Tacrine inhibits nicotinic secretory and current responses in adrenal chromaffin cells.

Tacrine enhanced acetylcholine-induced catecholamine secretion with a concentration of up to 10 microM, but inhibited it at over 10 microM in perfused adrenal glands. Qualitatively the same result was obtained with physostigmine. Both tacrine and physostigmine only inhibited the secretory responses to carbachol and/or nicotine in perfused glands and dispersed chromaffin cells. Acetylcholinesterase activity of adrenal homogenates was inhibited by tacrine and physostigmine in a concentration-dependent manner. In whole-cell patch-clamp experiments, tacrine and physostigmine caused reversible inhibition of nicotine-evoked inward currents with a dose range similar to that for the inhibitory action on the secretory response. These results suggest that the enhancing effect of tacrine and physostigmine on acetylcholine-induced catecholamine secretion results from the prevention of enzymatic hydrolysis of acetylcholine in adrenal glands and that the inhibitory effect is due to the inhibition of nicotinic receptor-mediated membrane currents in adrenal chromaffin cells.