SEVERAL RECEPTORS MEDIATE THE ANTISECRETORY EFFECT OF PEPTIDE YY, NEUROPEPTIDE-Y, AND PANCREATIC-POLYPEPTIDE ON VIP-INDUCED FLUID SECRETIONIN THE RAT JEJUNUM IN-VIVO

Several Y receptor subtypes have been cloned and/or pharmacologically characterized that mediate the effects of the regulatory peptides pept ide YY (PYY), neuropeptide Y (NPY), and pancreatic polypeptide (PP). T hese peptides possess antisecretory properties on the intestine. This effect can be blocked in vivo by neural antagonists, suggesting the in tervention of neural receptors, although epithelial PYY-preferring rec eptors have been evidenced on jejunal crypt cells. The purpose of the present experiments was to compare the antisecretory properties in viv o of a series of PYY and NPY derivatives with various affinities for d ifferent Y receptor subtypes, in order to determine which subtypes wer e involved. A model of VIP-stimulated secretion by rat jejunal loops w as used. The results were compared with the binding affinities for PYY -preferring receptors determined on rat jejunal crypt cell membranes. Full-length PYY(1-36) was about three times more potent than NPY(1-36) , and 10 times more potent than PP in the low dose range. PP, however, had a low efficacy limited to about 50% inhibition of VIP effect. Bot h Y-1 agonists ([Leu(31),Pro(34)]PYY and [Leu(31),Pro(34)]NPY), and Y- 2 agonists [C-terminal fragments ranging from PYY(3-36) and NPY(3-36) to PYY(22-36) to NPY(22-36)] displayed potent antisecretory properties . PYY derivatives and fragments were always more potent than their res pective NPY counterparts. In contrast, Y-1 derivatives and PP had very low affinity for the epithelial PYY receptor as measured in vitro by radioreceptor assay. These data suggest that the antisecretory effect of PYY/NPY/PP peptides in vivo involves the effets of several receptor s: a Y-2-like,PYY-preferring receptor identical to the epithelial rece ptor, a Y-1-like receptor, and a third receptor with high affinity for PP. (C) 1997 Elsevier Science Inc.