Hostname: page-component-77c89778f8-swr86 Total loading time: 0 Render date: 2024-07-19T06:00:26.513Z Has data issue: false hasContentIssue false
  • English
  • Français

Dose dependency of the effect of ornithine α-ketoglutarate on tissue glutamine concentrations and hypercatabolic response in endotoxaemic rats

Published online by Cambridge University Press:  09 March 2007

Pascal Pernet ,
Colette Coudray-Lucas ,
Christina Schneid ,
Alain Jardel  and
Luc Cynober
Pascal Pernet*
Affiliation:
Service de Biochimie A, Hôpital Saint-Antoine, AP-HP, Paris, France Laboratoire de Biologie de la Nutrition EA 2498, Faculté de Pharmacie, Paris, France
Colette Coudray-Lucas
Affiliation:
Service de Biochimie A, Hôpital Saint-Antoine, AP-HP, Paris, France Laboratoire de Biologie de la Nutrition EA 2498, Faculté de Pharmacie, Paris, France
Christina Schneid
Affiliation:
Laboratoire de Biologie de la Nutrition EA 2498, Faculté de Pharmacie, Paris, France
Alain Jardel
Affiliation:
Laboratoire de Physiologie, Faculté de Pharmacie, Angers, France
Luc Cynober
Affiliation:
Laboratoire de Biologie de la Nutrition EA 2498, Faculté de Pharmacie, Paris, France Service de Biochimie A, Hôtel-Dieu, AP-HP, Paris, France
*
*Corresponding author: Dr Pascal Pernet, fax +33 1 49 28 20 77, email pascal.pernet@sat.ap-hop-paris.fr
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The optimal dosage of ornithine α-ketoglutarate (OKG) for repleting tissue glutamine (Gln) concentrations and maintaining N homeostasis after injury is unknown. We set out to perform ‘dose-ranging’ of OKG supplementation after an endotoxaemic challenge. Sixty-one male Wistar rats were injected with 3 mg lipopolysaccharide (LPS) from Escherichia coli/kg (n 50) or saline vehicle (9 g NaCl/l; controls n 11). After a 24 h fast, survivors were fed by gavage for 48 h with a polymeric standard diet (879 kJ/kg per d and 1·18 g N/kg per d) supplemented with non-essential amino acids (control, n 11; LPS-OKG-0·0, n 9), or with 0·5 g OKG/kg per d (LPS-OKG-0·5, n 12), 1·5 OKG/kg per d (LPS-OKG-1.5, n 11) or 4·5 g OKG/kg per d (LPS-OKG-4·5, n 10). The diets for all groups were made isonitrogenous with the LPS-OKG-4·5 diet by adding an appropriate amount of non-essential amino acids. Rats were killed on day 3 for blood and tissue sampling (muscle, jejunum mucosa, liver). Urine was collected daily for 3-methylhistidine and total N assays. The OKG dose was correlated with Gln concentrations in every tissue and with cumulative N balance (Spearman test, P<0·01). 3-Methylhistidine excretion was increased in endotoxaemic groups compared with controls (ANOVA, P<0·05) except in the LPS-OKG-4·5 group. Only the LPS-OKG-4·5 group achieved a positive post-injury N balance (t test, P<0·05). In conclusion, OKG exerted a dose-dependent effect on tissue Gln concentration and N balance, but only the highest dosage counteracted myofibrillar hypercatabolism and caused a positive N balance.

Keywords

Ornithine α-ketoglutarateGlutamineEndotoxaemiaInjury
Type
Research Article
Information
British Journal of Nutrition , Volume 92 , Issue 4 , October 2004 , pp. 627 - 634
Copyright
Copyright © The Nutrition Society 2004

