Ammonia is a major pathogenic factor in hepatic encephalopathy (HE). Cerebral edema resulting from astrocytic swelling is a major complication of HE. This study addresses a hypothesis linking brain edema to the dysfunction of inwardly rectifying potassium channels ñ the major route of potassium clearance by astrocytes. We measured the effect of thioacetamide (TAA)-induced HE and in vitro treatment of cultured astrocytes with ammonia, on the expression of Kir 4.1, the most common of the channels. Three TAA administrations (250 mg/kg, ip) at 24 h intervals induce liver failure associated with edematous changes in the cerebral cortex. Real-time PCR and Western-blot analysis revealed a markedly decreased expression of Kir4.1 mRNA and protein, respectively, in the cerebral cortex of the TAA-treated rats. Treatment of cerebral cortical astrocytes with 5mM ammonium chloride for 72 h, which induced astrocytic swelling as measured with the [3H]OMG (Kletzien method for cell volume measurement), likewise decreased Kir4.1 expression at the mRNA and protein level. However, a considerable variation has been observed with different preparations used, and the degree of correlation between cell swelling and Kir4.1 expression remains to be established. Treatment of cultured astrocytes with 5 mM glutamine for 72 h reproduced the effects of ammonia on Kir4.1 mRNA expression, adding credence to the current view that the cell swelling-inducing effect of ammonia is mediated by glutamine (Albrecht and Norenberg 2006, Hepatology). Supported by the Ministry of Science and High Education, grant no S005/P-N/2007/01
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