NEUROPEPTIDE-Y (NPY) AND PEPTIDE YY (PYY) EFFECTS IN THE EPIDIDYMIS OF THE GUINEA-PIG - EVIDENCE OF A PREJUNCTIONAL PYY-SELECTIVE RECEPTOR

1 The effects of peptide YY (PYY), neuropeptide Y (NPY) and structural ly related peptides upon field stimulation-induced and phenylephrine-m ediated contractile responses in the cauda epididymis of the guinea-pi g were investigated. 2 Preparations of cauda epididymis responded to f ield stimulation with contractions which were completely attenuated by both the neurotoxin, tetrodotoxin (500 nM), and also by the alpha-adr enoceptor antagonist, phentolamine (3 mu M). PW (n=7) and the truncate d peptide analogue PYY(3-36) (n=5) inhibited field stimulation-induced contractions (pIC(50)+s.e.mean: 8.9+/-0.2 and 9.4+/-0.2, respectively ). Pancreatic polypeptide (PP, up to 1 mu M, n=6), NPY (up to 100 nhl, n=6) and the NPY analogues [Leu(31),Pro(34)]NPY (n=6) and NPY (13-36) (both up to 1 mu M, n = 5) had no significant effect. 3 The NPY Y-1 r eceptor antagonist BIBP3226 ylacetyl)-N[(4-hydroxyphenyl)-methyl]argin inamide) at 750 nM (n=6) and 7.5 mu M (n=6) did not affect the PYY-med iated inhibition of field stimulation-induced contractions (pIC(50) 8. 9+/-0.3 and 9.0+/-0.3, respectively). In the presence of BIBP3226 (7.5 mu M), NPY (n=6) inhibited held stimulation-induced contractions (pIC (50) 8.0+/-0.2). 4 NPY, PW and PYY(3-36) inhibited [H-3]-noradrenaline release from preparations of epididymis (pIC(50) values 7.9+/-0.7, 9. 6+/-0.8 and 10.0+/-0.9, respectively, all n=6). The agonists PP and [L eu(31),Pro(33)]pyy (both up to 100 nM) were without significant effect (both n=6). 5 In preparations of cauda epididymis, stimulated with th reshold concentrations of the alpha(1)-adrenoceptor agonist, phenyleph rine (1 mu M), both NPY (n = 6) and PYY (n = 7) elicited concentration -dependent increases in contractile force (with pEC(50) values of 8.9/-0.2 and 8.6+/-0.1, respectively). The effects of both NPY (n=6) and PW (n=6) were antagonized by preincubation with BIBP3226 (75 nM; appar ent pK(B) +/- s.e. values 8.3 +/- 1.0 and 8.2 +/- 0.6, respectively). The peptide analogues NPY(13-36) (n = 5), PYY (3-36) (n=7) and [Leu(31 ),Pro(34)]NPY (n=5) did not significantly augment responses to thresho ld concentrations of phenylephrine. 6 These results are consistent wit h the proposal that distinct NPY receptors mediate the (prejunctional) inhibition of held stimulation-induced contractions and the (postjunc tional) potentiation of responses to phenylephrine in the cauda epidid ymis of the guinea-pig. The rank order of agonist potency (NPY greater than or equal to PYY much greater than NPY(13-36), [Leu(31),Pro(34)]N PY and PW(3-36) and the high potency of BIBP3226 indicate that the pos tjunctional receptor may be Y-1-like. The rank orders of agonist poten cy in inhibiting held stimulation-induced contractile responses and [H -3]-noradrenaline release (PW(3-36)greater than or equal to PYY>NPY mu ch greater than PP, NPY(13-36), [Leu(31),Pro(34)]NPY and PYY(3-36)grea ter than or equal to PYY>NPY much greater than PP,[Leu(31),Pro(34)]PYY , respectively) are consistent with the action of these peptides at a PW-preferring receptor subtype, which may be distinct from the present ly characterized NPY receptor subtypes.