Anti- and proconvulsive actions of levcromakalim, an opener of ATP-sensitive K+ channel, in the model of hippocampus-generating partial seizures in rats.
We assessed the effect of an opener of ATP-sensitive K+ channel, levcromakalim (BRL 38227, (-)6-cyano-3,4-dihydro-2, 2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl)-2H-1-benzopyran-3-ol) on seizure threshold and severity of the hippocampus-generating partial seizures in rats. For comparison, an ATP-sensitive K+ channel blocker, glibenclamide; K+ channel blocker, tetraethylammonium; Ca2+ channel antagonist, nimodipine and Ca2+ channel agonist, (+/-)-BAY K 8644 (1,4-dihydro-2, 6-dimethyl-5-nitro-4-[2-(trifluoromethyl)-phenyl]-3-pyridinecarboxyli c acid methyl ester) were also examined. Seizure threshold was determined using pulse number threshold and seizure severity was ascertained using afterdischarge duration. Levcromakalim decreased afterdischarge duration at 10 nmol i.c.v. and decreased pulse number threshold at 100 nmol i.c.v. Tetraethylammonium at 10 nmol i.c.v. increased afterdischarge duration selectively and at 100 nmol i.c.v. induced spontaneous seizures. Glibenclamide (1-100 nmol i.c.v.) failed to change pulse number threshold and afterdischarge duration. Nimodipine (40 mg/kg i.p.) decreased afterdischarge duration and pulse number threshold. BAY K 8644 (1 mg/kg i.p.) decreased pulse number threshold and increased afterdischarge duration. In addition, voltage-clamp recording from neuroblastoma x glioma hybrid cells indicates that levcromakalim inhibited the fast component of Ca(2+)-dependent K+ currents, in addition to the inhibition of T- and L-types of voltage-dependent Ca2+ currents reported (Ito et al., FEBS Lett. 262, 313, 1990). These results suggest that levcromakalim shows anti- and proconvulsive actions in the hippocampus-generating partial seizures in rats and these effects might be, at least partly, caused by inhibiting Ca2+ channel and Ca(2+)-dependent K+ channel, respectively.
Katsumori
H
H
National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
Ito
Y
Y
Higashida
H
H
Hashii
M
M
Minabe
Y
Y
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000494:pharmacology*; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003292:Convulsants / Q000008:administration & dosage / Q000494:pharmacology*; D019806:Cromakalim; D018891:Dentate Gyrus / Q000502:physiology; D004558:Electric Stimulation; D004569:Electroencephalography / Q000187:drug effects; D004828:Epilepsies, Partial / Q000503:physiopathology*; D005905:Glyburide / Q000494:pharmacology; D006624:Hippocampus / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000927:Anticonvulsants; D001578:Benzopyrans; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D003292:Convulsants; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D011758:Pyrroles; D013757:Tetraethylammonium Compounds; D019806:Cromakalim; D000255:Adenosine Triphosphate; D005905:Glyburide