metabolism was examined. Infusions of ketone bodies did not affect glutamine use by the portal-drained viscera of non-diabetic rats. Prolonged diabetes had no effect on the activity of 3-oxoacid CoA-transferase in the small intestine or on the rate of ketone-body utilization in isolated enterocytes. Glutamine (2 mM) utilization was decreased in enterocytes isolated from diabetic rats as compared with those from control animals. However, glutaminase activity in homogenates of enterocytes was unchanged by diabetes. In enterocytes isolated from diabetic rats the addition of ketone bodies or octanoate decreased glutamine use. It is proposed that during prolonged diabetes ketone bodies, and possibly fatty acids, replace glutamine as the major respiratory fuel of the small intestine.

Renal regulation of interorgan glutamine flow in metabolic acidosis

The regulation of interorgan glutamine flow was studied in control and chronically metabolically acidotic rats. Net glutamine extraction or production across the kidneys, gut, liver, and hindquarters was determined in fasted anesthetized animals from organ blood flows and the arteriovenous glutamine concentration difference. In control animals glutamine flows from the hindquarters to the splanchnic bed. In chronic acidosis glutamine production by the hindquarters rose threefold and was redirected to the kidneys; splanchnic bed glutamine uptake was eliminated. Associated with this was a 39% fall and a 62% rise in arterial glutamine and ammonia concentrations, respectively. Removing the kidneys from the circulation returned arterial glutamine and ammonia concentrations to control nonacidotic levels within 30 min. Net glutamine production by the hindquarters decreased, whereas splanchnic bed glutamine extraction increased. Hindquarter glutamine production appears to be modulated by renal venous ammonia; splanchnic bed glutamine extraction is load dependent, reflecting the influence of renal glutamine consumption on the steady-state arterial levels. Thus the removal of the kidneys returns interorgan glutamine flow to that observed in nonacidotic animals consistent with a major role of the kidneys in regulating glutamine flow and nitrogen metabolism in chronic metabolic acidosis.

Regulation of interorganal glutamine flow in metabolic acidosis.

Metabolic acidosis redirects interorgan glutamine flow from hepatic utilization to renal ammoniagenesis at the expense of ureagenesis. The roles of arterial glutamine load and organ glutaminase capacity in the regulation of glutamine balance across the gut, liver, and kidneys were studied in control and chronically acidotic rats. In control rats these organs combined to remove 733 nmol glutamine X min-1 X 100 g-1 in agreement with their respective glutaminase content, gut greater than liver greater than kidneys. In chronic metabolic acidosis renal glutamine extraction alone increased to 1,158 nmol X min-1 X 100 g-1 associated with an increased glutaminase capacity. However, the total glutamine deficit across these organs rose to only 1,043 nmol glutamine consumed X min-1 X 100 g-1 as a consequence of hepatic glutamine uptake reversing to net release. This reversal was not dependent on increased hepatic glutamine synthetase capacity, but rather appears to be dependent on the combined effect of reduced portal venous glutamine load and increased ammonia load. The reduction in portal glutamine load is, in turn, a consequence of renal glutamine extraction and reduced arterial glutamine concentration in metabolic acidosis as well as maintained gut glutamine extraction. Elevating arterial glutamine concentration in metabolic acidosis has no effect on renal uptake, but enhances splanchnic bed extraction with the restoration of ureagenesis. Thus the interorgan flow of glutamine and deposition of N into either urea or ammonia appears to be dependent on arterial glutamine concentration and hence glutamine availability in chronic metabolic acidosis in the rat.

Hepatic glutaminase flux regulation of glutamine homeostasis. Studies in vivo.

The role of hepatic glutaminase flux in regulating plasma glutamine homeostasis was studied in the intact rat. Interorgan glutamine flow during chronic metabolic acidosis was away from the splanchnic bed and to the kidneys. Hindquarter and hepatic glutamine release were the major sources of glutamine removed by the kidneys. Interorgan glutamate flow was from the liver to the hindquarters and kidneys. Chronic metabolic acidosis reduced arterial glutamine concentration 30%. Acute respiratory acidosis (pH 7.12 +/- 0.02) returned arterial glutamine concentration to normal values, increasing and decreasing hepatic glutamine and glutamate release respectively; renal and gut glutamine removal rates were not decreased. Hepatic unidirectional glutamine utilization measured isotopically was decreased 51% by acute acidosis; unidirectional glutamine production was unchanged. The results are consistent with the proposed role of ammonia-activated hepatic glutaminase in the regulation of glutamine homeostasis during acute acidosis.

Renal metabolism and ammoniagenesis during acute respiratory alkalosis in the dog.

