Summary: Hyperammonemia causes glutamine accumulation and astrocyte swelling. Inhibition of glutamine synthesis re duces ammonia-induced edema formation and watery swelling in astrocyte processes. Ordinarily, astrocytes tightly control ex tracellular K+ activity [K+le. We tested the hypothesis that acute hyperammonemia interferes with this tight regulation such that [K+le increases and that inhibition of glutamine syn thetase reduces this increase in [K+le. Ion-sensitive microelec trodes were used to measure [K+le in parietal cortex continu ously over a 6-h period in anesthetized rats. After i.v. sodium acetate infusion in eight control rats, plasma ammonia concen tration was 33 ± 26 fLmollL (± SD) and [K+le remained stable at 4.3 ± 1.6 mmollL. During ammonium acetate infusion in nine rats, plasma ammonia increased to 594 ± 124 fLmollL at 2 h and to 628 ± 135 fLmollL at 6 h. There was a gradual increase Various forms of liver disease and congenital urea cycle disorders cause selective swelling of astrocytes (Bruton et aI., 1970; Martinez, 1968; Zimmerman et aI., 1981). Experimental hyperammonemia also causes se lective astrocyte swelling (Diemer, 1978; Gibson et aI., 1974; Voorhies et aI., 1983). Plasma-labelled ammonia is rapidly taken up by brain (Cooper et aI., 1979(Cooper et aI., , 1985 and used in the amidation of glutamate by glutamine synthe tase, an enzyme enriched in astrocytes (Norenberg and Martinez-Hernandez, 1979). With acute hyperammone mia, tissue glutamine concentration increases over a pe riod of several hours (Bosman et aI., 1990; Fitzpatrick et Received April I, 1996; final revision received June 10, 1996; ac cepted June 10, 1996.
44in [K+le from 3.9 ± 0.7 to 6.8 ± 2.7 mmollL at 2 h and 11.8 ± 6.7 mmollL at 6 h. In eight rats, L-methionine-D,L-sulfoximine (150 mg/kg) was infused 3 h before ammonium acetate infu sion to inhibit glutamine synthetase. At 2 and 6 h of ammonium acetate infusion, plasma ammonia concentration was 727 ± 228 and 845 ± 326 fLmollL, and [K+le was 4.5 ± 1.9 and 6.1 ± 3.8 mmollL, respectively. The [K+Je value at 6 h was significantly less than that obtained with ammonium acetate infusion alone but was not different from that obtained with sodium acetate infusion. We conclude that acute hyperammonemia impairs astrocytic control of [K+lc and that this impairment is linked to glutamine accumulation rather than ammonium ions per se. Key Words: Ammonia-Astrocytes-Glutamine-Hepatic encephalopathy-Potassium-Rats.aI., 1989), and watery astrocyte processes are observed at 6 h (Willard-Mack et aI., 1996). We found that inhibition of glutamine synthetase with L-methionine-D,L sulfoximine (MSO) pretreatment prevented increased cortical glutamine concentration and tissue water content (Takahashi et aI., 1991), increased intracranial pressure (Takahashi et aI., 1992), watery swelling of astrocyte processes (Willard-Mack et aI., 1996), and loss of cere brovascular CO2 reactivity (Hirata et aI., 1996; Takaha shi et aI., 1992) associated with acute hyperammonemia. Thus, some of the ...