Regional Blood‐Brain Barrier Permeability to Amino Acids After Portacaval Anastomosis

Mans, Anke M.; Biebuyck, Julien F.; Shelly, Kirk; Hawkins, Richard A.

doi:10.1111/j.1471-4159.1982.tb08689.x

Cited by 120 publications

(73 citation statements)

References 46 publications

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“…The higher concentrations in the TPN rats result from the high concentrations of these amino acids in the infused TPN solution (Table 1). Steady-state blood leucine concentration in the TPN rats, 0.79 ± 0.04 jimol/g (n = 4), is severalfold higher than that reported for normal rats, 0.14-0.18~.tmol/g (Mans et al, 1982(Mans et al, , 1984. Although plasma glycine concentration is also high, glycine does not measurably penetrate the blood-brain barrier (Oldendorf and Szabo, 1976), and its concentration in the brain of TPN rats is near-normal.…”

Section: Time Course Of Increase In Brain ['5n] Glutamatementioning

confidence: 83%

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

Kanamori

Ross

Kondrat

1998

Journal of Neurochemistry

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Abstract:The rate of glutamate synthesis from leucine by the branched-chain aminotransferase was measured in rat brain in vivo at steady state. The rats were fed exclusively by intravenous infusion of a nutrient solution containing [15N]leucine. The rate of glutamate synthesis from leucine, determined from the rate of increase of brain [15N]glutamate measured by 15N NMR and the 15N enrichments of brain and blood leucine analyzed by gas chromatography-mass spectrometry, was 0.7-1.8 j.tmol/g/ h at a steady-state brain leucine concentration of 0.25 mol/g. A comparison of the observed fractional 15N enrichments of brain leucine (0.42 ±0.03) and glutamate (0.21 ±0.015) showed that leucine provides '-.~50%of glutamate nitrogen under our experimental condition. From the observed rate (0.7-1.8 j.imol/g) and the known Km of the branched-chain aminotransferase for leucine (1.2 mM), the rate of glutamate synthesis from leucine at physiological brain leucine concentration (0.11~mol/ g) was estimated to be 0.35-0.9~mol/g/h, with leucine providing~25% of glutamate nitrogen. The results strongly suggest that plasma leucine from dietary source, transported into the brain, is an important external source of nitrogen for replenishment of brain glutamate in vivo. Implications of the results for treatment of maple-syrup urine disease patients with leucine-restricted diet are discussed. Key Words: Leucine-Glutamate-BrainBranched-chain aminotransferase-1 5N NMR-In vivo. J. Neurochem. 70, 1304Neurochem. 70, -1315Neurochem. 70, (1998.The branched-chain amino acids (BCAA) -leucine, isoleucine, and valine-are essential amino acids that readily cross the blood-brain barrier. Leucine is the predominant BCAA in most dietary proteins (Berry et al., 1989) and has the highest influx rate into the brain (Smith et al., 1987). In the brain, leucine has two metabolic fates: (a) incorporation into proteins and (b) transamination to a-ketoglutarate to form glutamate, catalyzed by branched-chain aminotransferase (BCAT; EC 2.6.1.42):

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Section: Time Course Of Increase In Brain ['5n] Glutamatementioning

confidence: 83%

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

Kanamori

Ross

Kondrat

1998

Journal of Neurochemistry

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“…The brain glutamine levels in these rats are -11-15 j.Lmol/g, and their plasma and brain glucose levels are mostly within the normoglycemic range until 14-16 weeks (Dejoseph and Hawkins, 199 1;Hawk ins et al, 1993) (Tables 3-6). When the glue method (Mans et al, 1982) is used to construct the porta caval shunt, ammonia and glutamine levels in brain are usually about twice as high (i.e., -0.8-1.3 and 21-24 j.Lmol/g, respectively; Table 6) as those ob tained when the suture method is used; brain glu tamine levels are positively correlated with brain and plasma ammonia contents (Williams et aI., 1972). Brain glucose levels and glucose distribution ratios in these rats are either normal or about half normal (see next section).…”

Section: Traits Of Portacaval-shunted Ratsmentioning

confidence: 99%

“…(1983);Rigotti et al (1985); (6) Giguere and Butterworth (1984), Butterworth and Giguere (1986); Butterworth et al (1988);Girard and Butterworth (1992); (7) Holmin and Siesj6 (1974); (8) Mans et al (1982Mans et al ( , 1983aMans et al ( ,b, 1984aMans et al ( ,b, 1986aMans et al ( , 1990; White and Mans (1984).…”

