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Differential inhibitory response to telcagepant on αCGRP induced vasorelaxation and intracellular Ca2+ levels in the perfused and non-perfused isolated rat middle cerebral artery

Erdling, André LU ; Sheykhzade, Majid and Edvinsson, Lars LU (2017) In Journal of Headache and Pain 18(1). p.1-9
Abstract

Background: Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date. The present study elucidates the differential interaction of CGRP, its receptor and the effect of the CGRP-receptor antagonist telcagepant on intracellular Ca2+ -levels and tension in rat middle cerebral arteries (MCA) by pressurized arteriography, FURA-2/wire myography and immunohistochemistry. Methods: A pressurized arteriograph system was used to evaluate changes in MCA tension when subjected to CGRP and/or telcagepant. Intracellular calcium levels were evaluated using a FURA-2/wire myograph system. Localization of the CGRP-receptor components was verified using immunohistochemistry. Results: Abluminal... (More)

Background: Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date. The present study elucidates the differential interaction of CGRP, its receptor and the effect of the CGRP-receptor antagonist telcagepant on intracellular Ca2+ -levels and tension in rat middle cerebral arteries (MCA) by pressurized arteriography, FURA-2/wire myography and immunohistochemistry. Methods: A pressurized arteriograph system was used to evaluate changes in MCA tension when subjected to CGRP and/or telcagepant. Intracellular calcium levels were evaluated using a FURA-2/wire myograph system. Localization of the CGRP-receptor components was verified using immunohistochemistry. Results: Abluminal but not luminal αCGRP (10-12-10-6 M) caused concentration-dependent vasorelaxation in rat MCA. Luminal telcagepant (10-6 M) failed to inhibit this relaxation, while abluminal telcagepant inhibited the relaxation (10-6 M). Using the FURA-2 method in combination with wire myography we observed that αCGRP reduced intracellular calcium levels and in parallel the vascular tone. Telcagepant (10-6 M) inhibited both vasorelaxation and drop in intracellular calcium levels. Both functional components of the CGRP receptor, CLR (calcitonin receptor-like receptor) and RAMP1 (receptor activity modifying peptide 1) were found in the smooth muscle cells but not in the endothelial cells of the cerebral vasculature. Conclusions: This study thus demonstrates the relaxant effect of αCGRP on rat MCA. The vasorelaxation is associated with a simultaneous decrease in intracellular calcium levels. Telcagepant reduced relaxation and thwarted the reduction in intracellular calcium levels localized in the vascular smooth muscle cells. In addition, telcagepant may act as a non-competitive antagonist at concentrations greater than 10-8 M.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Calcitonin gene related peptide, CGRP, FURA-2, Middle cerebral artery, Pressurized arteriography, Telcagepant
in
Journal of Headache and Pain
volume
18
issue
1
pages
1 - 9
publisher
Springer
external identifiers
  • scopus:85020047365
  • wos:000407153300003
ISSN
1129-2369
DOI
10.1186/s10194-017-0768-4
language
English
LU publication?
yes
id
45bb1b5d-88d7-49e8-ac6c-56e5f43abdb9
date added to LUP
2017-06-16 10:51:29
date last changed
2017-09-18 11:41:29
@article{45bb1b5d-88d7-49e8-ac6c-56e5f43abdb9,
  abstract     = {<p>Background: Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date. The present study elucidates the differential interaction of CGRP, its receptor and the effect of the CGRP-receptor antagonist telcagepant on intracellular Ca<sup>2+</sup> -levels and tension in rat middle cerebral arteries (MCA) by pressurized arteriography, FURA-2/wire myography and immunohistochemistry. Methods: A pressurized arteriograph system was used to evaluate changes in MCA tension when subjected to CGRP and/or telcagepant. Intracellular calcium levels were evaluated using a FURA-2/wire myograph system. Localization of the CGRP-receptor components was verified using immunohistochemistry. Results: Abluminal but not luminal αCGRP (10<sup>-12</sup>-10<sup>-6</sup> M) caused concentration-dependent vasorelaxation in rat MCA. Luminal telcagepant (10<sup>-6</sup> M) failed to inhibit this relaxation, while abluminal telcagepant inhibited the relaxation (10<sup>-6</sup> M). Using the FURA-2 method in combination with wire myography we observed that αCGRP reduced intracellular calcium levels and in parallel the vascular tone. Telcagepant (10<sup>-6</sup> M) inhibited both vasorelaxation and drop in intracellular calcium levels. Both functional components of the CGRP receptor, CLR (calcitonin receptor-like receptor) and RAMP1 (receptor activity modifying peptide 1) were found in the smooth muscle cells but not in the endothelial cells of the cerebral vasculature. Conclusions: This study thus demonstrates the relaxant effect of αCGRP on rat MCA. The vasorelaxation is associated with a simultaneous decrease in intracellular calcium levels. Telcagepant reduced relaxation and thwarted the reduction in intracellular calcium levels localized in the vascular smooth muscle cells. In addition, telcagepant may act as a non-competitive antagonist at concentrations greater than 10<sup>-8</sup> M.</p>},
  articleno    = {61},
  author       = {Erdling, André and Sheykhzade, Majid and Edvinsson, Lars},
  issn         = {1129-2369},
  keyword      = {Calcitonin gene related peptide,CGRP,FURA-2,Middle cerebral artery,Pressurized arteriography,Telcagepant},
  language     = {eng},
  month        = {12},
  number       = {1},
  pages        = {1--9},
  publisher    = {Springer},
  series       = {Journal of Headache and Pain},
  title        = {Differential inhibitory response to telcagepant on αCGRP induced vasorelaxation and intracellular Ca<sup>2+</sup> levels in the perfused and non-perfused isolated rat middle cerebral artery},
  url          = {http://dx.doi.org/10.1186/s10194-017-0768-4},
  volume       = {18},
  year         = {2017},
}