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

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 n M ) 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 μ M ) 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 )‐ N 2‐[[1‐[2‐[4‐[( R,S )‐5,11‐dihydro‐6(6h)‐oxodibenz[b,e]azepin‐11‐y1]‐1‐piperazinyl]‐2‐oxoethyl]cyclo‐pentyl‐ N ‐[2‐[1,2‐dihydro–3,5 (4 H )‐dioxo‐1,2‐diphenyl‐3 H ‐1,2, 4‐triazol‐4‐yl]ethyl]‐argininamide) (0.3 μ M ), 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.British Journal of Pharmacology (2004) 143 , 976–986. doi: 10.1038/sj.bjp.0706005