Intra- and extracellular amino acid concentrations in portacaval-shunted rabbits. Role of hyperammonemia and effects of branched-chain amino acid-enriched parenteral nutrition

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Abstract
Summary Intra- and extracellular amino acid concentrations were measured in rabbits in order to elucidate the possible role of hyperammonemia in lowering the postabsorptive plasma levels of branched-chain amino acids (BCAA) and to assess the effects of BCAA-enriched total parenteral nutrition (TPN) on the amino acid pattern of muscle. The pathophysiological part of this paper deals with portacaval anastomosis (PCA) and is aimed at substantiating or rejecting our hypothesis that excessive ammonia — by stimulating glutamine synthesis — reduces the intracellular glutamate pool which is then restored, at least in part, by an intensified BCAA degradation. Regarding infusion therapy, we were mainly interested in whether an amino acid solution adapted to the metabolism in liver cirrhosis causes an accumulation of BCAA in muscle or modifies the intracellular content of glutamate and glutamine. Eighteen rabbits did not undergo surgery and served as controls (group A), while 30 were given a portacaval end-to-side anastomosis (group B). Two weeks after creating the PCA, venous blood samples were taken and muscle biopsies (Bergström's technique) were performed postabsorptively. An 18-h TPN was then started, the regimen administered included dextrose, fat and, in addition, either a conventional (group B1, n=15) or an adapted amino acid solution (group B2, n=15). We obtained second blood specimens and muscle biopsies at the end of the infusion period. With the control animals, the same time schedule for blood sampling and muscle biopsies was followed. Fourteen days after the operation, the PCA rabbits displayed a mean plasma ammonia level 5.1 times higher than that measured in the controls (p≤0.001). Conventional blood chemistry did not reveal any impairment of liver cell integrity or over-all hepatic function, whereas the nutritional state of the shunted animals worsened, as indicated by body weight and biochemical variables. Since in the PCA rabbits, the total amino acid pools of muscle and plasma were seen to be increased and decreased, respectively, the results concerning the individual amino acids are given in terms of both the absolute and percentage values, the latter more often revealing high levels of statistical significance. PCA induced a marked rise in the intra- and extracellular concentrations of glutamine, while the values of glutamate and alanine showed a decline in muscle and plasma. The extracellular levels of methionine, phenylalanine, and tyrosine were raised, while those of the BCAA were diminished. During TPN, the intracellular concentrations of glutamate and glutamine fell in the animal group B 1 but remained stable in group B2. Only a slight and insignificant accumulation of BCAA occurred in the latter group. Secondary findings confirmed that conventional TPN aggravates the pre-existing increase in the plasma levels of methionine and phenylalanine, and that BCAA-enriched TPN results in almost normalized values of these amino acids. In conclusion, the PCA-induced alterations in the intracellular amino acid concentrations support the above-formulated hypothesis concerning the role of hyperammonemia in lowering plasma BCAA values, the preferential maintenance of intra-, rather than extracellular BCAA levels being a well-known fact. The largely stable concentrations of BCAA in muscle during BCAA-enriched TPN may indicate in intensified utilization of these amino acids, which probably involves ammonia detoxification. The observation that this type of TPN prevented a fall in the muscular levels of glutamate and glutamine fits into this concept.