BACKGROUND Peptide YY (PYY) given intravenously was shown to inhibit pancreatic exocrine secretion both in the dog and the rat. However, a possible physiological role of PYY on the pancreatic secretion has not been clarified. The present study was undertaken to investigate its physiological role on the exocrine pancreas. METHODS In conscious rats, plasma PYY was determined in response to oral ingestion of a 6-mL meal and intravenous infusion of PYY; small intestinal transit time was measured by phenol red as a nonabsorbable marker, and pancreatic secretory studies were performed in rats with pancreatic fistulas and jugular vein catheters. RESULTS Oral ingestion of the meal (containing phenol red, 1.6 mg/100 mL) significantly increased plasma PYY within 30 minutes. During this period, most (97%) of the phenol red was detected in the proximal two-thirds of the small intestine. Intravenous infusion of PYY in 25, 50, and 100 pmol.kg-1 x h-1 produced a dose-dependent increase in plasma PYY. The dose of PYY that simulated the peak postprandial level was 50 pmol.kg-1 x h-1, and this dose of PYY significantly inhibited the pancreatic secretion stimulated by physiological doses of secretin and cholecystokinin-8 (CCK-8). After the meal, pancreatic secretion of bicarbonate and protein significantly increased in rats pretreated with normal rabbit serum, whereas this increase was significantly augmented in rats pretreated with an anti-PYY serum because the postprandial increase in plasma PYY was abolished. CONCLUSIONS PYY plays a regulatory role in the postprandial pancreatic exocrine secretion in rats.