Butterworth R F, Girard G, Giguère J F
Laboratory of Neurochemistry, André-Viallet Clinical Research Centre, Hôpital Saint-Luc, (Université de Montréal), Quebec, Canada.
J Neurochem. 1988 Aug;51(2):486-90. doi: 10.1111/j.1471-4159.1988.tb01064.x.
Portocaval anastomosis (PCA) in the rat leads, within 4 weeks, to severe liver atrophy, sustained hyperammonemia, and increased brain ammonia. Because brain is not equipped with an effective urea cycle, removal of ammonia involves glutamine synthesis and PCA results in significantly increased brain glutamine. Glutamine synthetase activities, however, are decreased by 15% in cerebral cortex and are unchanged in brainstem of shunted rats. Administration of ammonium acetate to rats following PCA results in severe encephalopathy (loss of righting reflex and, ultimately, coma). Glutamine concentrations in brainstem of comatose rats are increased a further two-fold, whereas those of cerebral cortex are unchanged. Consequently, ammonia levels in cerebral cortex reach disproportionately high levels (of the order of 5 mM). These findings suggest a limitation in the capacity of cerebral cortex to remove additional blood-borne ammonia by glutamine formation following PCA. Such mechanisms may explain the hypersensitivity of rats with PCA and of patients with portal-systemic shunting to small increases of blood ammonia. Disproportionately high levels of brain ammonia in certain regions, such as cerebral cortex, may then result in alterations of inhibitory neurotransmission and, ultimately, loss of cellular (astrocytic) integrity.
大鼠的门腔静脉吻合术（PCA）在4周内会导致严重的肝脏萎缩、持续性高氨血症以及脑内氨含量增加。由于大脑没有有效的尿素循环，氨的清除涉及谷氨酰胺的合成，而PCA会导致脑内谷氨酰胺显著增加。然而，分流大鼠大脑皮层中的谷氨酰胺合成酶活性降低了15%，脑干中的活性则未发生变化。PCA术后给大鼠注射醋酸铵会导致严重的脑病（翻正反射丧失，最终昏迷）。昏迷大鼠脑干中的谷氨酰胺浓度进一步增加了两倍，而大脑皮层中的谷氨酰胺浓度则未改变。因此，大脑皮层中的氨水平达到了极高的比例（约5 mM）。这些发现表明，PCA后大脑皮层通过谷氨酰胺形成清除额外血源性氨的能力存在局限性。这种机制可能解释了PCA大鼠和门体分流患者对血氨小幅升高的超敏反应。某些区域（如大脑皮层）中过高比例的脑氨水平可能会导致抑制性神经传递的改变，最终导致细胞（星形细胞）完整性丧失。
