Effect of Orally Administered L–Carnitine on Blood Ammonia and L–Carnitine Concentrations in Portacaval–Shunted Rats

Hearn, Timothy J.; Coleman, Anton E.; Lai, James C. K.; Cooper, Arthur J. L.

doi:10.1002/hep.1840100512

Cited by 22 publications

(14 citation statements)

References 39 publications

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“…A recent report indicated that L-carnitine treatment also failed to reduce ammonia toxicity in postcaval-shunted rats (7). In this study, the ammonia levels in carnitine-treated animals were not different from those in untreated animals.…”

Section: Resultssupporting

confidence: 42%

“…It is not clear whether the increase in L-carnitine content of brain observed in that study is sufiicient to protect animals against ammonia toxicity. Studies carried out by Hearn et al (7) indicate that the protection by L-carnitine against ammonia toxicity does not correlate with brain carnitine levels.…”

Section: Resultsmentioning

confidence: 97%

“…Hearn et al (7) also reported that L-carnitine crosses the bloodbrain barrier at a very slow rate. In the protocol used by O'Connor et al (3), L-carnitine is administered only 30 min before ammonium acetate challenge.…”

Section: Resultsmentioning

confidence: 99%

“…fluid could cause a significant difference in the molarity of a given dose of ammonium acetate in the peritoneal cavity. This may be the reason for failure of L-carnitine to suppress death in rats challenged with ammonium acetate (7,14).…”

Section: Resultsmentioning

confidence: 99%

“…Hearn et al (7) recently reported that the protective effect of L-carnitine was short lived and was not consistently reproducible. They observed that in some experiments 100% of rats treated with L-carnitine survived an ammonium acetate challenge, whereas in other experiments more than 60% of the animals died after an identical treatment (7).…”

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Failure of L-Carnitine to Protect Mice against Hyperammonemia Induced by Ammonium Acetate or Urease Injection

et al. 1990

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ABSTRACT. Reports indicate that L-carnitine administration before 100% lethal dose of ammonium acetate suppresses the symptoms of ammonia toxicity and prevents death in mice. However, we have been unable to confirm this observation. The cause of discrepancy between our results and the results of others was investigated with two models of hyperammonemia in mice: I) that induced by intraperitoneal injection of urease and 2) that induced by intraperitoneal injection of ammonium acetate. L-Carnitine administration failed to protect mice against ammonia toxicity induced by intraperitoneal injection of urease. Mortality in mice treated with L-carnitine 30 min before injection of ammonium acetate was similar to that of controls pretreated with saline. Ammonia and urea levels in plasma, liver, and brain were also similar in both groups. However, the values were significantly lower than those in mice denied either pretreatment before the ammonium acetate challenge. These results indicate that pretreatment acts to reduce blood and tissue ammonia simply by diminishing the rate of absorption of the challenge, owing to the dilution of ammonium acetate upon mixing with the contents of the peritoneal cavity. Thus, any protocol that does not compare results of a putative protective agent with those obtained with an equal volume of solvents or saline runs the risk of ascribing protective property to the agent when the protection may, in fact, have been afforded by the solvent. (Pediatr Res 28: [256][257][258][259][260] 1990) Abbreviations Hyperammonemia occurs in several pathologic conditions such as cirrhosis of the liver, inborn errors of the urea cycle, and other hereditary disorders such as organic acidemia and hyperlysinemia. Elevated ammonia is toxic to the brain and leads to convulsions, coma, and death. Several approaches have been recommended to combat hyperamrnonemia. These include limiting nitrogen intake, improving protein quality, supplying dietary metabolites such as arginine, and increasing nitrogen excretion in the form of derived conjugates (1,2). It has been reported that L-carnitine administration to mice prevents the lethal effects of acute hyperammonemia induced by ammonium acetate injection (3, 4). These authors proposed that L-carnitine decreases the ammonia in blood and brain by inducing ureagenesis. Another group of investigators carried out similar studies using an identical protocol and also reported that L-carnitine protected mice against ammonia toxicity (5). However, when we attempted to repeat this work, we were unable to demonstrate the eficacy of L-carnitine in reducing hyperammonemia (6). Hearn et al. (7) recently reported that the protective effect of L-carnitine was short lived and was not consistently reproducible. They observed that in some experiments 100% of rats treated with L-carnitine survived an ammonium acetate challenge, whereas in other experiments more than 60% of the animals died after an identical treatment (7).The first objective of our study was to investigate the cause for ...

