title: Chloride channel blockers inhibit ACTH secretion from mouse pituitary tumor cells.
abstract: The effect of several chemically related chloride channel blocking drugs was investigated on the adrenocorticotropic hormone (ACTH) secretory process in mouse clonal AtT-20 corticotrophs. When cells were simultaneously exposed to diphenylamine-2-carboxylate (DPC) or related substances (Hoechst compounds 131, 143, and 144) and the adenylate cyclase activator forskolin, ACTH secretion was inhibited by 76-95% [half-maximal inhibitory concentration (IC50) 450, 15, 84, and 32 microM, respectively]. All four compounds also blocked forskolin-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) synthesis in AtT-20 cells by 51-87% (IC50 190, 29, 100, and 130 microM for DPC and compounds 131, 143, and 144, respectively). Pertussis toxin pretreatment of cells caused a partial reversal of DPC-inhibited forskolin-stimulated cAMP formation. The toxin had no effect on inhibition of forskolin-stimulated ACTH secretion by DPC. Secretion of ACTH in response to cAMP-independent stimulants such as the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate or the calcium channel agonist BAY K 8644 were blocked by compound 131 as was the secretory response to 8-bromoadenosine 3',5'-cyclic monophosphate. These results suggest that phenylanthranilic acids have adenylate cyclase inhibiting action but that the postcyclase activity is more relevant to the ability of these compounds to block ACTH secretion. DPC also blocked 125I efflux (an index of Cl- secretion) from AtT-20 cells. Because an increase in osmotic strength of the culture media reduced forskolin-stimulated ACTH secretion, these data suggest that DPC and related compounds may negatively modulate chloride-dependent osmotically driven ACTH secretion from AtT-20 cells.
authors.affiliation: Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Heisler
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D018118:Chloride Channels; D005576:Colforsin / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D007473:Ion Channels / Q000502:physiology*; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D009994:Osmolar Concentration; D037342:Pertussis Toxin; D010911:Pituitary Neoplasms / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D018118:Chloride Channels; D007473:Ion Channels; D008565:Membrane Proteins; D010566:Virulence Factors, Bordetella; D062367:ortho-Aminobenzoates; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; C001209:fenamic acid; D037342:Pertussis Toxin; D013755:Tetradecanoylphorbol Acetate