Ammonia Intoxication in Rats: Protection by N -Carbamoyl-L-Glutamate Plus L-Arginine

Abstract

Rats given a lethal dose (LD99.9) 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-IL-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.Thq 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.

Carbamyl glutamate prevents the potentiation of ammonia toxicity by sodium benzoate

“…The administration of carbamyl glutamate has been reported to be of benefit in some cases of hyperammonaemia [1,8] and increases urea synthesis in exprimental animals [13].…”

Mixture of N-carbamoyl-l-glutamate plus l-arginine can protect rats with liver cirrhosis from acute ammonia intoxication

“…In the present study, we encountered a serious obstacle in administration of ammonium acetate and CG plus Arg, because of an unpredictable absorption due to ascites. Therefore, these compounds were subcutaneously given to cirrhotic rats, and the effect was much more delayed than intraperitoneal injection; therefore, CG plus Arg were injected 4 h before the ammonium acetate injection, instead of 1 h of intraperitoneal injection to non-cirrhotic rats [5,8].…”

“…For the control group, the same volume of PBS without the compounds was injected. Four hours later, a solution containing a sub-lethal dose of ammonium acetate (3.4 mmol/kg body weight in 1 ml PBS which was about one-third of LD99.9 [5,8]) was subcutaneously injected at the right side of the flank of both the control and test group rats. There was no difference between body weights of control and test group rats (data not shown).…”

“…These types of therapy, however, have a number of limitations and are not considered to be ideal. An alternate therapy aiming mainly at enhancing the activities of urea cycle enzymes has suggested the use of N-carbamoyl-l-glutamate (CG) and/or l-arginine (Arg) to provide critical substances for an efficient operation of the urea cycle [5]. Indeed, the clinical use of these compounds for the treatment of patients with liver disease was suggested some years ago [6], however, no progress has been made in this area.…”

“…Since N-acetyl-l-glutamate is readily hydrolyzed in vivo, whereas its analogue CG is stable both in vivo and in vitro, we [5] earlier employed CG plus Arg to study the protective effect of these compounds on rats from intoxication by a lethal dose of ammonium acetate, and also recently demonstrated the ammonia-lowering effect of these compounds in rats whose liver mass was reduced by 70% after partial hepatectomy [8]. Since the largest ammonia-lowering effect was observed when two compounds were used together in the rat [5,8], the present study was designed to address whether the ammonia-lowering effect of the mixture can also be observed in cirrhotic conditions.…”