Neuropeptide Y-induced contraction is mediated by neuropeptide YY2 and Y-4receptors 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 r esponses are (a) completely eliminated by tetrodotoxin (1 mu M), (b) reduce d to a variable extent (20 to 60%) by atropine (1 mu M) and (c) not modifie d by indomethacin, diphenhydramine or methysergide. The order of potency of agonists for peptides related to neuropeptide Y was as follows: human panc reatic polypeptide = rat pancreatic polypeptide > peptide YY = peptide YY-( 3-36)= [Leu(31),Pro(34)]neuropeptide Y > neuropeptide Y-(2-36) > C2-neurope ptide Y = neuropeptide Y > neuropeptide Y-(13-36), with minor differences o bserved between the two parts of the colon. This selectivity pattern does n ot 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, pep tide YY-(3-36) and C2-neuropeptide Y without affecting those of human pancr eatic polypeptide, rat pancreatic polypeptide, and [Leu31,Pro34]neuropeptid e Y. JCF 104 (compound 28), a putative neuropeptide Y Y-5 receptor antagoni st, showed no effect or a weak inhibition of human pancreatic polypeptide o r [Leu(31),Pro(34)]neuropeptide Y-induced contraction. Taken together, thes e data suggest that: (1) at least two neuropeptide Y receptor types are pre sent in the rat colon autonomic nerve terminals and modulate the release of acetylcholine and possibly other transmitters; (2) a proportion of the rec eptors mediating the contractile response of the rat colon (especially desc ending 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 rec eptor 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 re ceptor sub-type and appears to be located on enteric nerves. (C) 1999 Elsev ier Science B.V. All rights reserved.