Transcerebral exchange kinetics of large neutral amino acids during acute inspiratory hypoxia in humans

Abstract

Hypoxaemia is present in many critically ill patients, and may contribute to encephalopathy. Changes in the passage of large neutral amino acids (LNAAs) across the blood-brain barrier (BBB) with an increased cerebral influx of aromatic amino acids into the brain may concurrently be present and also contribute to encephalopathy, but it has not been established whether hypoxaemia per se may trigger such changes. We measured cerebral blood flow (CBF) in 11 healthy men using the Kety-Schmidt technique and obtained paired arterial and jugular-venous blood samples for the determination of LNAAs by high performance liquid chromatography at baseline and after 9 hours of poikilocapnic normobaric hypoxia (12% O₂). Transcerebral net exchange was determined by the Fick principle, and transport of LNAAs across the BBB was determined mathematically. Hypoxia increased both the systemic and corresponding cerebral delivery of the aromatic amino acid phenylalanine, and the branched-chain amino acids leucine and isoleucine. Despite this, the transcerebral net exchange values and mathematically derived brain extracellular concentrations for all LNAAs were unaffected. In conclusion, the observed changes in circulating LNAAs triggered by hypoxaemia do not affect the transcerebral exchange kinetics of LNAAs to such an extent that their brain extracellular concentrations are affected.

Keywords:

• (MeSH ID): Aromatic amino acids (D024322)
• blood-brain barrier (D001812)
• branched-chain amino acids (D000597)
• metabolism (D008660)
• hypoxia (D000860)

Author contributions

RHD defined the model, performed the calculations, interpreted the data, prepared tables and figures, performed statistical analyses, and drafted the manuscript. RMGB conducted and conceived of the study, handled supervision, interpreted the data, and drafted the manuscript. ST, DMB, and CL conducted the study and acquired and interpreted the data. MC conducted the amino acid analyses. FSL interpreted the data. KM conceived of and designed the research, conducted the study, acquired, analyzed, and interpreted the data, drafted the manuscript, and handled funding and supervision. All authors made critical revisions and read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Copenhagen Hospital Corporation, The Laerdal Foundation, Danish National Research Council, The Larsen Foundation, The Jensa la Cour Foundation, The Danish National Research Foundation, The AP Møller Foundation, and The Højmosegaard Foundation.