SEVERITY OF HYPERAMMONEMIC ENCEPHALOPATHY CORRELATES WITH BRAIN AMMONIA LEVEL AND SATURATION OF GLUTAMINE-SYNTHETASE IN-VIVO

Correlation among in vivo glutamine synthetase (GS) activity, brain am monia and glutamine concentrations, and severity of encephalopathy was examined in hyperammonemic rats to obtain quantitative information on the capacity of GS to control these metabolites implicated in the eti ology of hepatic encephalopathy, Awake rats were observed for neurobeh avioral impairments after ammonium acetate infusion to attain a steady -state blood ammonia concentration of 0.9 (group A) or 1.3 mu mol/g (g roup B). As encephalopathy progressed from grade III to IV, brain ammo nia concentration increased from 1.9 to 3.3 mu mol/g and then decrease d to 1.3 mu mol/g on recovery to grade III. In contrast, brain glutami ne concentration was 26, 23, and 21 mu mol/g, respectively, NH4+-infus ed rats pretreated with L-methionine DL-sulfoximine reached grade IV w hen brain ammonia and glutamine concentrations were 3.0 and 5.5 mu mol /g, respectively; severity of encephalopathy correlates with brain amm onia, but not glutamine, In vivo GS activity, measured by NMR, was 6.8 +/- 0.7 mu mol/h/g for group A and 6.2 +/- 0.6 mu mol/h/g for group B . Hence, the in vivo activity, shown previously to increase with blood ammonia over a range of 0.4-0.64 mu mol/g, approaches saturation at b lood ammonia >0.9 mu mol/g. This is likely to be the major cause of th e observed accumulation of brain ammonia and the onset of grade IV enc ephalopathy.