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Introduction Dibutyltin dichloride (DBTC) is widely used as a stabilizer for polyvinylchloride plastics and is of particular toxicologic interest. Aim To examine the effects of DBTC on pancreatic exocrine function in isolated rat pancreatic acini. Methodology Isolated rat pancreatic acini were incubated with various secretagogues in the presence or absence of DBTC. We investigated the effects of DBTC on amylase release, receptor binding, and protein kinase C (PKC) enzyme activity. Results DBTC reduced cholecystokinin octapeptide (CCK-8)–stimulated and carbamylcholine-stimulated amylase release and the binding of [125I]CCK-8 to isolated rat pancreatic acini. Conversely, DBTC potentiated secretin-stimulated amylase release, although it slightly inhibited [125I]secretin binding to its receptors. In addition, DBTC potentiated amylase release stimulated by vasoactive intestinal peptide, 8-bromoadenosine 3´, 5´-monophosphate (8Br-cAMP) or calcium ionophore A23187, whereas it had no influence on amylase release stimulated by 12-O-tetradecanoylphorbol 13-acetate. The protein kinase C (PKC) inhibitor calphostin C abolished the DBTC-induced potentiation of amylase release stimulated by 8Br-cAMP or A23187. Moreover, DBTC caused a significant translocation of PKC enzyme activity from cytosol to membrane fraction. Conclusions These results indicate that DBTC reduces CCK-8- and carbamylcholine-stimulated amylase release by inhibiting their receptor bindings to pancreatic acini, whereas it potentiates cAMP-mediated amylase release by activating PKC in isolated rat pancreatic acini.

Biochemical and pharmacologic characteristics of a newly developed benzodiazepine derivative (S)-N-[1-(2-fluorophenyl)-3,4, 6,7-tetrahydro-4-oxo-pyrrolo-[3,2,1-jk] [1,4]benzodiazepine-3-yl]-1H-indole-2-carboxamide (FK480) as a cholecystokinin (CCK) receptor antagonist were examined in the isolated rat pancreatic acini and compared with those of MK-329 and loxiglumide. FK480, MK-329, and loxiglumide inhibited CCK octapeptide (CCK-8)-stimulated amylase release and binding of [125I]CCK-8 in a concentration-dependent manner, with a half-maximal inhibition (ID50) at 1.30 +/- 0.12 nM, 1.33 +/- 0.21 nM, and 1.27 +/- 0.23 microM, respectively, for amylase release, and 0.40 +/- 0.06 nM, 0.68 +/- 0.08 nM, and 0.38 +/- 0.03 microM, respectively, for [125I]CCK-8 binding. The antagonism was competitive in nature because these three compounds caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase secretion, without altering the maximal increase. The antagonism produced by FK480 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. FK480 not only prevented but also reversed CCK-8-stimulated amylase release. This compound caused a residual inhibition of the action of CCK-8. When acini were preincubated with 100 nM FK480 for 30 min, the subsequent dose-response curve to CCK-8 was shifted 10-fold toward higher concentration. Similar results were obtained with MK-329 but not with loxiglumide. FK480 appeared to be bound to the receptors on acinar cells in a slowly dissociating state.(ABSTRACT TRUNCATED AT 250 WORDS)