Functional consequences of neuropeptide Y Y 2 receptor knockout and Y2 antagonism in mouse and human colonic tissues.

1 Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) differentially activate three Y receptors (Y(1), Y(2) and Y(4)) in mouse and human isolated colon. 2 The aim of this study was to characterise Y(2) receptor-mediated responses in colon mucosa and longitudinal smooth muscle preparations from wild type (Y(2)+/+) and knockout (Y(2)-/-) mice and to compare the former with human mucosal Y agonist responses. Inhibition of mucosal short-circuit current and increases in muscle tone were monitored in colonic tissues from Y(2)+/+ and Y(2)-/- mice+/-Y(1) ((R)-N-[[4-(aminocarbonylaminomethyl)phenyl)methyl]-N(2)-(diphenylacetyl)-argininamide-trifluoroacetate (BIBO3304) or Y(2) (S)-N(2)-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6H)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide (BIIE0246) antagonists. 3 Predictably, Y(2)-/- tissues were insensitive to Y(2)-preferred agonist PYY(3-36) (