cyclic-gmp and guanidinosuccinic-acid

Renal insufficient patients suffer from a variety of complications as direct and indirect consequence of accumulation of retention solutes. Guanidinosuccinic acid (GSA) is an important probable uremic toxin, increased in plasma, urine, cerebrospinal fluid and brain of patients with uremia and supposed to play a role in the pathogenesis of some neurological symptoms. GSA, an NMDA-receptor agonist and GABA-receptor antagonist, is suggested to act as an excitotoxin and shown to be convulsive. The effect of hippocampal (i.h.) GSA injection on behavior and hippocampal volume in mice is presented here. In addition, hippocampal cGMP concentration after systemic injection of GSA was measured. The effect of co-application of NMDA-receptor antagonist CGP37849 with GSA was tested, in vivo, after hippocampal GSA injection and, in vitro, on GSA evoked currents in spinal cord neurons. A significant dose-dependent effect of i.h. injection of GSA on cognitive performance, activity and social exploratory behavior was observed. There was a protective effect of CGP37849 on GSA induced behavioral alterations. Volume of hippocampal cornu ammonis region decreased significantly and dose-dependently after GSA injection. Systemic GSA injection increased cGMP concentration in hippocampal formation. It can be concluded that GSA is an important neurotoxin. As GSA is increased in patients with uremia, it probably contributes to their neurological symptoms. Knowledge of neurotoxic effects and mechanisms of action of GSA and other uremic retention solutes could help in the development of more efficient treatment of uremic patients. Animal models like the 'GSA mouse model' are useful tools for research in this context.

Topics: 2-Amino-5-phosphonovalerate; Animals; Behavior, Animal; Brain Chemistry; Cyclic GMP; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Escape Reaction; Excitatory Amino Acid Antagonists; Exploratory Behavior; Guanidines; Hippocampus; In Vitro Techniques; Maze Learning; Membrane Potentials; Mice; Mice, Inbred C57BL; Neurons; Patch-Clamp Techniques; Psychomotor Performance; Reaction Time; Spinal Cord; Succinates; Time Factors

Using a specific HPLC analysis for guanidines, we find that rat aorta contains guanidino succinate (GS), guanidino acetate (GA), guanidino propionate (GP), guanidino butyrate (GB), methyl guanidine (MG) and guanidine. The concentration of L-arginine (0.05 nmol/mg tissue) is significantly lower than the other guanidines. GS is found to be the most potent vasodilator-guanidine in the rat aorta preparation and this vasodilation depends predominantly on the presence of the endothelium. This effect of GS is antagonized by NG-monomethyl L-arginine (L-NMMA), NW-nitro L-arginine benzyl ester (L-NABA), hemoglobin and by methylene blue, all of which are known to block or attenuate endothelium dependent relaxation. Further, the relaxation mediated by GS is accompanied by the formation of cGMP in the rat aorta. From these results we suggest that GS may be a major endogenous source of EDRF.

Topics: Animals; Aorta; Arginine; Cyclic GMP; Endothelium, Vascular; Glycine; Guanidines; Muscle Relaxation; Nitric Oxide; Propionates; Rats; Succinates