The goal of this research is to define some of the physiological and biochemical changes which occur during chronic hepatic encephalopathy. This is a necessary first step toward defining objective criteria by which therapeutic measures can be judged. Carefully characterized rats with portal-systemic shunts will be used as a model of chronic encephalopathy. The supply of essential nutrients to brain is determined by the plasma concentrations and the transport systems which facilitate their passage across the blood-brain barrier. In normal animals, the blood-brain barrier mediates a delicate balance between supply and need, but following portal-systemic shunting, the permeability characteristics of several transport systems are markedly altered. This is believed to be of etiologic significance to the development of encephalopathy since brain receives an excess of some nutrients but may be almost starved of others. Among the essential nutrients to be studied are neutral and basic amino acids, glucose, choline, purines and nucleosides. The time course of specific changes in regional transport will be determined. The results will be compared to changes in neural function as determined by measuring glucose utilization using [2-14C]glucose in either whole brain or at the structural level. The mechanism of the blood-brain barrier changes may be closely related to metabolism of NH4+ to glutamine. This will be studied in vivo by manipulating blood NH4 concentrations and cerebral glutamine content in chronic and acute experiments. Reduction of basic amino acid influx is so extreme that protein synthesis may be retarded. This possibility will be examined in whole brain and in individual structures by determination of the rate of protein synthesis.
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