Brain metabolism and specific transport at the blood-brain barrier after portocaval anastomosis in the rat.

The rapid metabolism of [1-14C]butyrate and [2-14C]pyruvate in the brain was studied after intracarotid injection in control rats and rats given an end-to-side portocaval anastomosis (PCA). At 10 or 50 sec after injection there was a 40-50% lowering of the total amount of radioactivity in the brain of operated rats for both compounds. The percentage distribution of label in various metabolic fractions, e.g. amino acids, was unaltered by PCA. The results from the metabolic studies focused on an impaired transport of short chain monocarboxylic acids between blood and brain in rats with a PCA. The brain uptake index (BUI) of acetate, butyrate, pyruvate and glucose was determined by rapid intracarotid injection of the 14C test compound plus 3H2O as a reference marker. At 3 weeks after PCA, transport of all 3 monocarboxylic acids into brain was reduced by 40-50%. The reduction in [2-14C]pyruvate uptake was absent at one week, but thereafter, up to 50 weeks after operation, was consistently present. Eadie-Hofstee analysis of influx at varying substrate concentrations indicated a reduction in Vmax values of pyruvate and butyrate uptake without changes in Km. The calculated influx rate of glucose in operated rats was reduced in direct proportion to the lowering of plasma glucose. Portocaval anastomosis in the rat induces selective changes on substrates that are transported across the blood-brain barrier via a facilitated transport process.

Inhibition, by 2-oxo acids that accumulate in maple-syrup-urine disease, of lactate, pyruvate, and 3-hydroxybutyrate transport across the blood-brain barrier.

Data are presented in support of the transport of (-)-D-3-hydroxybutyrate across the blood-brain barrier (BBB) being a carrier-mediated process. The kinetic parameters in 21-day-old pentobarbital-anaesthetized rats were Vmax 2.0 mumol.g-1.min-1, Km 29 mM, and KD 0.024 ml.g-1.min-1. The value for Vmax was the same as that for L-lactate and pyruvate transport in animals of the same age. The transport of all three substrates was sensitive to inhibition by low concentrations of either 2-oxo-3-methylbutanoate or 2-oxo-4-methylpentanoate, the 2-oxo acids that can accumulate in patients with maple-syrup-urine disease. The Ki values for the 2-oxo acids were severalfold lower than the respective Km values. 2-Oxo-3-phenylpropionate was a poor inhibitor. The relative affinities of the various monocarboxylic acids for the transport system of the BBB distinguished it from similar systems described in brain, heart, and liver mitochondria; human erythrocytes; and Ehrlich ascites-tumour cells.