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4-Acetamido-4' -Isothiocy anostilbene-2,2' -Disulfonic Acid Inhibits Adrenocorticotropin Secretion from Anterior Pituitary Cells^*

Unité de Biorégulation Cellulaire, Centre Hospitalier de I'Université Laval Sainte-Foy, Quebec, Canada G1V4G2

Address all correspondence and requests for reprints to: Dr. Seymour Heisler, Unité de Biorégulation Cellulaire, Centre Hospitalier de I'Université Laval, 2705 boulevard Laurier, Local S-110, Sainte-Foy Quebec, Canada GlV 4G2.

Abstract

Mouse clonal ACTH-secreting corticotrophs (AtT-20 cells) possess a membrane Ca²⁺activated Cl^– conductance which is partially blocked by the disulfonic stilbene derivative 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS). In the current study the effect of SITS on the ACTH secretory process was evaluated. SITS markedly blocked basal and forskolin-stimulated ACTH secretion from AtT-20 cells (IC₅₀ = 2.7 x 10^–4 M). Both CRF-induced ACTH secretion and forskolin-stimulated GH secretion from acutely dispersed rat anterior pituitary cells were inhibited by SITS (IC₅₀ = 2.4 and 1.3 x 10^–4 M, respectively). SITS did not alter unstimulated or forskolin-elicited cAMP synthesis in AtT-20 cells, and in fact, could inhibit ACTH secretion in response to cAMP-independent agonists such as the calcium channel activator BAY-K-8644 or the protein kinase-C activator 12-tetradecanoyl-phorbol-13-acetate (IC60 = 2.6 and 2.4 x 10^–4 M, respectively). SITS did not alter the secretion of amylase from isolated exocrine pancreatic acinar cells. Its action was also fully reversible; after its removal from the incubation medium, cells secreted ACTH without a change in response to forskolin activation. Increasing extracellular Ca²⁺ or the addition of up to 10^–3 M tetraethylammonium or 4-aminopyridine did not reverse the inhibitory pattern of SITS action, suggesting that its inhibitory effect is most likely not due to hyperpolarization of AtT-20 cell membranes. The inability of amiloride to inhibit ACTH secretion further suggests that inhibition of ACTH secretion provoked by SITS is not due to a blockade of C1^–HC0₃^– exchange. On the other hand, SITS was able to block 44% of basal ³⁶C1 uptake by AtT-20 cells. Exchange of incubation medium chloride for gluconate or a reduction in the osmotic strength of the medium reduced both basal and secretagogue-stimulated ACTH secretion. The data suggest that SITS may modulate chloride-dependent, osmotically driven secretion from AtT-20 cells.

Footnotes

^* This work was supported by grants from the Cystic Fibrosis Foundation of Canada and the Medical Research Council of Canada.

Received April 17, 1989.