BACKGROUND Peptide YY (PYY) is promptly released from endocrine cells of the distal part of the gut after food intake. To test the possibility that hormones produced by the proximal small intestine or transmitters of the enteric nervous system may take part in the early phase of meal-induced PYY release, various regulatory peptides and neurotransmitters of the gut were administered intra-arterially in the isolated, vascularly perfused rat colon. METHODS A colonic loop was perfused with a Krebs-Henseleit buffer containing 20% washed bovine erythrocytes via the superior mesenteric artery. The release of PYY in portal effluent was measured by radioimmunoassay. RESULTS Cholecystokinin and secretin produced a small release of PYY. In contrast, infusion of gastric inhibitory polypeptide (GIP) over the concentration range 0.25-1 nM for 30 min produced a dose-dependent secretion of PYY with a maximal response at 800% above basal. Tetrodotoxin (TTX) did not modify the GIP-induced PYY release. Bethanechol (10(-5) M, 10(-4) M) produced a PYY release that was maximal at the end of the 30-min infusion period. The beta-adrenergic agonist isoproterenol (10(-7) M, 10(-6) M) caused a prompt release of PYY, followed by a sustained release at a lower value. Calcitonin gene-related peptide (CGRP) (5.10(-9) M and 5.10(-8) M) induced a PYY release with kinetics similar to that found for isoproterenol. Finally, bombesin (10(-9)-10(-7) M) provoked a dose-dependent release of PYY, consisting of an early peak followed by a sustained response. TTX did not modify the bethanechol-, isoproterenol-, CGRP-, and bombesin-induced PYY secretion. CONCLUSIONS The hormonal peptide GIP and several transmitters of the nervous enteric system may mediate the release of PYY through the occupation of receptors possibly located at the surface of the colonic L-cells.