Enteral administration of ornithine alpha-ketoglutarate or arginine alpha-ketoglutarate: a comparative study of their effects on glutamine pools in burn-injured rats.

OBJECTIVES: Ornithine alpha-ketoglutarate has proved to be an efficient nutritional support in trauma situations, especially after burn injury. To determine whether the action of ornithine alpha-ketoglutarate is due to its alpha-ketoglutarate moiety (as a glutamine precursor), we studied the effects of alpha-ketoglutarate administered to rats as ornithine alpha-ketoglutarate, or in combination with arginine salt (arginine alpha-ketoglutarate), as the two closely related amino acids have similar metabolic behavior. DESIGN: Prospective, randomized trial. SETTING: Animal laboratory. SUBJECTS: Forty-six male Wistar rats, weighing approximately 90 g. INTERVENTIONS: Rats were burned over 20% of their body surface area, starved for 24 hrs, with water ad libitum, and then enterally refed for 48 hrs using Osmolite (210 kcal/kg/day, 1.2 g of nitrogen/kg/day), supplemented with one of the following: a) an amount of glycine isonitrogenous to ornithine alpha-ketoglutarate (group 1); b) 5 g of monohydrated ornithine alpha-ketoglutarate/kg/day (group 2); c) an amount of arginine alpha-ketoglutarate isonitrogenous to ornithine alpha-ketoglutarate (group 3); or d) an amount of arginine alpha-ketoglutarate isomolar to ornithine alpha-ketoglutarate (group 4). MEASUREMENTS AND MAIN RESULTS: We measured amino acid concentrations in plasma, muscle, and liver, and plasma urea concentration. At refeeding, ornithine alpha-ketoglutarate increased plasma glutamine concentration (p < .05 vs. the three other groups), and counteracted the increase in plasma phenylalanine concentration. In muscle, although the three alpha-ketoglutarate combinations induced similar increases in the glutamate pool, ornithine alpha-ketoglutarate induced the highest increase in glutamine (7.0 +/- 0.3 vs. 5.4 +/- 0.3 micromol/g in group 3, 6.3 +/- 0.3 in group 4, and 4.6 +/- 0.2 in group 1, p < .01 between group 2 and groups 3 or 1). Also, only ornithine alpha-ketoglutarate increased liver glutamine concentration. Finally, isomolar arginine alpha-ketoglutarate increased plasma urea concentration (+50% vs. the three other groups, p < .01). CONCLUSIONS: Our results demonstrate, for the first time, the following: a) the action of ornithine alpha-ketoglutarate as a glutamine precursor cannot solely be ascribed to alpha-ketoglutarate since arginine alpha-ketoglutarate combinations did not exhibit this effect to the same extent; and b) the action of ornithine alpha-ketoglutarate is not due to its nitrogen content since isonitrogenous arginine alpha-ketoglutarate did not reproduce the effects of ornithine alpha-ketoglutarate.

Ornithine alpha-ketoglutarate and glutamine supplementation during refeeding of food-deprived rats.

The aim of this study was to compare the efficiency of ornithine alpha-ketoglutarate (OKG) and glutamine supplementation in an experimental model of denutrition that provides well-characterized disturbances of amino acid patterns. Male Wistar rats (187 +/- 11 g; five in each group) were starved for 3 days and then refed for 7 days with an oral diet (192 kcal kg-1.day-1 and 2.25 g of nitrogen kg-1.day-1), supplemented with 0.19 g of nitrogen kg-1.day-1 in the form of OKG, glutamine, or casein (control group). Food deprivation induced a fall in most tissue amino acids, with the notable exception of muscle leucine and liver glutamate, which increased by 43% (p < .01), and 11% (p < .05), respectively. The main effect of OKG was seen in the viscera, with a normalization of most amino acid pools (including proline and branched-chain amino acids) in the small bowel and liver. The main effect of glutamine was observed in the muscle, with a normalization of the glutamine and leucine pools. We conclude that, in this model and with the doses used, OKG and glutamine act in different target tissues, ie, splanchnic areas and muscle, respectively.

