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

Abstract

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 microM) 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 microM) blocked nonselectively both fast and slow phases of Ca2+ uptake. Diazepam (60 microM) and diphenylhydantoin (200 microM) 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.

Effect of calcium on anxiolytic activity of diazepam and verapamil in rats

“…[10] The possibility of interaction between benzodiazepines and calcium is supported by the fact that benzodiazepines mediate some of their pharmacological actions in nervous system through calcium channels. [1112] The finding that nifedipine blocks the hypnotic effect of flurazepam (a benzodiazepine) is suggestive of benzodiazepines mediating their anxiolytic activity through calcium channels. [11] Unlike at the other sites where nifedipine blocks the entry of calcium by blocking calcium channels, it has paradoxical effect of facilitation of 45 Ca (radioisotope calcium) uptake by rat hippocampal synaptosomes; supposed to be operated by tetrodotoxin-sensitive Na + channels.…”

Iminodipropionitrile‐Induced Dyskinesia in Mice: Striatal Calcium Channel Changes and Sensitivity to Calcium Channel Antagonists

“…Calcium uptake was performed according to the method described by Rampe et al (1986) with some modifications. Synaptosomes from whole brain, cortex, or striatum in 5Kf buffer were incubated for 12 min at 30°C, and 50-pl aliquots were transferred to 450 p1 of 5K' or stimulating buffer (containing 68.5 mM K+ by equimolar substitution of choline chloride), both containing 0.8 pCi of 45Ca2'.…”