Vinpocetine blockade of sodium channels inhibits the rise in sodium and calcium induced by 4-aminopyridine in synaptosomes

The objective of this study was to get a more understandable picture of the mechanism underlying the anticonvulsant action of vinpocetine. The question of how the cerebral excitability is affected was investigated by determining the effect of vinpocetine on the changes on the internal concentrations of Na+ (Nai) and Ca2+ (Cai) induced by different concentrations of the convulsing agent 4-aminopyridine (4-AP) in striatal isolated nerve endings. The cytosolic concentrations of Nai and Cai were detected fluorimetrically with sodium-binding benzofuran isophthalate (SBFI) and fura-2, respectively. Vinpocetine, like the Na+ channel blocker, tetrodotoxin, abolished the increase in Nai induced by 0.1 mM 4-AP and only inhibited in 30% the rise in Nai induced by 1 mM 4-AP. In contrast with the different sensitivity of the rise in Nai induced by 0.1 and 1 mM 4-AP to vinpocetine and tetrodotoxin, the rise in Cai induced by the two concentrations of 4-AP was markedly inhibited by vinpocetine (and tetrodotoxin), indicating that only the voltage-sensitive sodium channels (VSSC)-mediated fraction of the rise in Nai induced by 4-AP is linked with the activation of pre-synaptic Ca2+ channels. The elevation of Ca2+ induced by high K+ (30 mM) does not require a Na+ gradient and is vinpocetine and tetrodotoxin insensitive. In contrast, the elevation of Cai induced by 4-AP, requires a physiological (out/in) Na+ gradient and is vinpocetine and tetrodotoxin-sensitive. It is concluded that by blocking the tetrodotoxin-sensitive fraction of the rise in Nai induced by 4-AP, vinpocetine inhibits the concomitant rise in Cai induced by 4-AP. The inhibitory effect of vinpocetine on pre-synaptic voltage-sensitive sodium channels may underlie the in vivo anticonvulsant action of vinpocetine.