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Section: Resultssupporting

confidence: 42%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Failure of L-Carnitine to Protect Mice against Hyperammonemia Induced by Ammonium Acetate or Urease Injection

et al. 1990

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Protective Effect of L–Carnitine in Ammonia–Precipitated Encephalopathy in the Portacaval Shunted Rat

et al. 1997

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as gastrointestinal bleeding, constipation, or sedative use. 1 L-carnitine administration prevents the neurological Symptoms of PSE are generally reversible suggesting a metasymptoms of acute ammonia toxicity. To further evalubolic cause. ate its efficacy in the prevention of hepatic encephalopaOf the possible neurotoxins implicated in PSE, ammonia thy in hyperammonemic conditions, L-carnitine (16 was the first to be incriminated 2 and is still considered a mmol/kg, intraperitoneally [ip]) was administered 1 leading candidate. [2][3][4][5] Neurochemical mechanisms so far prohour before ammonium acetate (NH 4 OAc) (8.5 mmol/kg, posed to explain the neurotoxic effects of ammonia include subcutaneously) to portacaval shunted (PCS) rats. Ceredirect effects on excitatory and inhibitory neurotransmisbrospinal fluid (CSF) ammonia, lactate, and amino acid sion 6,7 and on neuron-astrocytic metabolic trafficking 8 as well levels were measured in relation to deteriorating neuroas effects mediated via glutamine accumulation in brain. 9 logical status in these animals. None of 35 L-carnitineIf sufficiently prolonged or severe, ammonia may also have treated animals showed neurological deterioration after adverse effects on brain energy metabolism. 10,11 In this latter NH 4 OAC administration compared with saline-treated regard, there is evidence to suggest disruption of the malatecontrols; the latter manifested severe encephalopathy aspartate shuttle in brain in experimental PSE. 11 In addition, progressing through loss of righting reflex to coma. Surresults of in vitro studies suggest inhibition of the tricarboxvival rate was 100% in the L-carnitine -treated group ylic acid cycle enzyme a-ketoglutarate dehydrogenase compared with 5% in saline-treated controls. Following (aKGDH) by pathophysiological concentrations of ammonia 12 NH 4 OAC administration to PCS rats, CSF ammonia inand thus the potential for impaired cerebral energy metabocreased to 0.93 { 0.15 mmol/L and 1.24 { 0.15 mmol/L at lism. precoma and coma stages of encephalopathy (P õ .01)Few treatments of hyperammonemic syndromes are specifrespectively. Treatment with L-carnitine reduced CSF ically designed at counteracting the molecular actions of amammonia at both precoma and coma stages; the timemonia. It has been reported that L-carnitine administration course of this protective effect paralleled blood and CSF to mice 1 hour before a lethal injection of ammonium acetate L-carnitine accumulation. CSF alanine and lactate in-(NH 4 OAc) prevents both symptoms of ammonia toxicity and creases following NH 4 OAC administration to PCS rats death. 13 It was suggested that L-carnitine led to decreased were significantly attenuated following L-carnitine blood and brain ammonia in part by induction of ureagenesis. treatment. However, L-carnitine treatment did not leadSubsequently, the ammonia-lowering effects of L-carnitine to significant reductions in plasma ammonia nor CSF or were confirmed in portacaval shunted rats. 14 brain glutamine in these animals. These findings sho...

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Portal-Systemic Encephalopathy: a Disorder of Multiple Neurotransmitter Systems

Butterworth

1994

Advances in Experimental Medicine and Biology

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Effect of Orally Administered L–Carnitine on Blood Ammonia and L–Carnitine Concentrations in Portacaval–Shunted Rats

Cited by 22 publications

References 39 publications

Failure of L-Carnitine to Protect Mice against Hyperammonemia Induced by Ammonium Acetate or Urease Injection

Failure of L-Carnitine to Protect Mice against Hyperammonemia Induced by Ammonium Acetate or Urease Injection

Protective Effect of L–Carnitine in Ammonia–Precipitated Encephalopathy in the Portacaval Shunted Rat

Portal-Systemic Encephalopathy: a Disorder of Multiple Neurotransmitter Systems

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