Pancreatic polypeptide is released mainly from the pancreas, and is thought to be one of the major endogenous agonists of the neuropeptide Y Y(4) receptor. Pancreatic polypeptide has been shown to stimulate colonic muscle contraction, but whether pancreatic polypeptide has in vivo functional activity with respect to colonic transit is unclear. The present report investigated the effects of pancreatic polypeptide on fecal output as an index of colonic transit as well as intestinal motor activity, using wild-type (WT) and neuropeptide Y Y(4) receptor-deficient (KO) mice. Peripheral administration of pancreatic polypeptide increased fecal weight and caused diarrhea in WT mice in a dose-dependent manner (0.01-3mg/kg s.c.). Pancreatic polypeptide-induced increases in fecal weight and diarrhea completely disappeared in KO mice, while basal fecal weights did not differ between WT and KO mice. In longitudinal and circular muscles of mouse isolated colon, pancreatic polypeptide (0.01-1 microM) increased basal tone and frequency of spontaneous contraction in WT mice, but not in KO mice. Atropine did not affect pancreatic polypeptide-induced fecal output or increase in colonic muscle tone, indicating that the actions of pancreatic polypeptide are not mediated through cholinergic mechanisms. The present findings demonstrate that pancreatic polypeptide enhances colonic contractile activity and fecal output through neuropeptide Y Y(4) receptor, and a neuropeptide Y Y(4) receptor agonist might offer a novel therapeutic approach to ameliorate constipation.
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