Does dietary ornithine alpha-ketoglutarate supplementation protect the liver against ischemia-reperfusion injury?
Nutritional supplementation with glutamine, arginine and their precursors has been proposed to contribute to the protection against ischemia-reperfusion-related injuries. The aim of this study was to evaluate in an isolated perfused rat liver model the preventive effect of a 4-day oral ornithine alpha-ketoglutarate (OKG) supplementation against warm ischemia-reperfusion (I-R) injury, and the involvement of nitric oxide synthesis. Rats were fed a controlled regimen supplemented with either OKG (5 g kg(-1); n=15) or an isonitrogenous mixture of non-essential amino acids (Control; n=6) for 4 days. Livers were subsequently prepared for isolated perfusion experiments, including a 45 min no-flow ischemic period. The OKG-treated group was divided into two groups according to the absence (OKG; n=8) or presence of a NO-synthase inhibitor, L-N(omega)-nitro-arginine methyl ester (OKG L-NAME; n=7) during liver perfusion. Liver cytolysis after ischemia was demonstrated by an elevated alanine aminotransferase release during the last 15 min of reperfusion that was significantly higher in the OKG-L-NAME group. Tumor necrosis factor alpha (TNF(alpha)) production was transiently increased only in the control group just after ischemia. At the end of the reperfusion period, liver superoxide dismutase activity was significantly lower in the OKG-L-NAME group compared to control animals. Dietary OKG administration had only a limited effect in this model of mild hepatic I-R, leading mainly to reduced TNF(alpha) production. As the content of lipid peroxidation products was not modified, it seems that OKG acts on the inflammatory response rather than on oxidative reactions. This action can tentatively be attributed to the role of OKG as a glutamine precursor rather than to the synthesis of arginine and nitric oxide.
Schuster
Heidi
H
Laboratoire de Biologie de la Nutrition, EA2498, Faculté de Pharmacie, Université Paris 5, 4 avenue de l'Observatoire, 75270 Paris Cedex 06, France. heidi.schuster@etu.univ-paris5.fr
Blanc
Marie-Céline
MC
Genthon
Carine
C
Thérond
Patrice
P
Bonnefont-Rousselot
Dominique
D
Le Tourneau
Agnès
A
De Bandt
Jean-Pascal
JP
Cynober
Luc
L
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000097:blood; D066298:In Vitro Techniques; D008099:Liver / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009952:Ornithine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D018384:Oxidative Stress; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000097:blood / Q000517:prevention & control*
D004791:Enzyme Inhibitors; D018698:Glutamic Acid; C002118:ornithine alpha-ketoglutarate; D009952:Ornithine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester