The present study investigated the mechanisms of vasodilatation of the human pancreatic polypeptide [cPP1–7, NPY19–23,Ala31,Aib32,Gln34]hPP (hPP) in mesenteric small arteries from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). The arteries were isolated and mounted in microvascular myographs for isometric tension recording. In vasopressin-contracted preparations with endothelium from WKY rats, hPP evoked concentration-dependent relaxations with maximal responses of 50 ± 2% (n = 5). hPP relaxation was reduced by endothelial cell removal and abolished in the presence of a nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine-methylester (L-NAME). hPP relaxation was blunted in segments with endothelium, and absent in segments without endothelium from SHR. The combined neuropeptideY1- and Y4-receptor antagonist, GR23118 (Ile-Glu-Pro-Dpr-Tyr-Arg-Leu-Arg-Tyr-CONH2), and the neuropeptide Y1 receptor antagonist, BIBP3226 ((R) -N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-arginineamide), inhibited hPP-induced vasodilatation. Calcitonin gene-related peptide (CGRP) relaxation was reduced in arteries from SHR compared to WKY. The CGRP receptor antagonist, CGRP (8–37), antagonized vasodilatation induced by CGRP and rightward shifted concentration–response curves for hPP in arteries from WKY rats. There were no differences in nerves immunoreactive for CGRP in arteries from SHR compared to WKY rats. In contrast to neuropeptide Y which evokes contraction by activation of neuropeptide Y1 and Y2 receptors, the present results suggest hPP evokes relaxation of mesenteric small arteries by activation of prejunctional neuropeptide Y1-like receptors localized in CGRP-containing nerves followed by release of CGRP and of endothelium-derived NO. hPP relaxation is blunted in arteries from SHR probably as a consequence of endothelial cell dysfunction leading to reduced efficacy of CGRP.