D. Budd, G. May, D. Nicholls
May 1, 1996
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Journal
British Journal of Pharmacology
Abstract
1 . The effects of lifarizine (RS‐87476) on intracellular Ca2+ rises and the release of glutamate from rat cerebrocortical synaptosomes depolarized with 30 mM KCl were investigated by use of entrapped fura 2 and exogenous glutamate dehydrogenase. 2 . Prior (1 min) addition of lifarizine decreased 30 mM KCl‐induced total glutamate release, with 3 μm and 10μm causing 39% and 72% averaged decreases from controls. The calcium‐dependent component of glutamate release (approx. 40% of total) was similarly decreased by 47% and 74%, whereas the calcium‐independent component was decreased by only 32% and 43% respectively. 3 . In parallel experiments with fura‐2‐loaded synaptosomes, lifarizine reduced the depolarization‐induced increases in intracellular [Ca2+], suggesting that this is the means by which the decreases in glutamate release are brought about. Lifarizine inhibited both the plateau and the spike phases of the Ca2+ increases suggesting that, in addition to its known sodium channel blocking properties, it may also inhibit more than one class of calcium channel in the synaptosomes. 4 . Lifarizine at 1 μm and 3 μm also inhibited the rises in intracellular [Ca2+] in rat cultured cortical neurones depolarized with 60 mM KCl. 5 . These effects of lifarizine on intracellular Ca2+ and glutamate exocytosis may contribute to its neuroprotective action.