Organic calcium channel blockers have been demonstrated to abolish epileptic activity in various experimental models. Furthermore, it was shown that the antiepileptic efficacy of the organic calcium channel blocker verapamil was significantly augmented when the KCl concentration background was elevated to levels normally occurring during epileptic seizures. The aim of the present investigation was to test whether flunarizine, which in contrast to verapamil is able to penetrate the blood brain barrier, suppresses epileptic activity in neocortical slice preparations, and whether this effect would be enhanced by raising the KCl background concentration. Epileptic activity was induced in neocortical slices of guinea pigs by omission of Mg2+ from the superfusate. As a measure of epileptic activity, field potentials were recorded from layers III and V. They appeared within approx 30 min after omission of Mg2+ from the bath solutions. The frequency of occurrence in normal and elevated KCl concentration was 47 +/- 10/5 min and 46 +/- 9/5 min, respectively. Flunarizine, in concentrations of 3.2 and 18 mumol/l, abolished epileptiform activity dose dependently. A 90% depression occurred within 194 +/- 27 and 376 +/- 27 min for flunarizine concentrations of 18 and 3.2 mumol/l, respectively. Elevating the KCl back-ground concentration to 8 mmol/l significantly enhanced the antiepileptic efficacy of flunarizine. Under these conditions, a 90% depression occurred within 67 +/- 14 and 165 +/- 37 min for flunarizine. Under these conditions, a 90% depression occurred within 67 +/- 14 and 165 +/- 37 min for flunarizine concentrations of 18 and 3.2 mumol/l, respectively. The experiments demonstrate that flunarizine suppresses epileptic activity in neocortical preparations, with enhanced action in elevated K+ levels.
Animals Anticonvulsants