Inhibition of 22Na influx by tricyclic and tetracyclic antidepressants and binding of [3H]imipramine in bovine adrenal medullary cells.
In bovine adrenal medullary cells we investigated the effects of antidepressants on ionic channels and secretion of catecholamines. Tricyclic (imipramine, amitriptyline and nortriptyline) and tetracyclic (maprotiline and mianserin) antidepressants inhibited carbachol-induced influx of 22Na, 45Ca and secretion of catecholamines (IC50, 14-96 microM). Influx of 22Na, 45Ca and secretion of catecholamines due to veratridine also were inhibited by these drugs (IC50, 10-17 microM). However, antidepressants did not suppress high concentration of K-induced 45Ca influx and catecholamine secretion, suggesting that antidepressants do not inhibit voltage-dependent Ca channels. [3H]Imipramine bound specifically to adrenal medullary cells. Binding was saturable, reversible and with two different equilibrium dissociation constants (13.3 and 165.0 microM). Tricyclic and tetracyclic antidepressants competed for the specific binding of [3H]imipramine at the same concentrations as they inhibited 22Na influx caused by carbachol or veratridine. Carbachol, d-tubocurarine, hexamethonium, tetrodotoxin, veratridine and scorpion venom did not inhibit the specific binding of [3H]imipramine. These results suggest that tricyclic and tetracyclic antidepressants bind to two populations of binding sites which are functionally associated with nicotinic receptor-associated ionic channels and with voltage-dependent Na channels, and inhibit Na influx. Inhibition of Na influx leads to the reduction of Ca influx and catecholamine secretion caused by carbachol or veratridine.
Arita
M
M
Department of Pharmacology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
Wada
A
A
Takara
H
H
Izumi
F
F
D000313:Adrenal Medulla / Q000187:drug effects / Q000378:metabolism*; D000639:Amitriptyline / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins; D002395:Catecholamines / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D007099:Imipramine / Q000378:metabolism*; D007700:Kinetics; D008376:Maprotiline / Q000494:pharmacology*; D008803:Mianserin / Q000494:pharmacology*; D009661:Nortriptyline / Q000494:pharmacology*; D011955:Receptors, Drug; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D012979:Sodium Radioisotopes; D013329:Structure-Activity Relationship; D014316:Tritium
D000873:Anthracenes; D002352:Carrier Proteins; D002395:Catecholamines; D011955:Receptors, Drug; D017981:Receptors, Neurotransmitter; D012979:Sodium Radioisotopes; C027775:imipramine receptor; D014316:Tritium; D000639:Amitriptyline; D008803:Mianserin; D008376:Maprotiline; D012964:Sodium; D009661:Nortriptyline; D007099:Imipramine; D002118:Calcium