Ammonia intoxication in rats: protection by N-carbamoyl-L-glutamate plus L-arginine

Rats given a lethal dose (LD(99.9)) of ammonium acetate (10.8 mmol/kg of body weight) were protected to the extent of 85 and 76% when previously injected with N-carbamoyl glutamate or L-arginine, respectively, at a level of 4 mmol/kg of body weight. At a dose of 1 mmol/kg of body weight, L-arginine protected 24%, while N-carbamoyl-L-glutamate protected 61% of the animals. When a combination of N-carbamoyl-L-glutamate plus L-arginine (1 mmol each per kg of body weight) was injected, 100% of the rats were protected. The efficacy of N-carbamoyl-L-glutamate is related to its role as an activator of mitochondrial carbamoyl phosphate synthetase (EC 2.7.2.5) and its resistance to hydrolysis by tissue acylaminoacid acylase. N-Acetyl-L-glutamate, the naturally occurring and most effective activator of mitochondrial carbamoyl phosphate synthetase, was relatively ineffective in protection against lethal dose of ammonium acetate, because of its ready hydrolysis by acylaminoacid acylase. The findings reported provide a rational basis for the use of N-carbamoyl-L-glutamate plus L-arginine in the prevention and treatment of hyperammonemia in clinical conditions of liver disease and parental infusion of amino acids, and in feeding of urea supplements to ruminants.