METHIONINE SULFOXIMINE, A GLUTAMINE-SYNTHETASE INHIBITOR, ATTENUATES INCREASED EXTRACELLULAR POTASSIUM ACTIVITY DURING ACUTE HYPERAMMONEMIA

Hyperammonemia causes glutamine accumulation and astrocyte swelling. I nhibition of glutamine synthesis reduces ammonia-induced edema formati on and watery swelling in astrocyte processes. Ordinarily, astrocytes tightly control extracellular K+ activity [K+](e). We tested the hypot hesis that acute hyperammonemia interferes with this tight regulation such that [K+](e) increases and that inhibition of glutamine synthetas e reduces this increase in [K+](e). Ion-sensitive microelectrodes were used to measure [K+](e) in parietal cortex continuously over a 6-h pe riod in anesthetized rats. After i.v. sodium acetate infusion in eight control rats, plasma ammonia concentration was 33 +/- 26 mu mol/L (+/ - SD) and [K+](e) remained stable at 4.3 +/- 1.6 mmol/L. During ammoni um acetate infusion in nine rats, plasma ammonia increased to 594 +/- 124 mu mol/L at 2 h and to 628 +/- 135 mu mol/L at 6 h. There was a gr adual increase in [K+](e) from 3.9 +/- 0.7 to 6.8 +/- 2.7 mmol/L at 2 h and 11.8 +/- 6.7 mmol/L at 6 h. In eight rats, L-methionine-D,L-sulf oximine (150 mg/kg) was infused 3 h before ammonium acetate infusion t o inhibit glutamine synthetase. At 2 and 6 h of ammonium acetate infus ion, plasma ammonia concentration was 727 +/- 228 and 845 +/- 326 mu m ol/L, and [K+](e) was 4.5 +/- 1.9 and 6.1 +/- 3.8 mmol/L, respectively . The [K+](e) value at 6 h was significantly less than that obtained w ith ammonium acetate infusion alone but was not different from that ob tained with sodium acetate infusion. We conclude that acute hyperammon emia impairs astrocytic control of [K+](e) and that this impairment is linked to glutamine accumulation rather than ammonium ions per se.