Acute respiratory alkalosis (blood pH, 7.60; arterial PCO2, 15 mmHg (1 mmHg = 133.322 Pa); plasma bicarbonate, 14 mM) was induced in nine anesthetized dogs by increasing their respiratory rate and depth. Renal glutamine extraction and ammonia production expressed per 100 mL of glomerular filtration rate did not change during acute hypocapnia, whereas arterial glutamine concentration decreased significantly from 0.47 to 0.36 mM. Hypocapnia did not change plasma potassium concentration and its urinary excretion. Acute hypocapnia increased lactate extraction and pyruvate production, whereas citrate extraction and glutamate and alanine production did not change. Citraturia remained minimal. Renal cortical glutamine concentration fell from 0.64 to 0.38 mM during hypocapnia while alpha-ketoglutarate, glutamate, malate, oxaloacetate, and citrate did not change. Lactate concentration rose from 1.1 to 2.0 mM. Glutamine concentration in the liver and muscle decreased following acute hypocapnia. Our data are compatible with the hypothesis that an acute respiratory alkalosis might not result in any change in the hydrogen ion concentration and (or) gradient between the mitochondrial matrix and the cytosol. Consequently, renal glutamine extraction and ammonia production are not reduced, renal cortical concentrations of relevant metabolites in the ammoniagenic pathway are not changed, and renal handling of citrate remains unaffected.

Effect of intralumenal cation-exchange resin on excretion of ammonia in rat ileum.

Ammonia excretion was studied in rat ileal segments during perfusion of the animal through the saphenous vein. In the first 10 min during and after intravenous infusion of L-glutamine (116 mg/kg to double arterial glutamine concentration) average net change in lumenal ammonia was 13 +/- 8 (S.E.) nmole NH3/min/g ileum; average net change in ileal venous ammonia was 28 +/- 9 nmole NH3/min/g ileum; and average net change in total ammonia (lumen + ileal vein) was 41 +/- 13 compared to -5 +/- 10 nmole/min/g ileum for animals infused with saline P less than 0.025. These data suggest that ileal metabolism of arterial glutamine liberates ammonia to both ileal venous blood and intestinal lumen. When a cation-exchange resin which binds ammonia was infused intralumenally, average net change in lumenal ammonia in the first 10 min during and after intravenous infusion of 116 mg/kg L-glutamine was 415 +/- 156 nmole NH3/min/g ileum (p less than 0.01 compared to value during perfusion of Earle's solution alone). During the first 10 min during and after glutamine infusion net change in ileal venous plasma ammonia was -8 +/- 14 when resin was being perfused through the lumen compared to +28 +/- 9 nmole/min/g ileum during perfusion of Earle's solution alone without resin P less than 0.05. Thus resin in the small intestine can trap very large amounts of ammonia.

634 EFFECT OF INTRALUMENAL CATION-EXCHANGE RESIN ON EXCRETION OF AMMONIA IN RAT ILEUM

Ammonia excretion was studied in rat ileal segments during perfusion of the animal through the saphenous vein. Average net change in lumenal ammonia in the first 10 mins following intravenous infusion of L-glutamine (116 mg/kg to double arterial glutamine concentration) was 13 ± 8 nmol NH3/min/g ileum. Average net change in ileal venous ammonia post-glutamine was 28 ± 9 nmol NH3/min/g ileum. Average net change in total ammonia (lumen + ileal vein) post-glutamine was 41 ± 13 compared to -5 ± 10 nmol/min/g ileum for animals infused with saline p <0.025. These data suggest that ileal metabolism of arterial glutamine liberates ammonia to both ileal venous blood and intestinal lumen. When a cation-exchange resin which binds ammonia was infused intralumenally, average net change in lumenal ammonia in the first 10 minutes following intravenous infusion of 116 mg/kg L-glutamine was 415 ± 156 nmol NH3/min/g ileum (p<0.01 compared to value during perfusion of Earle's solution alone). During the first 10 minutes following glutamine infusion net change in ileal venous plasma ammonia was -8 ± 14 when resin was being perfused through the lumen compared to 28 ± 9 nmol/min/g ileum during perfusion of Earle's solution alone without resin p <0.05. Thus resin in the small intestine can trap very large amounts of ammonia & may be useful in treating hyperammonemia.

Effects of chronic renal insufficiency and metabolic acidosis on glutamine metabolism in man.

1. Arterial concentration and arterial-venous differences of glutamine across the kidney, forearm, hepato-splanchnic bed and brain were measured in patients with chronic renal insufficiency and in patients with normally functioning kidneys before and during chronic ammonium chloride acidosis. 2. In chronic renal insufficiency and in chronic metabolic acidosis there is a rise in glutamine release from the muscles and a suppression of glutamine uptake by the hepato-splanchnic bed and the brain. 3. In chronic renal insufficiency arterial glutamine concentrations is significantly increased in comparison with subjects with normal renal function and either normal acid-base balance or chronic metabolic acidosis. 4. In patients with chronic renal insufficiency the kidney extracts negligible amounts of glutamine, which cannot account for the renal ammonia production measured in the same patients.