Elsevier

Neuropharmacology

Volume 35, Issue 2, February 1996, Pages 179-186
Neuropharmacology

(±)-Kavain inhibits the veratridine- and KCl-induced increase in intracellular Ca2+ and glutamate-release of rat cerebrocortical synaptosomes

https://doi.org/10.1016/0028-3908(95)00163-8Get rights and content

Abstract

The action of (±)-kavain on the veratridine, monensin and KCl-depolarization evoked increase in free cytosolic Ca2− concentration ([Ca2+]i), and its influence on the release of endogenous glutamate from rat cerebrocortical synaptosomes were investigated. [Ca2+]i was fluorimetrically determined employing FURA as the Ca2+ sensitive fluorophore, and glutamate was detected by a continuous enzyme-linked fluorimetric assay. The incubation of synaptosomes in the presence of (±)-kavain up to a concentration of 500 μmol/l affected neither basal [Ca2+]i nor spontaneous release of glutamate, but dose-dependently reduced both veratridineelevated [Ca2+]i (IC50 = 63.2 μmol/l) and glutamate-release (IC50 = 116.4 μmol/l). The inhibition of these parameters, attained with 500 μmol/l (±)-kavain, could be overcome by inducing an artificial Na+ influx, using monensin as a Na+ ionophore. An application of (±)-kavain after veratridine caused a decrease in veratridineelevated [Ca2+]i, which was similar to the action of tetrodotoxin (TTX) with regard to time course, half-life of [Ca2+]i decline and the final steady state level of [Ca2+]i. Concomitantly, veratridine-induced glutamate-release was blocked. The results indicate that specific inhibition of voltage-dependent Na+ channels is a primary target of (±)-kavain, thus preventing a [Na+]i provoked increase in [Ca2+]i and glutamate-release. However, pathways related to the elevation of [Ca2+]i by [Na+]i itself, and the processes involved in normalization of elevated [Ca2+]i and glutamate-release downstream to enhanced [Ca2+]i, seems to be unaffected by (±)-kavain. Using KCl-depolarized synaptosomes, 400 μmol/l (±)-kavain reduced, in analogy to Aga-GI toxin, KCl-evoked [Ca2+]i and diminished the part of glutamate-exocytosis which is related to external Ca2+ to about 75% of control. At a concentration of 150 μmol/l, which is above the IC50 value necessary to block voltagedependent Na+ channels, (±)-kavain affected neither basal nor the KCl-induced increase in [Ca2+]i. These results might suggest that (±)-kavain at concentrations sufficient to block Na+ channels completely, moderately inhibits the non-inactivating Ca2+ channels located on mammalian presynaptic nerve endings.

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