NPY receptor subtype in the rabbit isolated ileum

1 The purpose of this work was to verify the hypothesis that the rabbit ile um is a selective preparation for the NPY Y5 receptor by using new selectiv e antagonists recently synthesized. Spontaneous contractions of the rabbit isolated ileum were recorded and binding experiments were performed in cell s expressing the human NPY Y1, Y2, Y4 or Y5 receptor subtype. 2 NPY analogues produced a concentration-dependent transient inhibition of the spontaneous contractions of the rabbit ileum with the following order o f potency hPP > rPP > PYY greater than or equal to [Leu(31), -Pro(34)]-NPY > NPY > > NPY13-36 Pre-exposure to rPP, PW, [Leu(31),Pro(34)]-NPY or NPY (b ut not NPY13-36) inhibited the effect of subsequent administration of hPP s uggesting cross-desensitization of the preparation. The apparent affinity o f the various agonists studied was correlated to the affinity reported for the human Y4 receptor subtype (and to a lesser extent for the rat Y4 subtyp e) but not to the affinity for the Y5 receptor subtype. 3 BIBO 3304, a selective NPY Y1 receptor antagonist, and CGP 71683A, a sele ctive NPY Y5 receptor antagonist, did not affect the response to hPP. JCF 1 09, another NPY Y5 receptor antagonist, produced an inhibition of the respo nse to hPP but only at the highest dose tested (10 mu M) which also, by its elf, produced intrinsic inhibitory effects. 4 1229U91, a non-selective ligand for Y1, Y2, Y4 and Y5 receptors with high affinity toward the Y1 and Y4 receptor subtypes, produced a concentration- dependent transient inhibition of the spontaneous contractions of the rabbi t ileum and a dose-dependent inhibition of the response to hPP (apparent pK (B): 7.2). 5 These results suggest that in the rabbit ileum, the NPY receptor involved in the inhibition of the spontaneous contractile activity is a NPY Y4 rece ptor subtype.