Long-lasting physiological antagonism of calcitonin gene-related peptide towards endothelin-1 in rat mesenteric arteries and human coronary arteries

Sieneke Labruijere, Matthijs G Compeer, Antoon J van den Bogaerdt, Antoinette Maassen van den Brink, Jo G R De Mey, A H Jan Danser, Wendy W Batenburg

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Endothelin-1 causes long-lasting contraction via endothelin type A receptor (ETAR) in isolated rat mesenteric arteries (RMA) that cannot be readily terminated by removing the agonist, or by adding the ETAR antagonist BQ123 or the NO donor sodium nitroprusside. It could be terminated by adding calcitonin-gene related peptide (CGRP), most likely because CGRP causes ET-1/ETAR dissociation. Here we investigated this phenomenon in human coronary microarteries (HCMA). We simultaneously verified the effects of CGRP in RMA and HCMA towards other vasoconstrictors, i.e., the α1-adrenoceptor agonist phenylephrine, the thromboxane A2 analog U46619 (9,11-dideoxy-11α,9α-epoxy-methano-prostaglandin F2α) and KCl. Long-lasting contraction (remaining after washing away the agonist) was observed for ET-1 in RMA, but not HCMA. Constrictions to phenylephrine, U46619 or KCl did not last upon washing. When added on top of ET-1-initiated contraction in RMA, CGRP effectively counteracted vasoconstriction, i.e., it caused full relaxation. Inhibitory effects of CGRP were also observed when briefly exposing RMA and HCMA to CGRP 1h before the addition of ET-1. Similar inhibitory effects of transient CGRP pre-incubation were seen towards phenylephrine, U46619 or KCl in RMA and HCMA. In conclusion, our data imply that CGRP, like ET-1, causes long-lasting effects that remain apparent up to 1h after its removal from the organ bath. Thus, in addition to the reported dissociation of ET-1/ETAR complexes, CGRP causes long-lasting non-selective arterial smooth muscle relaxation that may add to the neuropeptide being a physiological antagonist of arterial effects of ET-1. Long-lasting, washout-resistant ET-1/ETAR interaction does not occur in HCMAs.

Original languageEnglish
JournalEuropean Journal of Pharmacology
Volume720
Issue number1-3
Pages (from-to)303-309
ISSN0014-2999
DOIs
Publication statusPublished - 15. Nov 2013

Keywords

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Animals
  • Calcitonin Gene-Related Peptide
  • Coronary Vessels
  • Endothelin-1
  • Humans
  • Mesenteric Arteries
  • Nitroprusside
  • Peptides, Cyclic
  • Phenylephrine
  • Rats
  • Rats, Inbred WKY
  • Rats, Wistar
  • Vasoconstriction
  • Vasoconstrictor Agents
  • BQ123
  • Human coronary artery
  • Rat mesenteric artery
  • Calcitonin-gene related peptide

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