CARBAMAZEPINE-INDUCED UP-REGULATION OF VOLTAGE-DEPENDENT NA-MEDULLARYCELLS IN CULTURE( CHANNELS IN BOVINE ADRENAL)

Treatment of cultured bovine adrenal medullary cells with carbamazepin e (CBZ) for 5 days caused an increase in catecholamine secretion induc ed by veratridine, an activator of voltage-dependent Na+ channels. How ever, no increase was stimulated by carbachol, an agonist of nicotinic receptors, or by 56 mM K+, a depolarizing agent that activates voltag e-dependent Ca++ channels. CBZ (30 mu g/ml) treatment enhanced veratri dine-induced catecholamine secretion in a time-dependent manner (incre ases of 25%, 65% and 70% for 3, 5 and 7 days of treatment, respectivel y). 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 mu g/ml of CBZ, respectively). CBZ t reatment also increased Na-22(+) influx and Ca-45(++) influx stimulate d by veratridine. The stimulatory effect of CBZ treatment on catechola mine secretion was blocked by either actinomycin D or cycloheximide, a n inhibitor of protein synthesis. Additive responses of catecholamine secretion and Na-22(+) influx;induced by veratridine were associated w ith combined exposure of the cells to CBZ and dibutyryl cyclic AMP. CB Z treatment (30 mu g/ml, 5 days) significantly increased the specific binding of [H-3]saxitoxin to cell membranes. A Scatchard analysis of [ H-3]saxitoxin binding revealed that CBZ increased the B-max value with out any change in the dissociation constant. These findings suggest th at CBZ up-regulates the density and activity of voltage-dependent Nachannels.