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 swelling is a prominent neuropathological feature in experimental fulminant liver failure. It has been postulated that the osmotic effects of glutamine, generated in astrocytes from ammonia and glutamate in a reaction catalyzed by glutamine synthetase, could mediate brain swelling. Normal rats and rats that received a portacaval anastomosis were infused with ammonium acetate or a sodium acetate control; brain water in cerebral cortex was measured with the gravimetry method, intracranial pressure 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 magnitude 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 and pretreated with 150 mg/kg methionine-sulfoximine, an inhibitor of glutamine synthetase activity, brain edema was ameliorated and intracranial pressure did not rise. A dose-dependent reduction in brain glutamine levels was seen with increasing doses of methionine-sulfoximine; however, brain edema did not decrease beyond the 150 mg/kg dose, suggesting that the increase in brain water was not solely a result of glutamine accumulation. We conclude that brain edema of a magnitude that results in intracranial hypertension is more likely to develop in rats after portacaval anastomosis receiving a continuous ammonia infusion. The osmotic effects of glutamine appear to mediate, but only in part, the increase in brain water seen in this preparation.(ABSTRACT TRUNCATED AT 250 WORDS)
Blei
A T
AT
Department of Medicine, Lakeside VA Medical Center, Chicago, IL 60611.
Olafsson
S
S
Therrien
G
G
Butterworth
R F
RF
D000641:Ammonia / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure; D001834:Body Water; D001929:Brain Edema / Q000209:etiology*; D002540:Cerebral Cortex / Q000737:chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000378:metabolism; D005973:Glutamine / Q000096:biosynthesis*; D007427:Intracranial Pressure; D008297:Male; D008717:Methionine Sulfoximine / Q000494:pharmacology; D011167:Portacaval Shunt, Surgical; D011559:Pseudotumor Cerebri / Q000209:etiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D005971:Glutamates; D005973:Glutamine; D008717:Methionine Sulfoximine; D000641:Ammonia