Guanidino compounds that are increased in cerebrospinal fluid and brain of uremic patients inhibit GABA and glycine responses on mouse neurons in cell culture.
Four guanidino compounds that have been found to be markedly increased in cerebrospinal fluid and brain tissue of uremic patients, namely, guanidine, methylguanidine, creatinine, and guanidinosuccinic acid, were applied to mouse spinal cord neurons in primary dissociated cell culture to evaluate their effects on postsynaptic responses to gamma-aminobutyric acid (GABA) and glycine. Intracellular microelectrode recording techniques were used. Guanidine, methylguanidine, creatine, and guanidinosuccinic acid reversibly and in a dose-dependent manner inhibited both GABA and glycine responses. Guanidinosuccinic acid was the most potent inhibitor of the amino acid responses, followed in decreasing potency by methylguanidine, guanidine, and creatinine. Guanidinosuccinic acid inhibited responses to GABA and glycine, at concentrations similar to those found in cerebrospinal fluid and brain tissue of patients with terminal renal insufficiency. The other guanidino compounds tested exerted their effects only at concentrations higher than those found in uremic biological fluids and tissues. The inhibitory effect of guanidine and methylguanidine on responses to GABA was additive. The effect of the guanidino compounds on GABA responses was not antagonized by coapplication of the benzodiazepine-receptor antagonist CGS 9896. The results suggest that guanidine, methylguanidine, creatinine, and guanidinosuccinic acid inhibited responses to the inhibitory neurotransmitters GABA and glycine by blocking the chloride channel. The observed action of the studied guanidino compounds might contribute to the pathogenesis of the complex neurological symptomatology encountered in uremia.
De Deyn
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PP
Department of Neurology, University of Michigan Medical Center, Ann Arbor.
Macdonald
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RL
D000818:Animals; D001923:Brain Chemistry; D002478:Cells, Cultured; D003404:Creatinine / Q000494:pharmacology; D004357:Drug Synergism; D018756:GABA Antagonists; D005998:Glycine / Q000037:antagonists & inhibitors*; D019791:Guanidine; D006146:Guanidines / Q000032:analysis / Q000494:pharmacology*; D008760:Methylguanidine / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000196:embryology; D013386:Succinates / Q000494:pharmacology; D014511:Uremia / Q000134:cerebrospinal fluid / Q000378:metabolism*
D018756:GABA Antagonists; D006146:Guanidines; D011720:Pyrazoles; D013386:Succinates; D008760:Methylguanidine; C001318:guanidinosuccinic acid; C034704:2-(4-chlorophenyl)-2,5-dihydropyrazolo(4,3-c)quinoline-3(3H)-one; D003404:Creatinine; D019791:Guanidine; D005998:Glycine