Guanidino compounds that are increased in hyperargininemia inhibit GABA and glycine responses on mouse neurons in cell culture.
The effects of arginine, homoarginine, alpha-keto-delta-guanidinovaleric acid and argininic acid (guanidino compounds that were found to be increased in hyperargininemia) were evaluated on responses to gamma-aminoburtyric acid (GABA) and glycine (Gly) on mouse neurons in primary dissociated cell culture. GABA and Gly were applied iontophoretically and intracellular microelectrode recording techniques were used. The guanidino compounds rapidly and reversibly inhibited both GABA and Gly responses. The guanidino compounds inhibited GABA responses in a concentration-dependent manner and inhibited Gly responses at a concentration of 10 mM. Argininic acid was the most potent in reducing inhibitory amino acid responses, followed in decreasing potency by alpha-keto-delta-guanidinovaleric acid, homoarginine and arginine. The guanidino compounds were equally potent in decreasing Gly and GABA responses. Co-application of CGS 9896, a benzodiazepine receptor antagonist, did not antagonize the guanidino compound-induced inhibition of GABA responses. These findings suggest that the guanidino compounds inhibited responses to the inhibitory neurotransmitters GABA and Gly by blocking the chloride channel. This effect might underlie the in vivo epileptogenicity of some of the guanidino compounds and might contribute to the pathogenesis of seizures in hyperargininemia.
De Deyn
P P
PP
Department of Neurology, University of Michigan, Ann Arbor 48104.
Marescau
B
B
Macdonald
R L
RL
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood* / Q000494:pharmacology; D002478:Cells, Cultured; D004594:Electrophysiology; D005260:Female; D018756:GABA Antagonists; D005998:Glycine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006146:Guanidines / Q000378:metabolism / Q000494:pharmacology*; D006709:Homoarginine / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D011247:Pregnancy; D011720:Pyrazoles / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D018756:GABA Antagonists; D006146:Guanidines; D011720:Pyrazoles; D006709:Homoarginine; C022249:alpha-keto-delta-guanidinovaleric acid; D005680:gamma-Aminobutyric Acid; C000225:argininic acid; C034704:2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one; D001120:Arginine; D005998:Glycine