References

Blondé-Cynober, F, Aussel, C & Cynober, L (2003) Use of ornithine α-ketoglutarate in clinical nutrition of elderly patients. Nutrition 19, 73–75.CrossRefGoogle ScholarPubMed
Cardenas, D, Le Bricon, T & Cynober, L (2002) L'alpha-cétoglutarate d'ornithine: mécanismes d'action et place actuelle en nutrition artificielle (Ornithine α-ketoglutarate: mechanisms of action and role in clinical nutrition). Nutr Clin Metabol 16, 151–163.CrossRefGoogle Scholar
Chambon-Savanovitch, C, Felgines, C, Farges, MC, Raul, F, Cezard, JP, Davot, P, Vasson, MP & Cynober, LA (1999) Comparative study of glycine, alanine or casein as inert nitrogen sources in endotoxemic rats. J Nutr 129, 1866–1870.CrossRefGoogle ScholarPubMed
Coudray-Lucas, C, Le Bever, H, Cynober, L, De Bandt, JP & Carsin, H (2000) Ornithine α-ketoglutarate improves wound healing in severe burn patients. A prospective randomized double-blind trial versus isonitrogenous controls. Crit Care Med 28, 1772–1776.CrossRefGoogle ScholarPubMed
Cynober, L (1991) Ornithine α-ketoglutarate in nutritional support. Nutrition 7, 313–321.Google ScholarPubMed
Cynober, L (1995) Place des nouveaux substrats azotés en nutrition artificielle périopératoire de l'adulte (New nitrogen substrates in perioperative artificial nutrition). Nutr Clin Metabol 9, 113–117.CrossRefGoogle Scholar
Cynober, L (2004) Ornithine α-ketoglutarate. In Metabolic and Therapeutic Aspects of Amino Acids in Clinical Nutrition. 633 – 648. [Cynober, LA, editor] Boca Raton, FL: CRC Press.Google Scholar
Cynober, LA (1999) The use of α-ketoglutarate salts in clinical nutrition and metabolic care. Curr Opin Clin Nutr Metab Care 2, 33–37.Google ScholarPubMed
Cynober, L, Coudray-Lucas, C, De Bandt, JP, Guechot, J, Aussel, C, Salvucci, M & Giboudeau, J (1990) Action of ornithine α-ketoglutarate, ornithine hydrochloride, and calcium α-ketoglutarate on plasma amino acids and hormonal patterns in healthy subjects. J Am Coll Nutr 9, 2–12.CrossRefGoogle ScholarPubMed
Cynober, L, Vaubourdolle, M, Dore, A & Giboudeau, J (1984) Kinetics and metabolic effects of orally administered ornithine alpha-ketoglutarate in healthy subjects fed with a standardized regimen. Am J Clin Nutr 39, 514–519.CrossRefGoogle ScholarPubMed
De Bandt, JP, Coudray-lucas, C, Lioret, N, Lim, SK, Saizy, R, Giboudeau, J & Cynober, L (1998) A randomized controlled trial of the influence of the mode of enteral ornithine α-ketoglutarate administration in burn patients. J Nutr 128, 563–569.CrossRefGoogle ScholarPubMed
De Bandt, JP & Cynober, L (1998) Amino acids with anabolic properties. Curr Opin Clin Nutr Metab Care 1, 263–272.CrossRefGoogle ScholarPubMed
Donati, L, Ziegler, F, Pongelli, G & Signorini, MS (1999) Nutritional and clinical efficacy of ornithine alpha-ketoglutarate in severe burn patients. Clin Nutr 18, 307–311.CrossRefGoogle ScholarPubMed
Dumas, F, De Bandt, JP, Colomb, V, Le Boucher, J, Coudray-Lucas, C, Lavie, S, Brousse, N, Ricour, C, Cynober, L & Goulet, O (1998) Enteral ornithine alpha-ketoglutarate enhances intestinal adaptation to massive resection in rats. Metabolism 47, 1366–1371.CrossRefGoogle ScholarPubMed
Duranton, B, Schleiffer, R, Gossé, F & Raul, F (1998) Preventive administration of ornithine alpha-ketoglutarate improves intestinal mucosal repair after transient ischemia in rats. Crit Care Med 26, 120–125.Google ScholarPubMed
Fink, M & Heard, SO (1990) Laboratory models of sepsis and septic shock. J Surg Res 49, 186–196.CrossRefGoogle ScholarPubMed
Hall, JC (1998) Glycine. J Parenter Enteral Nutr 22, 393–398.CrossRefGoogle ScholarPubMed
Jeevanandam, M, Holaday, NJ & Ali, MR (1992) Altered tissue polyamine levels due to ornithine-alpha-ketoglutarate in traumatized growing rats. Metabolism 41, 1204–1209.CrossRefGoogle ScholarPubMed
