title: Protein kinase G is involved in ammonia-induced swelling of astrocytes.
abstract: Ammonia-induced swelling of astrocytes is a primary cause of brain edema associated with acute hepatic encephalopathy. Previous studies have shown that ammonia transiently increases cGMP in brain in vivo and in cultured astrocytes in vitro. We hypothesized that protein kinase G (PKG), an enzyme activated by cGMP and implicated in regulation of cell shape, size, and/or volume in peripheral and CNS cells, may play a role in the ammonia-induced astrocytic volume increase. Treatment of cultured rat cortical astrocytes with 1 or 5 mM NH4Cl (ammonia) for 24 h increased their cell volume by 50% and 80% above control, respectively, as measured by confocal imaging followed by 3D computational analysis. A cGMP analog, 8-(4-chlorophenylthio)-cGMP, increased the cell volume in control cells and potentiated the increase in 1 mM ammonia-treated cells. A soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) abrogated, and a PKG inhibitor [8-(4-chlorophenylthio)-cGMP-thioate, Rp-isomer] dose-dependently reduced the cell volume-increasing effect of 5 mM ammonia. The results suggest that (i) PKG may play a permissive role in ammonia-induced astrocytic swelling and (ii) elevation of brain cGMP associated with acute exposure to ammonia in vivo may aggravate the ensuing brain edema.
authors.affiliation: Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Konopacka
authors.forename: Filip A
authors.initials: FA
authors.lastname: Konopacki
authors.forename: Jan
authors.initials: J
authors.lastname: Albrecht
mesh_terms: D000641:Ammonia / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D001929:Brain Edema / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects; D048429:Cell Size; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D018613:Microscopy, Confocal; D009553:Nimodipine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D013873:Thionucleotides; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D009553:Nimodipine; D000641:Ammonia; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP