Heterogeneity of the neuropeptide Y (NPY) contractile and relaxing receptors in horse penile small arteries

Abstract

The distribution of neuropeptide Y (NPY)-immunorective nerves and the receptors involved in the effects of NPY upon electrical field stimulation (EFS)- and noradrenaline (NA)-elicited contractions were investigated in horse penile small arteries. NPY-immunoreactive nerves were widely distributed in the erectile tissues with a particularly high density around penile intracavernous small arteries. In small arteries isolated from the proximal part of the corpora cavernosa, NPY (30 nM) produced a variable modest enhancement of the contractions elicited by both EFS and NA. At the same concentration, the NPY Y 1 receptor agonist, [Leu 31, Pro 34]NPY, markedly potentiated responses to EFS and NA, whereas the NPY Y 2 receptor agonist, NPY(13-36), enhanced exogenous NA-induced contractions. In arteries precontracted with NA, NPY, peptide YY (PYY), [Leu 31, Pro 34]NPY and the NPY Y 2 receptor agonists, N-acetyl/[Leu 28,31]NPY (24-36) and NPY(13-36), elicited concentration-dependent contractile responses. Human pancreatic polypeptide (hPP) evoked a biphasic response consisting of a relaxation followed by contraction. NPY(3-36), the compound 1229U91 (Ile-Glu-Pro-Dapa-Tyr-Arg-Leu-Arg- Tyr-NH2, cyclic(2,4′)diamide) and eventually NPY(13-36) relaxed penile small arteries. The selective NPY Y 1 receptor antagonist BIBP3226 ((R)-N 2-(diphenacetyl)-N-[(4-hydroxyphenyl)methyl]D-arginineamide) (0.3 μM) shifted to the right the concentration-response curves to both NPY and [Leu 31, Pro 34]NPY and inhibited the contractions induced by the highest concentrations of hPP but not the relaxations observed at lower doses. In the presence of the selective NPY Y 2 receptor antagonist BIIE0246 ((S)-N2-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6h)-oxodibenz[b,e] azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclo-pentyl-N-[2-[1,2-dihydro-3,5 (4H)-dioxo-1,2-diphenyl-3H-1,2, 4-triazol-4-yl]ethyl]-argininamide) (0.3μM), the Y 2 receptor agonists NPY(13-36) and N-acetyl[Leu 28,31]NPY (24-36) evoked potent slow relaxations in NA-precontracted arteries, under conditions of nitric oxide (NO) synthase blockade. Mechanical removal of the endothelium markedly enhanced contractions of NPY on NA-precontracted arteries, whereas blockade of the neuronal voltage-dependent Ca 2+ channels did not alter NPY responses. These results demonstrate that NPY can elicit dual contractile/relaxing responses in penile small arteries through a heterogeneous population of postjunctional NPY receptors. Potentiation of the contractions evoked by NA involve both NPY Y 1 and NPY Y 2 receptors. An NO-independent relaxation probably mediated by an atypical endothelial NPY receptor is also shown and unmasked in the presence of selective antagonists of the NPY contractile receptors.