Intracerebroventricular injection of ethacrynic acid induces status epilepticus

The intracerebroventricular (i.c.v.) injection of ethacrynic acid to mice at a dose of more than 25 micrograms induced repeated tonic-clonic convulsions with subsequent death. Ethacrynic acid was more potent than other loop diuretics such as furosemide and bumetanide. Diazepam and 2-amino-5-phosphonovaleric acid notably reduced both the incidence of convulsion and the lethality seen after ethacrynic acid administration. Both phenobarbital and ketamine suppressed the incidence of convulsions but not the lethality. Without effects on the incidence of convulsions or lethality, dextromethorphan prolonged, while phenytoin or atropine shortened, the time to the onset of convulsion. Neither ethosuximide, carbamazepine, nor muscimol had a significant effect on the responses to ethacrynic acid. The present findings indicate that i.c.v. injected ethacrynic acid shows strong convulsive activity, probably due to impairment of Cl- transport processes, concomitant with enhancement of excitatory amino acid activity in the brain.