Neuropeptide Y-induced contraction is mediated by neuropeptide YY2 and Y4 receptors in the rat colon

Ascending and descending segments of the rat colon were studied to analyze their contractile responses to neuropeptide Y and related peptides. These responses are (a) completely eliminated by tetrodotoxin (1 mu M), (b) reduced to a variable extent (20 to 60%) by atropine (1 mu M) and (c) not modified by indomethacin, diphenhydramine or methysergide. The order of potency of agonists for peptides related to neuropeptide Y was as follows: human pancreatic polypeptide = rat pancreatic polypeptide > peptide YY = peptide YY-(3-36)= [Leu(31),Pro(34)]neuropeptide Y > neuropeptide Y-(2-36) > C2-neuropeptide Y = neuropeptide Y > neuropeptide Y-(13-36), with minor differences observed between the two parts of the colon. This selectivity pattern does not correspond to the profile of any known cloned neuropeptide Y receptors. BIBP3226, a selective antagonist for the neuropeptide YY1 receptor sub-type, was found to be inactive, while a neuropeptide YY2 receptor antagonist, T-4-[NPY-(33-36)](4), reduced the effects of neuropeptide Y, peptide YY, peptide YY-(3-36) and C2-neuropeptide Y without affecting those of human pancreatic polypeptide, rat pancreatic polypeptide, and [Leu31,Pro34]neuropeptide Y. JCF 104 (compound 28), a putative neuropeptide Y Y-5 receptor antagonist, showed no effect or a weak inhibition of human pancreatic polypeptide or [Leu(31),Pro(34)]neuropeptide Y-induced contraction. Taken together, these data suggest that: (1) at least two neuropeptide Y receptor types are present in the rat colon autonomic nerve terminals and modulate the release of acetylcholine and possibly other transmitters; (2) a proportion of the receptors mediating the contractile response of the rat colon (especially descending part) to neuropeptide Y and related peptides appears to be of the Y-2 type and (3) the significant portion of the response is mediated by a receptor which is insensitive to neuropeptide Y Y-1, Y-2 and to neuropeptide Y Y-5 receptor antagonists. This receptor behaves as a neuropeptide Y Y-4 receptor sub-type and appears to be located on enteric nerves. (C) 1999 Elsevier Science B.V. All rights reserved.