Loss of noradrenaline transporter sites in frontal cortex of rats with acute (ischemic) liver failure.

There is increasing evidence that central noradrenaline (NA) transport mechanisms are implicated in the central nervous system complications of acute liver failure. In order to assess this possibility, binding sites for the high affinity NA transporter ligand [3H]-nisoxetine were measured by quantitative receptor autoradiography in the brains of rats with acute liver failure resulting from hepatic devascularization and in appropriate controls. In vivo microdialysis was used to measure extracellular brain concentrations of NA. Severe encephalopathy resulted in a significant loss of [3H]-nisoxetine sites in frontal cortex and a concomitant increase in extracellular brain concentrations of NA in rats with acute liver failure. A loss of transporter sites was also observed in thalamus of rats with acute liver failure. This loss of NA transporter sites could result from depletion of central NA stores due to a reserpine-like effect of ammonia which is known to accumulate to millimolar concentrations in brain in ischemic liver failure. Impaired NA transport and the consequent increase in synaptic concentrations and increased stimulation of neuronal and astrocytic noradrenergic receptors could be implicated in the pathogenesis of the encephalopathy and brain edema characteristic of acute liver failure.

Evidence for altered central noradrenergic function in experimental acute liver failure in the rat.

These is increasing evidence to suggest that central noradrenergic mechanisms may contribute to the central nervous system manifestations of acute liver failure. To further elucidate this possibility, extracellular brain concentrations of the monoamines, noradrenaline (NA), dopamine (DA), and serotonin, were measured by high-performance liquid chromatography with electrochemical detection in microdialysates from the extracellular compartment of frontal cortex in rats with acute (ischemic) liver failure at various times during the progression of encephalopathy and brain edema, as well as in obligate control groups of animals. In addition, binding sites for the noradrenergic receptor subtype ligands, [3H]-prazosin (alpha1 sites), [3H]-RX821002 (alpha2 sites), and [125]I-iodopindolol (beta sites), were assessed using quantitative receptor autoradiography in regions of the brains of rats at coma stage of acute liver failure and of control groups of animals. Coma stages of encephalopathy in acute liver failure were associated with selectively increased noradrenaline concentrations (P < .05) and a concomitant selective loss of alpha1 and beta1 sites in frontal cortex and thalamus. These findings add to a growing body of evidence that central noradrenergic function is modified in acute liver failure and suggest that alpha1/beta1 receptor-mediated noradrenergic mechanisms may play a role in the pathogenesis of brain edema and encephalopathy in this condition.

Tissue acylcarnitine and acyl-coenzyme A profiles in chronically hyperammonemic mice treated with sodium benzoate and supplementary L-carnitine.

The aim of the present study, was to establish the hepatic profile of acyl-coenzyme A (acyl-CoA) in relation to the hepatic profile of acylcarnitines in chronically hyperammonemic spf mice (hereditary deficiency in ornithine transcarbamylase) treated with sodium benzoate alone or in combination with L-carnitine. The muscular profile of the acylcarnitines and the stability of sarcolemma were also assessed in the same mice. Following administration of sodium benzoate, we observed decreases in hepatic total and free coenzyme A and in acetyl-CoA, which was accompanied by an increase in hepatic acyl-CoA. This treatment also resulted in increased free carnitine, decreased total carnitine, and decreased short and medium chain acylcarnitines in the liver. Increases in plasma creatine kinase levels, muscular free, total, and in short and medium chain acylcarnitines were also observed in this treatment group. In mice receiving a combination of sodium benzoate and L-carnitine, increases in free and total coenzyme A, acetyl-CoA and in free, total and esterified hepatic carnitines were observed. In this treatment group, the plasma level of creatine kinase was found to be reduced, while the free muscular carnitine was increased. Our results indicate that sodium benzoate is implicated in the decrease of total hepatic coenzyme A, through either an inhibition of CoA synthesis or activation of its degradation. The distribution of hepatic coenzyme-A and of hepatic and muscular carnitine (free or esterified) is altered following administration of sodium benzoate which results in a further destabilization of the sarcolemma induced by hyperammonemia. Supplemental treatment with L-carnitine was shown to have a positive effect by increasing hepatic coenzyme A and carnitine levels and restoring the stability of the sarcolemma caused by the treatment of sodium benzoate alone.

A profile of cerebral and hepatic carnitine, ammonia, and energy metabolism in a model of organic aciduria: BALB/cByJ mouse with short-chain acyl-CoA dehydrogenase deficiency.

Spontaneous animal models of inborn errors of metabolism are valuable tools for defining the pathogenesis of these disorders and also the mechanism of various therapeutic approaches. In the present study, we have employed BALB/cByJ mice with an autosomal recessive deficiency of short-chain acyl-CoA dehydrogenase (SCAD). These animals were characterized by a marked urinary excretion of ethylmalonic and methylsuccinic acids along with butyrylglycine. Using adult homozygous mice we have studied the basic cerebral and hepatic profile of carnitine, ammonia, and energy metabolism. The effects of fasting and a short-term supplement of L-carnitine have been evaluated in comparison with control BALB/cJ mice. The mutant mice had low levels of acetyl-CoA and high levels of lactate compared to control mice. Fasting aggravated this condition by further decreasing acetyl-CoA and increasing lactate levels in the mutant mice. Free carnitine levels were significantly decreased in liver with fasting. Long-chain acylcarnitines were significantly lower in the brain of mutant mice. A short-term supplementation of L-carnitine resulted in general increases of carnitine levels in liver and muscle, but they still remained lower in mutant BALB/cByJ mice as compared to control BALB/cJ mice. L-Carnitine treatment increased cerebral CoA-SH levels and both hepatic and cerebral acetyl-CoA levels in mutant mice. Hyperammonemia which has been described frequently in acyl-CoA dehydrogenase deficiencies was not observed in adult BALB/cByJ mice. This could be due to a rapid conjugation of butyryl-CoA with glycine by an increased activity of glycine N-acyltransferase.

[Hypocarnitinemia in patients affected by a primary defect of ammonia metabolism treated with sodium benzoate]. / Hypocarnitinémie chez les patients atteints d'un défaut primaire du métabolisme de l'ammoniaque traités avec le benzoate de sodium.

We have studied the plasma and urinary levels of free and esterified carnitine in 18 patients affected by a primary defect of ammonia metabolism, which had been managed with or without a therapy of sodium benzoate. None of these patients presented with any acute neurologic or digestive symptoms during the study. Our group of non-treated patients showed an increase in the levels of plasma esterified carnitine and an elevation of urinary concentration of free carnitine, while the levels of urinary esterified carnitine clearly approached the superior limits of normal values. The group treated with sodium benzoate showed a more profoundly disturbed plasma and urinary carnitine profile: a significantly lower plasma and urinary free carnitine, accompanied by a clearly increased esterified/free carnitine ratio. We did not find any evidence of a relationship between the plasma levels of free or esterified carnitine and the protein intake or the plasma ammonia concentration. We are proposing a hypothesis to explain the hypocarnitinemia seen in our patients being treated with benzoate, along with other modifications observed in the carnitine profile. We believe that a supplement of carnitine could be beneficial in the management of some of these patients.