Action of enterally administered ornithine alpha-ketoglutarate on protein breakdown in skeletal muscle and liver of the burned rat.

Several studies concerning burn patients have shown that supplementation of enteral nutrition with ornithine alpha-ketoglutarate (OKG) favorably modifies protein metabolism. Therefore, the effect of OKG administration on muscular and hepatic protein catabolism was evaluated in burned rats. Four groups of six rats were used. Two groups were scalded by immersion of the dorsum in water at 90 degrees C for 10 seconds and then starved for 24 hours. Controlled enteral nutrition was then administered in three boluses daily (Osmolite, 210 kcal/kg/d, 1.2 g N/kg/d); one group was supplemented with OKG (5 g/kg/d, ie, 0.68 g N/kg/d), while the other group received an equivalent amount of nitrogen in the form of glycine. One group of healthy control rats received Osmolite supplemented with glycine and the last group was fed ad libitum. The animals were killed after 2 days of nutrition. Protein catabolism was assessed in vitro by measuring the amount of valine (liver catabolism) and phenylalanine (muscle catabolism) released into the incubation medium of isolated tissues. Tissular and serum glutamine were also assayed. Burn injury induced muscle hypercatabolism without affecting hepatic catabolism. The administration of OKG limited both muscle weight loss and muscle protein hypercatabolism and significantly improved the muscle glutamine pool. These results demonstrate the nitrogen-sparing effect of OKG in muscle in hypercatabolic states.

Neutral amino acid transport in human synovial cells: substrate specificity of adaptative regulation and transinhibition.

Neutral amino acid transport was characterized in human synovial cells. The amino acids tested are transported by all three major neutral amino acid transport systems, that is, A, L, and ASC. The model amino acid 2-aminoisobutyric acid (AIB) was found to be a strong specific substrate for system A in synovial cells. When cells were starved of amino acids, the activity of AIB transport increased, reaching a maximum within 1 h. The stimulation of transport activity was not blocked by cycloheximide and would thus appear to be related to a release from transinhibition. Similarly, the decrease in the activity of AIB transport observed after the addition of alpha-methyl-aminoisobutyric acid (meAIB) appeared to be related to transinhibition. However, using a different approach, that is, amino acid starvation followed by incubation with 10 mM meAIB and transfer to an amino acid-free medium with or without cycloheximide supplementation, a clear increase in AIB uptake, due both to derepression and a release from transinhibition, was observed. Unlike human fibroblasts, the depression of system A in these synovial cells was not serum-dependent. The process of derepression was observed only after preloading with meAIB. Neither AIB nor alanine produced this phenomenon. Moreover, alanine preloading led to a large increase in AIB transport activity due to a release from transinhibition. These observations indicate that the process of derepression and release from transinhibition are specific to the substrates present in the culture medium prior to amino acid starvation.

Fate of enterally administered ornithine in healthy animals: interactions with alpha-ketoglutarate.

In order to improve our understanding of the metabolic interactions between alpha-ketoglutarate (alpha KG) and ornithine (Orn), which constitute the two parts of ornithine alpha-ketoglutarate (OKG) used as an adjuvant in enteral nutrition, we have investigated the plasma appearance and tissue distribution (qualitative and quantitative) of enterally administered 14C-Orn and 14C-alpha KG in healthy mice and rats. The influence of unlabelled alpha KG or Orn on 14C-Orn or 14C-alpha KG metabolism, respectively, was also studied. Unlabelled alpha KG was able to reduce strongly the rate of intestinal absorption of 14C-Orn, whereas the inverse was not true. This alpha KG-induced loss in plasma radioactivity after a load of Orn was associated with a decrease of radioactivity in tissue with no modification of the qualitative distribution in organs. In this study, a direct interaction between alpha KG and Orn was demonstrated at the intestinal level. The mechanisms involved in this phenomenon probably involve the regulation of metabolic conversions among alpha KG, Glu, pyrroline-5-carboxylate, and Orn. This is of importance in the therapeutic use of ornithine salts in clinical nutrition.