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First published on November 30, 2007; DOI: 10.1124/jpet.107.133660

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Received for publication October 29, 2007.
Revised November 29, 2007.
Accepted for publication November 29, 2007.

Functional antagonism between endogenous NPY and CGRP in mesenteric resistance arteries

Jo De Mey 1*, Remco Megens 1, Gregorio Fazzi 1

1 University of Maastricht

* Address correspondence to: E-mail: j.demey{at}farmaco.unimaas.nl

Abstract

Abstract To test the hypothesis that endogenous neuropeptide Y (NPY) counteracts the vasodilator effects of calcitonin gene-related peptide (CGRP), we used isolated mesenteric resistance arteries of rats and mice. With immunohistochemistry we observed CGRP-containing fibers along and in the close vicinity of a subset of NPY- or tyrosine hydroxylase-immunoreactive fibers. The CGRP1-receptor component CRLR was expressed by peri-arterial nerves and smooth muscle cells; while receptor activity modifying protein 1 (RAMP1) was observed primarily on the smooth muscle. In organ chambers, exogenous CGRP caused relaxations that were reversed by exogenous NPY. The effects were inhibited by BIBN4096BS (CGRP1-receptor antagonist, pKB 8.54 ± 0.52) and BIBP3226 (Y1-antagonist, pKB 7.00 ± 0.49), respectively. Pretreatment with capsaicin (1 µmol/L, 20 min) and the presence of BIBN4096BS (20 nmol/L) increased contractile responses to K+ (20 - 40 mmol/L) and electrical field stimulation (EFS, 1 - 32 Hz). NPY increased contractile responses to K+ and BIBP3226 (400 nmol/L) reduced contractile responses to EFS. These effects were inhibited by capsaicin and BIBN4096BS, respectively. Furthermore, the relaxing effect of exogenous CGRP (10 nmol/L) during phenylephrine-induced contraction (30 µmol/L) was reversed by EFS and this effect was reduced in the presence of BIBP3226. We confirmed that bioactive concentrations of endogenous CGRP and NPY can be released from peri-arterial sensory-motor and sympathetic nerves, respectively, and demonstrate for the first time functional antagonism between endogenous NPY and CGRP at the level of the smooth muscle.


Key words: CGRP1-receptors, Y1-receptors, contractile reactivity, neuropeptides, resistance arteries, two-photon laser scanning microscopy


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