(+/-)-Kavain inhibits veratridine-activated voltage-dependent Na(+)-channels in synaptosomes prepared from rat cerebral cortex.

Kava pyrones are pharmacologically active compounds extracted from Piper methysticum Forst. Because kava pyrones were characterized by their anticonvulsive, analgesic and centrally muscle relaxing action, we investigated the influence of (+/-)-kavain, a synthetic kava pyrone, on veratridine-stimulated increase in intrasynaptosomal Na+ concentration ([Na+]i) of rat cerebrocortical synaptosomes. [Na+]i was measured spectrofluorometrically employing SBFI as Na+ sensitive fluorescence dye. Veratridine (5 mumol/I) enhanced basal [Na+]i 6.6-fold from 11.3 to 74.1 mmol/l Na+. Incubation of synaptosomes for 100 sec with (+/-)-kavain was sufficient to reduce dose dependently the stimulated increase of [Na+]i with an IC50 value of 86.0 mumol/l, and almost complete inhibition of Na(+)-channels was attained with 400 mumol/l) reduced veratridine-elevated [Na+]i to 30.4% and 7.9% of control whereas the centrally acting muscle relaxant mephenesin (400 mumol/l) was without any effect. Postapplication of 400 mumol/l (+/-)-kavain or 10 mumol/l TTX immediately diminished veratridine-elevated [Na+]i to nearly basal levels with a half life time of 69.7 and 41.8 sec, respectively. To study the influence of (+/-)-kavain on non stimulated synaptosomes, an increase in [Na+]i was induced by 200 mumol/l ouabain, which enhanced [Na+]i hyperbolically with an initial rate of 18.4 mmol Na+/l min. Preincubation of synaptosomes with 400 mumol/l (+/-)-kavain or 10 mumol/l TTX partly prevented Na(+)-influx for both compounds to the same extent of about 57% of control. The presented data indicate a fast and specific inhibition of voltage-dependent Na(+)-channels by (+/-)-kavain.