L-ornithine vs. L-ornithine-L-aspartate as a treatment for hyperammonemia-induced encephalopathy in rats

Abstract

Background/aims: The effect of L-ornithine (ORN) and L-ornithine-L-aspartate (OA) therapy on "extracerebral" nitrogen metabolism, brain metabolism and neurotransmission has been investigated in portacaval shunted rats with hyperammonemia-induced encephalopathy.

Methods: One day before ammonium-acetate infusion, a portacaval shunt was performed in three experimental groups: 1-control rats, 2-ORN-treated rats and 3-OA-treated rats. Ammonium-acetate was given as an intravenous bolus injection (0.4 mmol.kg bw-1) followed by a constant infusion (1.9 mmol.kg bw-1.h-1) so that steady-state blood ammonia concentrations (500-800 microM) were obtained in the course of 5 h. After 1 h, ammonium-acetate infusion, either L-ornithine or L-ornithine-L-aspartate, was infused for the next 4 h (3.0 mmol.kg bw-1.h-1) in the treated groups. The following parameters were measured: clinical grade of encephalopathy, EEG activity (n = 10 - 20/group), amino acids in plasma (n = 10 - 20/group) and brain dialysate (n = 5 - 9/group), and brain metabolites obtained by in vivo cerebral 1H-MRS (n = 4 - 6/group).

Results: ORN and OA treatment resulted in significantly lower blood (34% and 39%) and brain (42% and 22%) ammonia concentrations, significantly higher urea production (39% and 86%) and significantly smaller increases in brain glutamine and lactate concentrations than in controls. These changes were associated with a significantly smaller increase in clinical grade of encephalopathy in ORN- and OA-treated rats, and a significant improvement in EEG activity in ORN-treated rats. OA-treated rats showed a significant increase in aspartate and glutamate concentrations in brain dialysate.

Conclusions: The beneficial effects of both treatments on the manifestations of hyperammonemia-induced encephalopathy can be explained by a reduction in blood and brain ammonia concentrations. It is suggested that when OA is administered, the effect of ornithine is partly counteracted by aspartate, inducing high brain extracellular concentrations of the two excitatory amino acids glutamate and aspartate, and perhaps causing overstimulation of NMDA receptors.