Abstract

Treatment of cultured bovine adrenal medullary cells with carbamazepine (CBZ) for 5 days caused an increase in catecholamine secretion induced by veratridine, an activator of voltage-dependent Na⁺channels. However, no increase was stimulated by carbachol, an agonist of nicotinic receptors, or by 56 mM K⁺, a depolarizing agent that activates voltage-dependent Ca⁺⁺ channels. CBZ (30 μg/ml) treatment enhanced veratridine-induced catecholamine secretion in a time-dependent manner (increases of 25%, 65% and 70% for 3, 5 and 7 days of treatment, respectively). CBZ treatment (5 days) increased veratridine-induced catecholamine secretion in a concentration-dependent manner (increases of 27%, 36%, 45% and 55% at 10, 15, 20 and 30 μg/ml of CBZ, respectively). CBZ treatment also increased ²²Na⁺ influx and⁴⁵Ca⁺⁺ influx stimulated by veratridine. The stimulatory effect of CBZ treatment on catecholamine secretion was blocked by either actinomycin D or cycloheximide, an inhibitor of protein synthesis. Additive responses of catecholamine secretion and²²Na⁺ influx induced by veratridine were associated with combined exposure of the cells to CBZ and dibutyryl cyclic AMP. CBZ treatment (30 μg/ml, 5 days) significantly increased the specific binding of [³H]saxitoxin to cell membranes. A Scatchard analysis of [³H]saxitoxin binding revealed that CBZ increased the B_max value without any change in the dissociation constant. These findings suggest that CBZ up-regulates the density and activity of voltage-dependent Na⁺ channels.