Astrocyte swelling in liver failure: role of glutamine and benzodiazepines

We examined the effect of methionine sulfoximine (MSO) and peripheral benzodiazepine (BZD) ligands on ammonia-induced swelling of primary astrocyte cultures. Swelling was completely abolished by co-treatment with MSO, an inhibitor of glutamine synthetase. We also established that many of the effects caused by ammonia, including the reduction in K+ uptake, increase in Cl- uptake and reduction in myo-inositol uptake were diminished by co-treatment with MSO. Agonists of the peripheral-type BZD receptor aggravated ammonia-induced swelling, whereas a peripheral BZD receptor blocker, PK 11195, diminished the extent of swelling. Our findings implicate glutamine and the peripheral-type benzodiazepine receptor in the pathogenesis of the edema associated with fulminant hepatic failure.