Glutamine inhibits ammonia-induced accumulation of cGMP in rat striatum limiting arginine supply for NO synthesis.
Brain L-glutamine (Gln) accumulation and increased activity of the NO/cGMP pathway are immediate consequences of acute exposure to ammonia. This study tested whether excess Gln may influence NO and/or cGMP synthesis. Intrastriatal administration of the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine or the system A-specific Gln uptake inhibitor methylaminoisobutyrate increased microdialysate Gln concentration and reduced basal and ammonia-induced NO and cGMP accumulation. Gln applied in vivo (via microdialysis) or in vitro (to rat brain cortical slices) reduced NO and cGMP accumulation in the presence and/or absence of ammonia, but not cGMP synthesis induced by the NO donor sodium nitroprusside. Attenuation of cGMP synthesis by Gln was prevented by administration of L-arginine (Arg). The L-arginine co-substrates of y(+)LAT2 transport system, L-leucine and cyclo-leucine, mimicked the effect of exogenous Gln, suggesting that Gln limits Arg supply for NO synthesis by interfering with y+LAT2-mediated Arg uptake across the cell membrane.
Hilgier
Wojciech
W
Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
Freśko
Inez
I
Klemenska
Emilia
E
Beresewicz
Andrzej
A
Oja
Simo S
SS
Saransaari
Pirjo
P
Albrecht
Jan
J
Zielińska
Magdalena
M
D000641:Ammonia / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D002087:Butyrates / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D003980:Diazooxonorleucine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D055664:Electrochemical Techniques / Q000379:methods; D005973:Glutamine / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D058610:Isobutyrates; D008297:Male; D017551:Microdialysis / Q000379:methods; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors
D002087:Butyrates; D058610:Isobutyrates; D003980:Diazooxonorleucine; D005973:Glutamine; D009569:Nitric Oxide; D000641:Ammonia; C020380:isobutyric acid; D001120:Arginine; D006152:Cyclic GMP