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BIBN4096BS and CGRP8-37 antagonize the relaxant effects of α-CGRP more than those of β-CGRP in human extracranial arteries

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Abstract

We hypothesize that dilatation of extracranial arteries during migraine could be caused by CGRP. We compared the relaxant effects of α-calcitonin gene-related peptide (α-CGRP) and β-calcitonin gene-related peptide (β-CGRP) and the antagonism by BIBN4096BS and CGRP8-37 on rings of human temporal and occipital arteries precontracted with KCl. β-CGRP relaxed temporal (−logEC50M=8.1) and occipital arteries (−logEC50M=7.6) with 19-fold and 29-fold lower potencies respectively than α-CGRP. Nearly maximal effective concentrations of α-CGRP (4 nM) and β-CGRP (50 nM) caused stable relaxations of the temporal artery for 4 h without fading. BIBN4094BS antagonized the effects of α-CGRP (pKB=10.1 and 9.9, respectively) more than β-CGRP (pKB=9.3 and 9.2 respectively) on both temporal and occipital arteries. CGRP8-37 antagonized the effects of α-CGRP (pKB=6.6 and 6.4 respectively) more than β-CGRP (pKB=5.7 and 5.5 respectively) on both temporal and occipital arteries. Antagonism of the relaxant effects of α-CGRP (4 nM) and β-CGRP (50 nM) by BIBN4096BS (10 and 100 nM) was reversible for β-CGRP, but irreversible for α-CGRP, 1 h after BIBN4096BS washout. We conclude that α-CGRP and β-CGRP interact either at different binding sites of the same CGRP receptor system or all together with different receptor systems in human extracranial arteries. BIBN4096BS binds more firmly to the receptor activated by α-CGRP than to the receptor activated by β-CGRP.

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Abbreviations

Ach:

acetylcholine

BIBN4096BS 1-Piperidinecarboxamide:

N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-[R-(R*,S*)]-

α-CGRP:

α-calcitonin gene-related peptide

β-CGRP:

β-calcitonin gene-related peptide

5-HT:

5-hydroxytryptamine

SNP:

sodium nitroprusside

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Authors and Affiliations

  1. Department of Neurosurgery, University of Göttingen, 37075, Göttingen, Germany

    Raphaela Verheggen, Kordian Wojtas, Martin Webel & Steffi Hoffmann

  2. Department of Physiology, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK

    Alberto J. Kaumann

Authors
  1. Raphaela Verheggen
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  2. Kordian Wojtas
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  3. Martin Webel
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  4. Steffi Hoffmann
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  5. Alberto J. Kaumann
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Correspondence to Alberto J. Kaumann.

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Verheggen, R., Wojtas, K., Webel, M. et al. BIBN4096BS and CGRP8-37 antagonize the relaxant effects of α-CGRP more than those of β-CGRP in human extracranial arteries. Naunyn Schmied Arch Pharmacol 371, 383–392 (2005). https://doi.org/10.1007/s00210-005-1064-4

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  • DOI: https://doi.org/10.1007/s00210-005-1064-4

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