The actions of diazepam and diphenylhydantoin on fast and slow Ca²⁺ uptake processes in guinea pig cerebral cortex synaptosomes

The activities of diazepam and diphenylhydantoin as inhibitors of the fast and slow phases of ⁴⁵Ca²⁺ uptake in response to K⁺ depolarization and of [³H]nitrendipine binding were examined in guinea pig cerebral cortex synaptosomes. The slow phase of ⁴⁵Ca²⁺ uptake was abolished in Na⁺-free media (choline substitution) and was more sensitive to inhibition by 3,4-dichlorobenzamil and represents a Na⁺-dependent Ca²⁺ uptake process. The fast component of uptake represents activation of voltage-dependent Ca²⁺ channels. Diazepam (to 300 μM) was selectively active against the fast component of ⁴⁵Ca²⁺ uptake. The benzodiazepines Ro 11-3624 and Ro 11-3128 were similarly selective with a modest stereoselectivity against the fast component of ⁴⁵Ca²⁺ uptake. Diphenylhydantoin (100 and 200 μM) blocked nonselectively both fast and slow phases of Ca²⁺ uptake. Diazepam (60 μM) and diphenylhydantoin (200 μM) blocked [³H]nitrendipine binding in a competitive manner. Diazepam and diphenylhydantoin probably exert at least part of their anticonvulsant activity by inhibition of voltage-dependent Ca2+ channels.