TY - JOUR

T1 - Asymmetrical transport of amino acids across the blood-brain barrier in humans

AU - Knudsen, G M

AU - Pettigrew, K D

AU - Patlak, C S

AU - Hertz, M M

AU - Paulson, O B

PY - 1990/9

Y1 - 1990/9

N2 - Blood-brain barrier permeability to four large neutral and one basic amino acid was studied in 30 patients with the double indicator technique. The resultant 64 venous outflow curves were analyzed by means of two models that take tracer backflux and capillary heterogeneity into account. The first model considers the blood-brain barrier as a double membrane where amino acids from plasma enter the endothelial cell. When an endothelial cell volume of 0.001 ml/g was assumed, permeability from the blood into the endothelial cell was, for most amino acids, about 10-20 times larger than the permeability for the reverse direction. The second model assumes that the amino acids, after intracarotid injection, cross a single membrane barrier and enter a well-mixed compartment, the brain extracellular fluid, i.e., the endothelial cell is assumed to behave as a single membrane. With this model, for large neutral amino acids, the permeability out of the extracellular fluid space back to the blood was between 8 to 12 times higher than the permeability from the blood into the brain. Such a difference in permeabilities across the blood-brain barrier can almost entirely be ascribed to the effect of a nonlinear transport system combined with a relatively small brain amino acid metabolism. The significance of the possible presence of an energy-dependent A system at the abluminal side of the blood-brain barrier is discussed and related to the present findings. For both models, calculation of brain extraction by simple peak extraction values underestimates true unidirectional brain uptake by 17-40%. This raises methodological problems when estimating blood to brain transfer of amino acids with this traditional in vivo method.

AB - Blood-brain barrier permeability to four large neutral and one basic amino acid was studied in 30 patients with the double indicator technique. The resultant 64 venous outflow curves were analyzed by means of two models that take tracer backflux and capillary heterogeneity into account. The first model considers the blood-brain barrier as a double membrane where amino acids from plasma enter the endothelial cell. When an endothelial cell volume of 0.001 ml/g was assumed, permeability from the blood into the endothelial cell was, for most amino acids, about 10-20 times larger than the permeability for the reverse direction. The second model assumes that the amino acids, after intracarotid injection, cross a single membrane barrier and enter a well-mixed compartment, the brain extracellular fluid, i.e., the endothelial cell is assumed to behave as a single membrane. With this model, for large neutral amino acids, the permeability out of the extracellular fluid space back to the blood was between 8 to 12 times higher than the permeability from the blood into the brain. Such a difference in permeabilities across the blood-brain barrier can almost entirely be ascribed to the effect of a nonlinear transport system combined with a relatively small brain amino acid metabolism. The significance of the possible presence of an energy-dependent A system at the abluminal side of the blood-brain barrier is discussed and related to the present findings. For both models, calculation of brain extraction by simple peak extraction values underestimates true unidirectional brain uptake by 17-40%. This raises methodological problems when estimating blood to brain transfer of amino acids with this traditional in vivo method.

KW - Adult

KW - Amino Acids/pharmacokinetics

KW - Arginine/pharmacokinetics

KW - Biological Transport, Active

KW - Blood-Brain Barrier

KW - Cell Membrane Permeability

KW - Female

KW - Humans

KW - Leucine/pharmacokinetics

KW - Male

KW - Middle Aged

KW - Models, Neurological

KW - Phenylalanine/pharmacokinetics

KW - Tryptophan/pharmacokinetics

KW - Tyrosine/pharmacokinetics

U2 - 10.1038/jcbfm.1990.123

DO - 10.1038/jcbfm.1990.123

M3 - Journal article

C2 - 2384542

VL - 10

SP - 698

EP - 706

JO - Journal of Cerebral Blood Flow and Metabolism

JF - Journal of Cerebral Blood Flow and Metabolism

SN - 0271-678X

IS - 5

ER -