Section: Lumped Constant In Shunted Ratsmentioning

confidence: 99%

Brain Glucose Levels in Portacaval-Shunted Rats with Chronic, Moderate Hyperammonemia: Implications for Determination of Local Cerebral Glucose Utilization

Cruz

Dienel

1994

J Cereb Blood Flow Metab

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Summary: Rates of glucose utilization (lCMRglc) in many structures of the brain of fed, portacaval-shunted rats, when assayed with the [14C]deoxyglucose (DG) method in our laboratory, were previously found to be unchanged (30 of 36 structures) or depressed (6 structures) during the first 4 weeks after shunting, but to rise progressively to higher than normal values in 25 of 36 structures from 4-12 weeks. In contrast, ICMRglc, when assayed with the [14C]glucose method in another laboratory, was de pressed in most structures of brains of 4-8-week shunted rats that had relatively high brain ammonia levels. There was a possibility that the increases in ICMRglc obtained with the [14C]DG method may have been artifactual, due, in part, to a change in brain glucose content which could alter the value of the lumped constant of the DG method. Brain glucose levels of shunted rats were, therefore, as sayed by both direct chemical measurement in freeze blown samples and by determination of steady-state brain:plasma distribution ratios for e4C]methylglucose; Liver disease is accompanied by chronic hyper ammonemia and alterations in behavior and mental state. Ammonia is widely regarded as a toxin with a "threshold level for neurotoxicity" of about 1 j-Lmol/g of brain; above this level EEG abnormalities and behavioral changes (e.g., lethargy, stupor, and coma) are observed in experimental animals Cooper and Plum, 1987;Raabe, 1990). Construction of a portacaval shunt chroni cally elevates ammonia levels in blood and brain,

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“…Ammonia was estimated in the non-radioactive plasma sample and amino acids were measured in plasma and brain. The permeability-to-surface area products, measure of transport, of tryptophan and leucine were calculated in accordance with Mans et al (1982 The rats were left in restraining cages for 1 h to recover from the effects of surgery. Arterial blood was sampled and the plasma separated by centrifugation.…”

Section: Experimental Designmentioning

confidence: 99%

Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

Hawkins

Jessy

1991

Biochemical Journal

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1. It has been established that chronic hyperammonaemia, whether caused by portacaval shunting or other means, leads to a variety of metabolic changes, including a depression in the cerebral metabolic rate of glucose (CMRGIC), increased permeability of the blood-brain barrier to neutral amino acids, and an increase in the brain content of aromatic amino acids. The preceding paper [Jessy, DeJoseph & Hawkins (1991) Biochem. J. 277, 693-696] showed that the depression in CMRGlC caused by hyperammonaemia correlated more closely with glutamine, a metabolite of ammonia, than with ammonia itself. This suggested that ammonia (NH3 and NH41) was without effect. The present experiments address the question whether ammonia, in the absence of net glutamine synthesis, induces any of the metabolic symptoms of cerebral dysfunction associated with hyperammonaemia. 2. Small doses of methionine sulphoximine, an inhibitor of glutamine synthetase, were used to raise the plasma ammonia levels of normal rats without increasing the brain glutamine content. These hyperammonaemic rats, with plasma and brain ammonia levels equivalent to those known to depress brain function, behaved normally over 48 h. There was no depression of cerebral energy metabolism (i.e. the rate of glucose consumption). Contents of key intermediary metabolites and high-energy phosphates were normal. Neutral amino acid transport (tryptophan and leucine) and the brain contents of aromatic amino acids were unchanged. 3. The data suggest that ammonia is without effect at concentrations less than 1 /tmol/ml if it is not converted into glutamine. The deleterious effect of chronic hyperammonaemia seems to begin with the synthesis of glutamine.

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Regional Blood‐Brain Barrier Permeability to Amino Acids After Portacaval Anastomosis

Cited by 120 publications

References 46 publications

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

Brain Glucose Levels in Portacaval-Shunted Rats with Chronic, Moderate Hyperammonemia: Implications for Determination of Local Cerebral Glucose Utilization

Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

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Regional Blood‐Brain Barrier Permeability to Amino Acids After Portacaval Anastomosis

Cited by 120 publications

References 46 publications

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by 15N NMR

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by 15N NMR

Brain Glucose Levels in Portacaval-Shunted Rats with Chronic, Moderate Hyperammonemia: Implications for Determination of Local Cerebral Glucose Utilization

Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis

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Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR

Rate of Glutamate Synthesis from Leucine in Rat Brain Measured In Vivo by ¹⁵N NMR