Excitotoxic mechanism of cell swelling in rat cerebral cortical slices treated acutely with ammonia.
Swelling of CNS cells due to endogenous ammonia is a major cause of cerebral oedema in hyperammonaemic encephalopathies. In the present study, incubation in the presence of 5mM ammonium acetate ("ammonia") decreased steady-state distribution of [14C]inulin within incubated rat cerebrocortical minislices, indicating cell swelling. NMDA receptor antagonists, MK-801 ((+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cycloheptene-5,10-imine maleate,10 microM) and DL-AP-5 (DL-2-amino-5-phosphonovaleric acid, 250 microM), a nitric oxide synthase inhibitor, L-nitroarginine (L-NNA, 500 microM), and an antioxidant, taurine (Tau, 10 mM), markedly attenuated the cell volume-increasing effect of ammonia. The effect of Tau (10mM) was abolished by the GABA(A) receptor antagonist bicuculline (100 microM), but was unaffected by the Tau transport inhibitor guanidynoethyl-sulfonate (GES, 500 microM). Ammonia increased the slice content of Gln, an amino acid whose excess accumulation has been implicated in hyperammonemic oedema. However, treatments that reduced the cell volume did not affect Gln content. These results indicate that ammonia-induced cell swelling is in a large degree mediated by overactivation of NMDA receptors and the ensuing generation of NO and free radicals.
Zielińska
Magdalena
M
Department of Neurotoxicology, Medical Research Centre, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland. madziul@cmdik.pan.pl
Law
Robert O
RO
Albrecht
Jan
J
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000641:Ammonia / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D019335:Nitroarginine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013654:Taurine / Q000494:pharmacology
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D013654:Taurine; D019335:Nitroarginine; D016291:Dizocilpine Maleate; D000641:Ammonia; D015763:2-Amino-5-phosphonovalerate