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M Costell

Publications and source records attributed to M Costell.

13 recordsLinked to original sources
PubMed1990

A smaller initial dose protects mice against several lethal doses of ammonium acetate.

The synthesis of urea in the liver is the main mechanism for the elimination of excess ammonia. Rapid stimulation of the synthesis of urea (e.g. by administration of carbamyl glutamate, the analog of the physiological activator of carbamyl phosphate synthetase I) protects animals given lethal doses of ammonia. Since ammonia enhances the activity of the urea cycle, we tested and show here that administration of small doses of ammonium acetate supresses the mortality induced by a series of repeated LD100 of ammonium acetate separated by one hour, when the first LD100 is injected i.p. starting from 30 min to 5 hours after the initial smaller dose of ammonium acetate. Under these conditions, the levels of ammonia in blood are elevated more than ten times, but in spite of the greater amount of ammonia administered, the ammonemia is much lower than in mice dying after a single LD100. The enhanced synthesis of urea observed is correlated with an increase in the intramitochondrial content of N-acetyl glutamate. These findings are of interest as far as the short-term regulation of urea cycle, the mechanism of ammonia toxicity and have clinical implications.

Acetates↗
PubMed1990

New roles of carnitine metabolism in ammonia cytotoxicity.

High levels of ammonia in blood and brain due to metabolic disorders are associated with neurological abnormalities. Although the mechanism of ammonia toxicity at the CNS level is still unknown, alterations in brain energy metabolism, in neurotransmitter function and direct effects on nervous impulse have been proposed. In most hyperammonemic conditions morphological changes in the liver and brain have been demonstrated, especially in mitochondria, endoplasmic reticulum and lysosomes, together with an accumulation of intracellular lipids. The treatment of hyperammonemias is uncertain and mostly directed to reduce the level of circulating ammonia; there is no current therapy aimed to counteract the molecular effects of ammonia. Administration of carnitine prevents acute ammonia toxicity and enhances the efficacy of ammonia elimination as urea and glutamine. In addition the cytotoxic effects of ammonia, possibly arising from lipid peroxidation, are ameliorated by carnitine. These data indicate the feasibility of utilization of carnitine in the therapy of human hyperammonemic syndromes, both for reducing the levels of ammonia and preventing its toxic effects.

Ammonia↗
PubMed1989

Age-dependent decrease of carnitine content in muscle of mice and humans.

Carnitine deficiency associated with impairment of muscle function has been described in infants and young adults as a result of inherited or acquired disease but there are no reports on carnitine levels in healthy aging people. In this paper we show a marked reduction of carnitine and its derivatives in muscle, and of long-chain acyl carnitine in heart of 6-month-old mice, when compared to animals of 6 weeks of age. Analysis of muscle samples of healthy humans of different ages showed a drastic reduction of carnitine and acetyl carnitine in the older subjects with a strong reverse correlation between age and carnitine levels.

Acetylcarnitine↗
PubMed1989

Carbamyl glutamate prevents the potentiation of ammonia toxicity by sodium benzoate.

Sodium benzoate has been recommended for the treatment of hyperammonaemia in humans. However, benzoate potentiates ammonia toxicity and reduces urea synthesis in vitro and in vivo by decreasing the intramitochondrial levels of N-acetyl glutamate. Pretreatment of mice with carbamyl glutamate, a structural analogue of N-acetyl glutamate, decreases mortality induced by ammonium acetate and sodium benzoate administration. The protective effect of carbamyl glutamate is accompanied by an increase in urea production and of carbamyl phosphate synthetase activity.

Ammonia↗
PubMed1987

Effect of L-carnitine on ketone bodies, redox state and free amino acids in the liver of hyperammonemic mice.

L-Carnitine stimulates urea synthesis in mice given a LD100 of ammonium acetate. Unprotected mice show decreased levels of hepatic ketone bodies and lowered NADH/NAD+ ratio in both cytosol and mitochondria. L-Carnitine enhances markedly the production of beta-hydroxybutyrate and raises the NADH/NAD+ ratio in mitochondria. The alterations induced by ammonium acetate in the free amino acid pool are prevented by L-carnitine. The results shown in this paper indicate that L-carnitine stimulates fatty acid oxidation as well as flux through the Krebs cycle in hyperammonemic mice and that these effects may be responsible for the increase in urea synthesis in these animals.

