DISSIMILAR EFFECTS OF THE PROTEIN-KINASE-C INHIBITORS, STAUROSPORINE AND H-7, ON CHOLECYSTOKININ-INDUCED ENZYME-SECRETION FROM RABBIT PANCREATIC ACINI

The effects of two putative inhibitors of protein kinase C activity, staurosporine and H‐7, on partially purified protein kinase C and amylase secretion from isolated rabbit pancreatic acini were investigated. Staurosporine dose‐dependently inhibited amylase release stimulated by an optimal concentration of cholecystokinin C‐terminal octapeptide. At a concentration of 100 nM, the drug inhibited the secretory response to the secretagogue by approximately 50%. At the same concentration, staurosporine inhibited 12‐O‐tetradecanoylphorbol 13‐acetatestimulated enzyme secretion by 90%. Moreover, the potentiating effect of this phorbol ester on cholecystokinin‐induced amylase release was completely abolished in the presence of staurosporine. Interestingly, amylase release was decreased to the level observed with the combination of cholecystokinin and staurosporine. In contrast, H‐7, potentiated rather than inhibited cholecystokinin‐stimulated enzyme secretion, whereas the secretory response to 12‐O‐tetradecanoylphorbol 13‐acetate was not affected by the drug. Both staurosporine and H‐7, however, inhibited protein kinase C purified from exocrine pancreatic tissue. Kinetic analysis revealed that both compounds inhibited protein kinase C competitively with respect to ATP. The Ki value for staurosporine was 0.55 nM and for H‐7 13.5 μM. Our results obtained with staurosporine are in line with a stimulatory role of protein kinase C in cholecystokinin‐induced enzyme secretion from the exocrine pancreas. The results obtained with H‐7 emphasize that care has to be taken in interpreting the biological effects of this drug. Copyright © 1990, Wiley Blackwell. All rights reserved