Induction of Coma in Normal Dogs by the Infusion of Aromatic Amino Acids and Its Prevention by the Addition of Branched-Chain Amino Acids

Abstract

Various abnormalities in plasma and brain or cerebrospinal fluid amino acid concentrations have been documented in patients and experimental animals in hepatic encephalopathy. To ascertain whether such plasma and cerebrospinal fluid (brain) changes in amino acid concentrations were causally related to metabolic encephalopathies, of which hepatic coma is one, amino acid infusions were carried out in 14 dogs prepared with bilateral carotid loops and permanent lateral ventricle cerebrospinal fluid cannulas. Of various intracarotid infusions performed in such prepared awake animals, neurologic deterioration clinically resembling hepatic encephalopathy and culminating in coma was observed only after the simultaneous infusion of 1% tryptophan and 1% or 1.5% phenylalanine. After this infusion, phenylalanine, tyrosine, octopamine, and phenylethanolamine levels in cerebrospinal fluid were elevated to levels similar to or slightly greater than those observed in spontaneous experimental hepatic encephalopathy. After this infusion, however, cerebrospinal fluid tryptophan concentrations were considerably higher than those seen in spontaneous hepatic coma. Blood ammonia levels and cerebrospinal fluid glutamine remained normal. In a second group of 6 normal dogs, infusion of 1% tryptophan + 1.5% phenylalanine resulted in unresponsive coma. One week later, the experiments were repeated, but with branched-chain amino acids: 0.63% leucine + 0.4% isoleucine + 0.46% valine were added to the infusate, and coma did not result. The addition of branched-chain amino acids to the infusate may have prevented coma by competing with the aromatic acids for transport across the blood-brain barrier.