Peptide YY is an ileocolonic peptide that inhibits meal-stimulated pancreatic secretion when infused in a dose of 400 pmol/kg X h. In this study pancreatic secretion was monitored in response to increasing doses of secretin or cholecystokinin-octapeptide (62.5, 125, 250, and 500 ng/kg X h) during the simultaneous infusion of either saline or peptide YY (400 pmol/kg X h). Peptide YY significantly (p less than 0.05) inhibited the secretory response to the three lowest doses of each pancreatic secretogogue, reducing the bicarbonate response to the 62.5-ng/kg X h dose of secretin by 86% +/- 6% and the protein response to the same dose of cholecystokinin by 57% +/- 16%. In the second limb of the study, the half-life of peptide YY (11.7 +/- 21 min) and the metabolic clearance rate (13.8 +/- 1.6 ml/kg X min) were found to be similar to those of other gastrointestinal hormones. We conclude that inhibition of meal-stimulated pancreatic secretion by peptide YY can be explained by its ability to decrease the responsiveness of the pancreas to endogenous secretogogues.