NPY receptor subtypes involved in the contraction of the proximal colon of the rat

Experiments were designed to determine the receptor subtype(s) involved in the contraction of the rat proximal colon to NPY. In this tissue, mRNA of Y 2 and Y 4 NPY receptor subtypes were highly expressed, whereas Y 5 mRNA levels were very low and Y 1 mRNA levels were intermediate. NPY analogues induced contractions with the following order of potency: rPP>hPP=PYY=NPY=[Leu 31 , Pro 34 ]NPY>NPY (2–36) =[ d -Trp 32 ]NPY>NPY (13–36) . Responses to NPY, PYY and NPY (13–36) were not or partially affected by tetrodotoxin, in contrast to the responses to [Leu 31 ,Pro 34 ]NPY, rPP, hPP and [ d -Trp 32 ]NPY which were fully blocked. Atropine did not inhibit the contractions to NPY, PYY and [Leu 31 ,Pro 34 ]NPY but significantly affected those to NPY (13–36) , [ d -Trp 32 ]NPY, rPP and hPP. The specific Y 1 receptor antagonist BIBP 3226 was ineffective but JCF 104 and JCF 105 (two compounds with preferential affinity toward the hY 5 receptor versus the hY 1 or hY 2 receptor) abolished the contractions provoked by the NPY analogues. These results suggest that NPY activates three receptor subtypes, a Y 2 subtype possibly by a direct action on the smooth muscle cells, as well as a Y 4 and a Y 5 (or `Y 5 -like') subtype which, respectively, release acetylcholine and an unknown neurotransmitter.