Acetates↗
PubMed1987

The potentiation of ammonia toxicity by sodium benzoate is prevented by L-carnitine.

Sodium benzoate has been recommended and even been used for the treatment of hyperammonemia in humans. More recently, a note of caution was raised since it has been shown that in experimental animals, sodium benzoate potentiates ammonia toxicity and inhibits urea synthesis in vitro. This has been further confirmed in the work presented here and the mechanism by which benzoate increases mortality and the levels of blood ammonia in mice given ammonium acetate have also been studied. In hyperammonemia, urea production and N-acetylglutamate levels were decreased by sodium benzoate. Pretreatment of mice with L-carnitine suppressed mortality following ammonium acetate plus sodium benzoate administration. Under these conditions L-carnitine lowered blood ammonia and increased urea production and N-acetylglutamate levels.

Ammonia↗
PubMed1987

Effect of hyperammonemia on the levels of carnitine in mice.

Decreased carnitine levels have been noted in conditions of hyperammonemia. We have measured carnitine and its derivatives in acute and sustained hyperammonemia in mice and studied the effect of carnitine administration thereon. Sustained hyperammonemia decreased carnitine in liver and muscle. Acetylcarnitine was decreased in liver and muscle in both acute and sustained hyperammonemia but increased in brain. Long-chain acylcarnitines decreased in brain and muscle in acute hyperammonemia and in liver and muscle is sustained ammonia intoxication. Intraperitoneal administration of carnitine increased the levels of free carnitine and acyl derivatives, especially in liver, but sustained hyperammonemia significantly affected the distribution of exogenous carnitine. The importance of these findings relative to the alterations of lipid metabolism observed in Reye's syndrome and inherited hyperammonemias, as well their implication in the protective effect of carnitine on hyperammonemia, are discussed.

Ammonia↗
PubMed1985

Decarbamoylating activity of ornithine transcarbamoylase.

We have purified from beef liver an enzyme which decarbamoylates carbamoyl-hemoglobin and to a much lesser extent carbamoyl histones. Carbamoyl casein was a poor substrate while carbamoyl trypsin, fibrinogen and ovoalbumin were not affected. The optimal pH is 7.4. Addition of Mg++, Mn++ or Ca++ was without effect. On testing citrulline as a substrate we found high activity leading us to suspect that the activity of the decarbamoylase preparation was due to contaminating ornithine transcarbamoylase activity. Evidence for this is the similar ratio of transcarbamoylase to decarbamoylase activities of both ornithine transcarbamoylase and of the purified preparation of decarbamoylase from beef liver. Also, delta-PALO, the specific inhibitor of ornithine transcarbamoylase inhibited both preparations to the same extent. Interestingly, ornithine transcarbamoylase from bacteria also has decarbamoylase activity while aspartic transcarbamoylase does not.

Amino Acids↗
PubMed1984

Effects of L-carnitine on urea synthesis following acute ammonia intoxication in mice.

L-Carnitine protects mice against acute ammonia intoxication. The effect of L-carnitine on in vivo incorporation of [14C] bicarbonate into urea has been investigated in mice given large doses of ammonium acetate. The hepatic content of N-acetylglutamate has been measured. Following ammonia administration the animals given L-carnitine have much higher production of urea than the unprotected mice. The marked protective effect of L-carnitine on ammonium acetate-induced hyperammonemia and on the increase in urea synthesis is not due primarily to activation of N-acetylglutamate synthetase.

Ammonia↗
PubMed1984

Prevention of ammonia toxicity by L-carnitine: metabolic changes in brain.

L-Carnitine when injected in mice 30 min before an LD100 of ammonium acetate (12 mmol/kg body weight, intraperitoneal) reduced mortality (100% survival with 16 mmol L-carnitine/kg) and prevented the appearance of symptoms of ammonia toxicity. Brain ammonia decreased in the animals given L-carnitine. Ammonia decreased the levels of glutamate in brain; they were partially restored by L-carnitine, which also reduced the increase in brain glutamine in animals given only ammonia. The redox state of the brain was altered following ammonia intoxication. The ratio of lactate to pyruvate in the cytosol increased while that of glutamate to alpha-ketoglutarate in the mitochondria decreased. These ratios were partially restored by L-carnitine. The implications of these findings are discussed relative to the mechanism of ammonia toxicity.

Acetates↗