Inhibitory effects of tacrine and physostigmine on catecholamine secretion and membrane currents in guinea-pig adrenal chromaffin cells.
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.
Sugawara
T
T
Laboratory of Pharmacology, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan.
Kitamura
N
N
Ohta
T
T
Ito
S
S
Nakazato
Y
Y
D000311:Adrenal Glands / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D019439:Chromaffin Cells / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010830:Physostigmine / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D013619:Tacrine / Q000494:pharmacology*; D014701:Veratridine / Q000037:antagonists & inhibitors / Q000494:pharmacology
D002395:Catecholamines; D002800:Cholinesterase Inhibitors; D007473:Ion Channels; D013619:Tacrine; D014701:Veratridine; D012964:Sodium; D010830:Physostigmine; D011188:Potassium; D002118:Calcium