CONTRASTING EFFECTS OF THIOACETAMIDE-INDUCED LIVER-DAMAGE ON THE BRAIN UPTAKE INDEXES OF ORNITHINE, ARGININE AND LYSINE - MODULATION BY TREATMENT WITH ORNITHINE ASPARTATE

The dibasic amino acids arginine (ARG), ornithine (ORN) and lysine (LY S) are transported by a common saturable transporter (system gamma(+)) at the blood-brain barrier (BBB). In the present study we compared th e brain uptake index (BUI) for radiolabelled ORN, ARG and LYS in contr ol rats and in rats treated with thioacetamide (TAA) to induce hepatic encephalopathy (HE). Some animals received i.v. ornithine aspartate ( OA), a drug structurally related to the gamma(+) substrates that ameli orates neurological symptoms following liver damage by improving detox ification of ammonia in peripheral tissues: the compound was administe red either by continuous infusion for 6h at a concentration of 2 g/kg (final blood concentration ranging from 0.19-0.5 mM), or as a 15 sec. bolus together with the radiolabelled amino acids, at a concentration of 0.35 mM. TAA treatment resulted in a delayed and progressive increa se of BUI for ORN, to 186% of control at 7d post-treatment and to 345% of control at 21d post-treatment, when despite sustained liver damage , HE symptoms were already absent. In contrast, the BUI for ARG decrea sed to 30% of control at 7d post-treatment and remained low (42% of co ntrol) at 21d post-treatment. A 6h infusion of OA to untreated rats re sulted in a reduction of the BUI for ARG and ORN to 51% and 62% of the control levels, respectively. Reductions of a similar magnitude were noted with both amino acids following the 15 sec OA bolus, indicating direct interaction of OA with the transport site in both cases. OA adm inistered by either route abolished the enhancement of BUI for ORN, bu t did not further inhibit the BUI for ARG in the TAA-treated animals. The results indicate that some as yet unspecified factors released fro m damaged liver either modify the structure or conformation of the gam ma(+) transporter at the BBB from the normally ARG-preferring to the O RN-preferring state, or activate (induce) a different transporter spec ific for ORN which is normally latent.