Endogenous peptide YY and neuropeptide Y inhibit colonic ion transport, contractility and transit differentially via Y1 and Y2 receptors

BACKGROUND AND PURPOSE Peptide YY (PYY) and neuropeptide Y (NPY) activate Y receptors, targets under consideration as treatments for diarrhoea and other intestinal disorders. We investigated the gastrointestinal consequences of selective PYY or NPY ablation on mucosal ion transport, smooth muscle activity and transit using wild-type, single and double peptide knockout mice, comparing mucosal responses with those from human colon. EXPERIMENTAL APPROACH Mucosae were pretreated with a Y-1 (BIBO3304) or Y-2 (BIIE0246) receptor antagonist and changes in short-circuit current recorded. Colonic transit and colonic migrating motor complexes (CMMCs) were assessed in vitro and upper gastrointestinal and colonic transit measured in vivo. KEY RESULTS Y receptor antagonists revealed tonic Y-1 and Y-2 receptor-mediated antisecretory effects in human and wild-type mouse colon mucosae. In both, Y-1 tone was epithelial while Y-2 tone was neuronal. Y-1 tone was reduced 90% in PYY-/- mucosa but unchanged in NPY-/- tissue. Y-2 tone was partially reduced in NPY-/- or PYY-/- mucosae and abolished in tetrodotoxin-pretreated PYY-/- tissue. Y-1 and Y-2 tone were absent in NPYPYY-/- tissue. Colonic transit was inhibited by Y-1 blockade and increased by Y-2 antagonism indicating tonic Y-1 excitation and Y-2 inhibition respectively. Upper GI transit was increased in PYY-/- mice only. Y-2 blockade reduced CMMC frequency in isolated mouse colon. CONCLUSIONS AND IMPLICATIONS Endogenous PYY and NPY induced significant mucosal antisecretory tone mediated by Y-1 and Y-2 receptors, via similar mechanisms in human and mouse colon mucosa. Both peptides contributed to tonic Y-2-receptor-mediated inhibition of colonic transit in vitro but only PYY attenuated upper GI transit.