Cerebral amino acid levels and uptake in rats after portocaval anastomosis: II. Regional studies in vivo.

Abstract

Amino acid levels have been determined in plasma and in four cerebral regions of rats one month after portocaval shunt. Many plasma amino acids are significantly lowered (asparagine, glutamine, theonine, serine, alanine, valine, leucine, isoleucine, cystine, lysine), while others remain unchanged (taurine, glycine, proline, tryptophan, ornithine, histidine, arginine). Asparagine and glutamine levels are significantly higher than in normal rats, and a net increase of tyrosine (100%), phenylalanine (50%) and citrulline (50%) is evident. In the shunted rat brain the most prominent feature is a very large rise (up to fivefold) of tyrosine, phenylalanine, histidine, citrulline, tryptophan, and glutamine uniformly in the tested regions. Other neutral amino acids are slightly increased. Lysine and arginine are decreased in cerebellum and pons-medulla; taurine, in forebrain and cerebellum. Cerebral permeability to L-amino acids was studied in vivo. Neutral amino acid permeability is greatly increased, whereas basic amino acids show a net decrease in their rate of passage from blood to the brain. No changes are observed for GABA and glutamic acid. These data suggest an altered permeability of the cerebral capillary membranes, which seems to be selective for the different amino acid transport classes. Competitive inhibition experiments demonstrated that the increased brain permeability to neutral amino acids after portocaval shunt is due to an enhancement of the saturable transport. The sharp rise in the brain of some essential neutral amino acids (phenylalanine, tyrosine, trytophan, histidine), largely exceeding their changes in plasma, and the slight cerebral increase of other neutral amino acids despite their lowered level and the rise of competing amino acids in the plasma, is consistent with our observation of enhanced transport for the neutral class. In hepatic encephalopathy, correction of the altered plasma amino acid levels has been reported to improve the clinical status. If this result is connected to the concomitant correction of the brain amino acid levels, carefully selected competitive inhibition among various plasma amino acids could be a useful therapeutic tool in this pathologic condition. However, the increased activity of the neutral amino acid transport system adds a new factor to the problem, since it probably implies that the competing amino acids will accumulate to unphysiological levels in the brain.