Sugawara_1998_Fundam.Clin.Pharmacol_12_279

The effects of tacrine and physostigmine on catecholamine secretion induced by veratridine and high K+, and on voltage-dependent Na+ and Ca2+ currents, were investigated in guinea-pig adrenal chromaffin cells. In perfused adrenal glands, tacrine (100 microM) caused an inhibition of veratridine-induced catecholamine secretion, but physostigmine (100 microM) did not. In dispersed cells, both tacrine (1 microM-1 mM) and physostigmine (1 microM-1 mM) decreased catecholamine secretion induced by veratridine in a dose-dependent manner. The inhibitory effect of tacrine was much greater than that of physostigmine. Tacrine alone at a high concentration (such as 1 mM) caused a substantial increase in catecholamine secretion by itself and completely abolished the veratridine-induced secretory response in dispersed cells. High-concentration physostigmine showed a similar effect, but to a much lesser extent. The high K+ (46.2 mM)-evoked catecholamine secretion from dispersed cells was not affected by tacrine (1-100 microM) or physostigmine (1 microM-1 mM). In fura-2 loaded cells, tacrine (100 microM) almost abolished [Ca2+]i rise induced by veratridine, but only slightly reduced that evoked by high K+. In voltage-clamped cells, tacrine (300 microM) depressed the voltage-dependent Na+ and Ca2+ current by about 93% and 69%, and physostigmine (300 microM) depressed them by about 30% and 17%, respectively. These results suggest that tacrine decreases the veratridine-induced catecholamine secretion primarily by inhibiting the voltage-dependent Na+ channels rather than the Ca2+ channels. Physostigmine acts in a manner similar to tacrine, but its potency is much lower than that of tacrine.