L-ORNITHINE-L-ASPARTATE IN EXPERIMENTAL PORTAL-SYSTEMIC ENCEPHALOPATHY - THERAPEUTIC EFFICACY AND MECHANISM OF ACTION

Strategies aimed at the lowering of blood ammonia remain the treatment of choice in portal-systemic encephalopathy (PSE). L-ornithine-L-aspa rtate (OA) has recently been shown to be effective in the prevention o f ammonia-precipitated coma in humans with PSE. These findings prompte d the study of mechanisms of the protective effect of OA in portacaval -shunted rats in which reversible coma was precipitated by ammonium ac etate administration (3.85 mmol/kg i.p.). OA infusions (300 mg/kg/h, i .v) offered complete protection in 12/12 animals compared to 0/12 sali ne-infused controls. This protective effect was accompanied by signifi cant reductions of blood ammonia, concomitant increases of urea produc tion and significant increases in blood and cerebrospinal fluid (CSF) glutamate and glutamine. Increased CSF concentrations of leucine and a lanine also accompanied the protective effect of OA. These findings de monstrate the therapeutic efficacy of OA in the prevention of ammonia- precipitated coma in portacaval-shunted rats and suggest that this pro tective effect is both peripherally-mediated (increased urea and gluta mine synthesis) and centrally-mediated (increased glutamine synthesis) .