title: Differential inhibition of catecholamine secretion by amitriptyline through blockage of nicotinic receptors, sodium channels, and calcium channels in bovine adrenal chromaffin cells.
abstract: We investigated the effects of amitriptyline, a tricyclic antidepressant, on [3H]norepinephrine ([3H]NE) secretion and ion flux in bovine adrenal chromaffin cells. Amitriptyline inhibited [3H]NE secretion induced by 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) and 70 mM K+. The half maximal inhibitory concentration (IC50) was 2 microM and 9 microM, respectively. Amitriptyline also inhibited the elevation of cytosolic calcium ([Ca2+]i) induced by DMPP and 70 mM K+ with IC50 values of 1.1 microM and 35 microM, respectively. The rises in cytosolic sodium ([Na+]i) and [Ca2+]i induced by the Na+ channel activator veratridine were also inhibited by amitriptyline with IC50 values of 7 microM and 30 microM, respectively. These results suggest that amitriptyline at micromolar concentrations inhibits both voltage-sensitive calcium (VSCCs) and sodium channels (VSSCs). Furthermore, submicromolar concentrations of amitriptyline significantly inhibited DMPP-induced [3H]NE secretion and [Ca2+]i rise, but not veratridine- or 70 mM K+-induced responses, suggesting that nicotinic acetylcholine receptors (nAChR) as well as VSCCs and VSSCs can be targeted by amitriptyline. DMPP-induced [Na+]i rise was much more sensitive to amitriptyline than the veratridine-induced rise, suggesting that the influx of Na+ and Ca2+, through the nAChR itself is blocked by amitriptyline. Receptor binding competition analysis showed that binding of [3H]nicotine to chromaffin cells was significantly affected by amitriptyline at submicromolar concentrations. The data suggest that amitriptyline inhibits catecholamine secretion by blocking nAChR, VSSC, and VSCC.
authors.affiliation: Department of Life Science, Pohang University of Science and Technology, Korea.
authors.forename: T J
authors.initials: TJ
authors.lastname: Park
authors.forename: S Y
authors.initials: SY
authors.lastname: Shin
authors.forename: B C
authors.initials: BC
authors.lastname: Suh
authors.forename: E K
authors.initials: EK
authors.lastname: Suh
authors.forename: I S
authors.initials: IS
authors.lastname: Lee
authors.forename: Y S
authors.initials: YS
authors.lastname: Kim
authors.forename: K T
authors.initials: KT
authors.lastname: Kim
mesh_terms: D000311:Adrenal Glands / Q000166:cytology / Q000378:metabolism*; D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002395:Catecholamines / Q000037:antagonists & inhibitors*; D002417:Cattle; D019439:Chromaffin Cells / Q000378:metabolism*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers; D013997:Time Factors; D014701:Veratridine / Q000494:pharmacology
chemical_list: D000929:Antidepressive Agents, Tricyclic; D002121:Calcium Channel Blockers; D002395:Catecholamines; D018733:Nicotinic Antagonists; D026941:Sodium Channel Blockers; D000639:Amitriptyline; D014701:Veratridine; D012964:Sodium; D002118:Calcium