Inhibitory effects of tacrine and physostigmine on catecholamine secretion and membrane currents in guinea‐pig adrenal chromaffin cells

Summary— 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 μM) caused an inhibition of veratridine‐induced catecholamine secretion, but physostigmine (100 μM) did not. In dispersed cells, both tacrine (1 μM‐1 mM) and physostigmine (1 μM‐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 μM) or physostigmine (1 μM‐1 mM). In fura‐2 loaded cells, tacrine (100 μM) almost abolished [Ca2+]i rise induced by veratridine, but only slightly reduced that evoked by high K+. In voltage‐clamped cells, tacrine (300 μM) depressed the voltage‐dependent Na+ and Ca2+ currents by about 93% and 69%, and physostigmine (300 μM) 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.