Blunted pancreatic polypeptide-induced vasodilatation in mesenteric resistance vessels from spontaneously hypertensive rats.
The present study investigated the mechanisms of vasodilatation of the human pancreatic polypeptide [cPP(1-7), NPY(19-23),Ala(31),Aib(32),Gln(34)]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, N(G)-nitro-L-arginine-methylester (L-NAME). hPP relaxation was blunted in segments with endothelium, and absent in segments without endothelium from SHR. The combined neuropeptide Y(1)- and Y(4)-receptor antagonist, GR23118 (Ile-Glu-Pro-Dpr-Tyr-Arg-Leu-Arg-Tyr-CONH(2)), and the neuropeptide Y(1) 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 Y(1) and Y(2) receptors, the present results suggest hPP evokes relaxation of mesenteric small arteries by activation of prejunctional neuropeptide Y(1)-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.
Institute of Neuroscience and Physiology, Section for Pharmacology, University of Göteborg, The Sahlgrenska Academy, Göteborg, Sweden. kathryn.gradin@pharm.gu.se
Kathryn A
KA
Gradin
Jia-Yi
JY
Li
Hong
H
Zhu
Ulf
U
Simonsen
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D010191:Pancreatic Polypeptide / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D014667:Vasopressins / Q000494:pharmacology
D009478:Neuropeptide Y; D018015:Receptors, Calcitonin Gene-Related Peptide; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; C095889:neuropeptide Y2 receptor; D014667:Vasopressins; D009569:Nitric Oxide; D010191:Pancreatic Polypeptide; D015740:Calcitonin Gene-Related Peptide