Methionine Sulfoximine, a Glutamine Synthetase Inhibitor, Attenuates Increased Extracellular Potassium Activity during Acute Hyperammonemia
Methionine Sulfoximine, a Glutamine Synthetase Inhibitor, Attenuates Increased Extracellular Potassium Activity during Acute Hyperammonemia
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DOI：
10.1097/00004647-199701000-00006
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发表时间：
1997-01
影响因子：
6.3
通讯作者：
H. Sugimoto;R. Koehler;D. A. Wilson;S. Brusilow;R. Traystman
中科院分区：
文献类型：
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作者：
H. Sugimoto;R. Koehler;D. A. Wilson;S. Brusilow;R. Traystman
高氨血症导致谷氨酰胺积聚和星形胶质细胞肿胀。谷氨酰胺合成的抑制减少氨诱导的水肿形成和星形胶质细胞过程中的水样肿胀。通常，星形胶质细胞严格控制细胞外K+活性[K+]e。我们检验了这样的假设，即急性高氨血症干扰了这种严格的调节，使得[K+]e增加，并且谷氨酰胺合成酶的抑制降低了[K+]e的这种增加。用离子敏感微电极连续测定麻醉大鼠顶叶皮层[K+]e超过6小时。8只对照大鼠静脉输注醋酸钠后，血浆氨浓度为33 ± 26 μmol/L（± SD），[K+]e稳定在4.3 ± 1.6 mmol/L。在9只大鼠输注醋酸铵期间，血浆氨在2 h时升高至594 ± 124 μmol/L，6 h时升高至628 ± 135 μmol/L。[K+]e从3.9 ± 0.7逐渐增加到2 h的6.8 ± 2.7 mmol/L和6 h的11.8 ± 6.7 mmol/L。在8只大鼠中，L-蛋氨酸-D，L-亚砜亚胺（150 mg/kg）在乙酸铵输注前3 h输注，以抑制谷氨酰胺合成酶。输注醋酸铵2和6 h时，血氨浓度分别为727 ± 228和845 ± 326 μmol/L，[K+]e分别为4.5 ± 1.9和6.1 ± 3.8 mmol/L。6 h时的[K+]e值显著低于单独醋酸铵输注获得的值，但与醋酸钠输注获得的值无差异。我们的结论是，急性高氨血症损害星形胶质细胞的[K+]e的控制，这种损害与谷氨酰胺的积累，而不是铵离子本身。
Hyperammonemia causes glutamine accumulation and astrocyte swelling. Inhibition of glutamine synthesis reduces ammonia-induced edema formation and watery swelling in astrocyte processes. Ordinarily, astrocytes tightly control extracellular K+ activity [K+]e. We tested the hypothesis that acute hyperammonemia interferes with this tight regulation such that [K+]e increases and that inhibition of glutamine synthetase reduces this increase in [K+]e. Ion-sensitive microelectrodes were used to measure [K+]e in parietal cortex continuously over a 6-h period in anesthetized rats. After i.v. sodium acetate infusion in eight control rats, plasma ammonia concentration was 33 ± 26 μmol/L (± SD) and [K+]e remained stable at 4.3 ± 1.6 mmol/L. During ammonium acetate infusion in nine rats, plasma ammonia increased to 594 ± 124 μmol/L at 2 h and to 628 ± 135 μmol/L at 6 h. There was a gradual 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-sulfoximine (150 mg/kg) was infused 3 h before ammonium acetate infusion to inhibit glutamine synthetase. At 2 and 6 h of ammonium acetate infusion, plasma ammonia concentration was 727 ± 228 and 845 ± 326 μmol/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 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+]e and that this impairment is linked to glutamine accumulation rather than ammonium ions per se.