Kalfarentzos, F, Spilioti, J, Melachrinou, M, Katsarou, CH, Spiliopoulou, I, Panagopoulos, C & Alexandrides, TH (1996) Oral ornithine α-ketoglutarate accelerates healing of the small intestine and reduces bacterial translocation after abdominal radiation. Clin Nutr 15, 29–33.CrossRefGoogle Scholar
Lasnier, E, Coudray-Lucas, C, Le Boucher, J, Jardel, A & Cynober, L (1996) Ornithine alpha-ketoglutarate counteracts thymus involution and glutamine depletion in endotoxemic rats. Clin Nutr 15, 197–200.CrossRefGoogle ScholarPubMed
Le Boucher, J, Coudray-Lucas, C, Lasnier, E, Jardel, A, Ekindjian, OG & Cynober, L (1997 a) Enteral administration of ornithine α-ketoglutarate or arginine α-ketoglutarate: a comparative study of their effects on glutamine pools in burn-injured rats. Crit Care Med 25, 293–298.CrossRefGoogle ScholarPubMed
Le Boucher, J & Cynober, LA (1998) Ornithine α-ketoglutarate: the puzzle. Nutrition 14, 870–873.Google ScholarPubMed
Le Boucher, J, Obled, C, Farges, MC & Cynober, L (1997 b) Ornithine alpha-ketoglutarate modulates tissue protein metabolism in burn-injured rats. Am J Physiol 273, E557–E563.Google ScholarPubMed
Le Bricon, T, Cynober, L & Baracos, V (1994) Ornithine α-ketoglutarate limits muscle protein breakdown without stimulating tumor growth in rats bearing Yoshida ascites hepatoma. Metabolism 7, 1–5.Google Scholar
Le Bricon, T, Coudray-Lucas, C, Lioret, N, Lim, SK, Plassart, F, Schlegel, L, De Bandt, JP, Saizy, R, Giboudeau, J & Cynober, L (1997) Ornithine α-ketoglutarate metabolism after enteral administration in burn patients: bolus compared with continuous infusion. Am J Clin Nutr 65, 512–518.CrossRefGoogle ScholarPubMed
Le Bricon, T, Cynober, L, Field, CJ & Baracos, VE (1995) Supplemental nutrition with ornithine alpha-ketoglutarate in rats with cancer-associated cachexia: surgical treatment of the tumor improves efficacy of nutritional support. J Nutr 125, 2999–3010.Google ScholarPubMed
Moinard, C, Caldefie, F, Walrand, S, Tridon, A, Chassagne, J, Vasson, MP & Cynober, L (2002) Effects of ornithine 2-oxoglutarate on neutrophils in stressed rats: evidence for the involvement of nitric oxide and polyamines. Clin Sci 102, 287–295.CrossRefGoogle ScholarPubMed
Pernet, P, Coudray-Lucas, C, Le Boucher, J, Schlegel, L, Giboudeau, J, Cynober, L & Aussel, C (1999) Is the l -arginine:nitric oxide pathway involved in endotoxemia-induced muscular hypercatabolism in rats? Metabolism 48, 190–193.CrossRefGoogle Scholar
Robinson, LE, Bussière, FI, Le Boucher, J, Farges, MC, Cynober, LA, Field, CJ & Baracos, VE (1999) Amino acid nutrition and immune function in tumour-bearing rats: a comparison of glutamine-, arginine- and ornithine 2-oxoglutarate-supplemented diets. Clin Sci 97, 657–669.CrossRefGoogle ScholarPubMed
Roch-Arveiller, M, Tissot, M, Coudray-Lucas, C, Fontagne, J, Le Boucher, J, Giroud, JP & Cynober, L (1996) Immunomodulatory effects of ornithine α-ketoglutarate in rats with burn injuries. Arch Surg 131, 718–723.CrossRefGoogle ScholarPubMed
Vaubourdolle, M, Coudray-Lucas, C, Jardel, A, Ziegler, F, Ekindjian, OG & Cynober, L (1991) Action of enterally administered ornithine alpha-ketoglutarate on protein breakdown in skeletal muscle and liver of the burned rat. J Parenter Enteral Nutr 15, 517–520.CrossRefGoogle ScholarPubMed
Wischmeyer, PE, Kahana, M, Wolfson, R, Ren, H, Musch, MM & Chang, EB (2001) Glutamine induces heat shock protein and protects against endotoxin shock in the rat. J Appl Physiol 90, 2403–2410.CrossRefGoogle ScholarPubMed
Young, VR & El-Khouri, A (1995) The notion of the nutritional essentiality of amino acids, revisited, with a note on the indispensable amino acid requirements in adults. Amino Acid Metabolism and Therapy in Health and Nutritional Disease 191 – 232 [Cynober, LA, editors ] Boca Raton, FL: CRC Press.Google Scholar
Ziegler, F, Coudray-Lucas, C, Jardel, A, Lasnier, E, Ekindjian, OG & Cynober, L (1991) Dose-related effect of ornithine alpha-ketoglutarate on glutamine pools in vivo. Clin Nutr 10 Suppl. 2 (abstract).CrossRefGoogle Scholar