N-methyl-D-aspartate receptor activation by guanidinosuccinate but not by methylguanidine: behavioural and electrophysiological evidence.
Levels of methylguanidine (MG) and guanidinosuccinate (GSA) are known to be highly increased in uraemic patients. In the present work, the effects of these uraemic guanidino compounds on the excitatory amino acid system were investigated in vivo and in vitro. It was found that convulsions induced by intracerebroventricular GSA injection in mice were antagonized by N-methyl-D-aspartate (NMDA) receptor blockade, whereas those induced by MG were not significantly altered. Application of GSA (between 25 and 10,000 microM) to mouse spinal cord neurones in primary dissociated cell cultures, evoked depolarizing, inward whole-cell currents in a dose-dependent fashion and with reversal potential at 0 mV; MG did not produce such effects. GSA-induced whole-cell currents were caused by NMDA receptor activation since NMDA receptor antagonists (2-amino-5-phosphonovalerate, Mg2+ and ketamine) blocked GSA-evoked whole-cell currents completely and reversibly, whereas co-application of a non-NMDA receptor antagonist (6-cyano-7-nitroquinoxaline-2,3-dione) did not affect GSA-induced current. Evoked field potentials in CA1 region of rat hippocampal slices were completely abolished by GSA, and this effect was antagonized by NMDA receptor blockade. All data were consistent with selective agonist action of GSA upon the NMDA-type glutamate receptor. In view of the results presented here, it should be examined whether NMDA receptors contribute to the neurological complications of renal failure through GSA-induced inappropriate or excessive activation of NMDA receptors.
D'Hooge
R
R
Laboratories of Neurochemistry and Behaviour, University of Antwerp, Belgium.
Raes
A
A
Lebrun
P
P
Diltoer
M
M
Van Bogaert
P P
PP
Manil
J
J
Colin
F
F
De Deyn
P P
PP
D000818:Animals; D002478:Cells, Cultured; D003292:Convulsants / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D008760:Methylguanidine / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects*; D013386:Succinates / Q000494:pharmacology*
D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D006146:Guanidines; D016194:Receptors, N-Methyl-D-Aspartate; D013386:Succinates; D008760:Methylguanidine; C001318:guanidinosuccinic acid