The effect of the desglycinyl metabolite of remacemide hydrochloride (FPL 12495AA) and dizocilpine (MK-801) on endogenous amino acid release from mouse cortex.
1. In this study the effect of FPL 12495AA, the desglycinyl metabolite of remacemide hydrochloride and dizocilpine (MK-801), on potassium- and veratridine-stimulated release of neurotransmitter amino acids from mouse cortical slices was investigated. 2. Veratridine (20 microM) and potassium (60 mM) produced a preferential release of glutamate and aspartate. Potassium-stimulated release was calcium-dependent, while veratridine-stimulated release was only partially affected by removal of calcium from the medium. 3. FPL 12495AA significantly inhibited veratridine- and potassium-stimulated release of glutamate and aspartate. Lower concentrations of FPL 12495AA were needed to inhibit veratridine-stimulated release of glutamate (12.5 microM) than potassium-stimulated release (100 microM). 4. Dizocilpine significantly inhibited veratridine- and potassium-stimulated release of glutamate and aspartate at concentrations of 100 microM and above. 5. FPL 12495AA and dizocilpine both have an affinity for the ion channel subsite of the N-methyl-D-aspartate (NMDA) receptor. The reduction of potassium-stimulated release of glutamate and aspartate by FPL 12495AA and dizocilpine is probably due to NMDA receptor blockade. 6. FPL 12495AA inhibited veratridine-stimulated release at a concentration of 12.5 microM while dizocilpine was effective only at a concentration of 100 microM. This difference in efficacy is probably due to the higher affinity of FPL 12495AA compared to dizocilpine at the veratridine-binding site on the sodium channel.
Srinivasan
J
J
Department of Pharmacology and Therapeutics, University of Wales College of Medicine, Heath Park, Cardiff.
Richens
A
A
Davies
J A
JA
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001224:Aspartic Acid / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010627:Phenethylamines / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
D000081:Acetamides; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D010627:Phenethylamines; C089135:FPL 12495; D001224:Aspartic Acid; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D014701:Veratridine; C067553:remacemide; D011188:Potassium