Neuroendocrine Peptides Neuropeptide-Y (NPY) and Peptide-YY (PYY) Suppress Cl^- Secretion and K⁺ Secretion in Guinea Pig Distal Colon through Action at Y2-Receptors

Electrogenic Cl ^– and K ⁺ secretion in isolated mucosa from guinea pig distal colon measured as short-circuit current (I _sc ) and transepithelial conductance (G _t ) were stimulated by epinephrine (epi), prostaglandin-E ₂ (PGE ₂ ) and carbachol (CCh). neuropeptide-Y (NPY) and peptide-YY (PYY) inhibited by 60% Cl ^– secretion activated by either PGE ₂ or PGE ₂ +CCh with EC ₅₀ ’s of 16nM and 6nM, respectively. Neither peptide markedly inhibited the transient component of the PGE ₂ +CCh response. Immunoreactivity (IR) for NPY was present in enteric ganglia and in proximity with crypts. Basolateral membranes of colonic crypt and surface epithelial cells had distinct IR for neuropeptide-Y receptors Y1 and Y2. Receptor expression was supported further by immuno-blot showing bands at molecular weights consistent with monomer and oligomer. Sub-type selective antagonists BVD10 (Y1) and BIIE0246 (Y2) indicated that secretory suppression occurred through Y2 receptors. The Y2 selective peptide PYY(3-36) also suppressed Cl ^– secretion with a EC ₅₀ of 9nM. BIIE0246 addition increased I _sc and G _t during PGE ₂ or PGE ₂ +CCh activation consistent with the presence of in vitro released PYY or NPY. PYY addition increased the epi EC ₅₀ to 18nM compared with BIIE0246 treated tissues, 4nM. Thus, PYY or NPY suppressed Cl ^– secretory capacity and desensitized the adrenergic K ⁺ secretory response, providing a negative feedback for secretory activation. [supported by NIH, DK65845]