THE DIACYLGLYCEROL KINASE INHIBITOR, R59022, POTENTIATES CHOLECYSTOKININ-INDUCED ENZYME-SECRETION FROM RABBIT PANCREATIC ACINI

The putative inhibitor of diacylglycerol kinase activity, 6‐{2‐[(4‐fluorophenyl)phenylmethylene]‐1‐piperidinyl}‐ethyl‐7‐methyl‐5H‐thiazolo[3,2‐a]pyrimidin‐5‐one (R59022), markedly potentiated cholecystokinin‐C‐terminal‐octapeptide(CCK‐8‐)stimulated enzyme secretion from isolated rabbit pancreatic acini. Maximal potentiation occurred when acini were stimulated in the presence of 5–10 μM R59022. Potentiation depended both on the concentration of R59022 and CCK‐8. No potentiation was observed when acini were half‐maximally stimulated, whereas the secretory response to maximal and supramaximal concentrations of secretagogue was increased by 50–60%. R59022 alone had no effect on basal enzyme secretion and the drug did not potentiate the secretory response to the Ca2+ ionophore A23187 or to the phorbol ester, 12‐O‐tetradecanoylphorbol 13‐acetate. Moreover, no increase in basal secretion was observed when acini were incubated in the presence of both R59022 and forskolin. These observations strongly suggest that receptor‐mediated activation of the inositol phospholipid pathway is required for R59022‐induced potentiation. R59022‐inhibited the CCK‐8‐stimulated incorporation of 32Pi into phosphatidic acid dose dependently, without affecting the CCK‐8‐stimulated hydrolysis of 32P‐labelled phosphatidylinositol 4,5‐bisphosphate. This is consistent with an inhibitory effect of R59022 on acinar cell diacylglycerol kinase activity. The potentiating effect of R59022 was mimicked by 12‐O‐tetradecanoylphorbol 13‐acetate added simultaneously with CCK‐8. Therefore, it is concluded that in the presence of 5–10 μM R59022 the receptor‐mediated increase in acinar cell diacylglycerol content is enhanced leading to enhanced activation of protein kinase C and to potentiation of the secretory response. The fact that the secretory response to maximal and supramaximal concentrations of CCK‐8 is potentiated by R59022 suggests that at these concentrations of secretagogue the diacylglycerol protein kinase C branch of the signal‐transduction route is rate‐limiting. Copyright © 1990, Wiley Blackwell. All rights reserved