PYY INHIBITION OF VIP-STIMULATED ION-TRANSPORT IN THE RABBIT DISTAL ILEUM

Vasoactive intestinal polypeptide (VIP) is the pathophysiologic mediat or of several small intestinal hypersecretion states. VIP exerts its e ffect by binding mucosal receptors and ultimately increasing intracell ular levels of cAMP. Peptide YY (PYY), a GI hormone concentrated in th e distal ileum and colon, has been demonstrated to decrease VIP-mediat ed secretion in the colon through a specific Y4 mucosal receptor. Char acterization of PYY's effect on VIP-stimulated small intestinal secret ion may provide a basis for future therapeutic interventions. We hypot hesized that ion transport in the small intestine is mediated through a novel Y receptor subtype. We performed Ussing chamber ion transport studies on rabbit ileum using VIP, PYY, and other pancreatic polypepti de (PP)-fold peptides in order to specifically examine: (1) the effect s of VIP and PYY on basal and VIP-stimulated short circuit current (I- sc), and (2) the changes in VIP-stimulated I-sc in response to NPY, PP , leucine(31),proline(31) neuropeptide Y fragment, ([Leu(31),Pro(34)]N PY) and the carboxy-terminal fragment of NPY (Npy(13-36)). VIP increas ed basal I-sc in a concentration-dependent manner, while PYY decreased basal I-sc. Graded concentrations of PYY decreased VIP-stimulated inc reases in I-sc. PYY added prior to VIP had no effect on VIP-stimulated increases in I-sc. Inhibition of VIP-stimulated I-sc increases was se en with NPY, but not with [Leu(31),pro(34)]NPY, PP, or NPY13-36. This distinct pattern of binding affinity characterizes a novel Y receptor subtype. Additionally, increases in I-sc by VIP despite pretreatment w ith PYY suggests that VIP-stimulated ion transport is mediated through mechanisms other than increases in cAMP. (C) 1995 Academic Press, Inc .