AMMONIA-INDUCED BRAIN EDEMA AND INTRACRANIAL HYPERTENSION IN RATS AFTER PORTACAVAL ANASTOMOSIS

Brain edema, leading to intracranial hypertension and brain herniation , is a major cause of death in fulminant liver failure. Astrocyte swel ling is a prominent neuropathological feature in experimental fulminan t liver failure. It has been postulated that the osmotic effects of gl utamine, generated in astrocytes from ammonia and glutamate in a react ion catalyzed by glutamine synthetase, could mediate brain swelling. N ormal rats and rats that received a portacaval anastomosis were infuse d with ammonium acetate or a sodium acetate control; brain water in ce rebral cortex was measured with the gravimetry method, intracranial pr essure by means of a cisterna magna catheter and cortical amino acids using high-performance liquid chromatography. Although brain edema was detected in both groups receiving ammonia, it was of a greater magnit ude in portacaval anastomosis rats (80.94% + 0.17% vs. 80.24% + 0.09%, p < 0.01), resulting in the development of intracranial hypertension. When portacaval anastomosis rats were infused with ammonium acetate a nd pretreated with 150 mg/kg methionine-sulfoximine, an inhibitor of g lutamine synthetase activity, brain edema was ameliorated and intracra nial pressure did not rise. A dose-dependent reduction in brain glutam ine levels was Seen with increasing doses of methionine-sulfoximine; h owever, brain edema did not decrease beyond the 150 mg/kg dose, sugges ting that the increase in brain water was not solely a result of gluta mine accumulation. We conclude that brain edema of a magnitude that re sults in intracranial hypertension is more likely to develop in rats a fter portacaval anastomosis receiving a continuous ammonia infusion. T he osmotic effects of glutamine appear to mediate, but only in part, t he increase in brain water seen in this preparation. Other mechanisms in addition to inhibition of glutamine synthesis may mediate the benef icial effects of methionine sulfoximine seen in this study.