It is generally accepted that peptide-YY (PYY), an ileocolonic peptide, is released by luminal nutrients and exogenous cholecystokinin (CCK). The importance of luminal nutrients as major PYY releasers was recently challenged when significant increases in plasma PYY were observed in response to pancreatic juice diversion in rats free of luminal nutrients. These recent data raise questions concerning the potential mediators of PYY release. This study was undertaken therefore to determine the role of endogenous CCK and the effects of exogenous caerulein, secretin and bombesin on PYY release. Male Wistar rats prepared with pancreatic, biliary, duodenal and jugular vein cannulae were used 4-7 days postoperatively. Pancreatic juice diversion significantly increased pancreatic volume and protein output with concomitant increases in plasma CCK and PYY concentrations. During pancreatic juice diversion, infusion of MK-329, a CCK-receptor antagonist, did not affect CCK release but completely abolished pancreatic volume and protein output and PYY release. The intraduodenal infusion of SBTI significantly stimulated pancreatic secretion and CCK release without any effect on PYY release. Furthermore, infusions of the CCK analog, caerulein, secretin and bombesin had no effect on PYY release. These results suggest the involvement of endogenous CCK in PYY release but this mediation seems to necessitate the participation of other as yet unknown factors since exogenous caerulein, secretin or bombesin cannot induce PYY release when given alone.