title: Hyperammonemia inhibits the natriuretic peptide receptor 2 (NPR-2)-mediated cyclic GMP synthesis in the astrocytic compartment of rat cerebral cortex slices.
abstract: The decrease of cyclic GMP (cGMP) level in the brain, contributing to cognitive and memory deficit in hyperammonemia (HA), has been attributed to the interference of ammonia with the NMDA/nitric oxide/soluble guanylate cyclase (GC)/cGMP pathway in neurons. The present study tested the hypotheses that (a) HA also affects cGMP synthesis elicited by stimulation of the natriuretic peptide receptor 2 (NPR-2) with its natural ligand, C-type natriuretic peptide (CNP) and (b) the latter effect may involve astrocytes, the ammonia-sensitive cells. In the cerebral cortical slices of control rats, CNP stimulated cGMP synthesis in a degree comparable to the NO donor, S-nitroso-N-acetylpenicillamine (SNAP) used at an optimal concentration. Fluoroacetate (FA), a metabolic inhibitor specifically affecting astrocytic mitochondria, inhibited the CNP-dependent cGMP synthesis by about 50%. Ammonium acetate-induced HA decreased by 68% the CNP-dependent cGMP generation in slices incubated in the absence of FA. In slices incubated in the presence of FA, cGMP synthesis in slices derived from HA rats did not differ from that in control slices. The results indicate that HA inhibits CNP-dependent cGMP synthesis in the FA-vulnerable, astrocytic compartment, but not in the FA-resistant compartment(s) of the brain. HA did not affect the expression of NPR-2 mRNA in the cerebral cortex tissue as tested using real-time PCR, indicating that the effect of ammonia involves as yet unidentified events occurring posttranscriptionally. Deregulation of NPR-2 function in astrocytes by ammonia may contribute to neurophysiological symptoms of HA.
authors.affiliation: Department of Neurotoxicology, Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zielińska
authors.forename: Inez
authors.initials: I
authors.lastname: Fresko
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Konopacka
authors.forename: Vicente
authors.initials: V
authors.lastname: Felipo
authors.forename: Jan
authors.initials: J
authors.lastname: Albrecht
mesh_terms: D000085:Acetates; D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D004195:Disease Models, Animal; D005463:Fluoroacetates / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D022124:Hyperammonemia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D000085:Acetates; D000154:Aconitate Hydratase; D006152:Cyclic GMP; D005463:Fluoroacetates; D006162:Guanylate Cyclase; D020098:Natriuretic Peptide, C-Type; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D017461:Receptors, Atrial Natriuretic Factor; D026423:S-Nitroso-N-Acetylpenicillamine; D000099242:Atrial Natriuretic Factor Receptor B; C014815:fluoroacetic acid; C018824:ammonium acetate