Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 371, Issue 5, pp 383–392

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

  • Raphaela Verheggen
  • Kordian Wojtas
  • Martin Webel
  • Steffi Hoffmann
  • Alberto J. Kaumann
Original Article

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.

Keywords

Human temporal arteries Occipital arteries α-CGRP-evoked relaxations β-CGRP-evoked relaxations BIBN4096BS CGRP8-37 

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

References

  1. Aiyar N, Disa J, Dang K, Pronin AN, Benovic JL, Nambi P (2000) Involvement of G protein-coupled receptor kinase-6 in desensitization of CGRP receptors. Eur J Pharmacol 403:1–7CrossRefPubMedGoogle Scholar
  2. Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM (1982) Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298:240–244CrossRefPubMedGoogle Scholar
  3. Amara SG, Arriza JL, Leff SE, Swanson LW, Evans RM, Rosenfeld MG (1985) Expression in brain of a messenger RNA encoding a novel neuropeptide homologous to calcitonin gene-related peptide. Science 229:1094–1097PubMedGoogle Scholar
  4. Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–59PubMedGoogle Scholar
  5. Dennis T, Fournier A, St Pierre S, Quirion R (1989) Structure–activity profile of calcitonin gene-related peptide in peripheral and brain tissues. Evidence for receptor multiplicity. J Pharmacol Exp Ther 251:718–725PubMedGoogle Scholar
  6. Dennis T, Fournier A, Cadieux A, Pomerleau F, Jolicoeur FB, St Pierre S, Quirion R (1990) hCGRP8-37, a calcitonin gene-related peptide antagonist revealing calcitonin gene-related peptide receptor heterogeneity in brain and periphery. J Pharmacol Exp Ther 254:123–128PubMedGoogle Scholar
  7. Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf H, Engel W, Eberlein W (2000) Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol 129:420–423Google Scholar
  8. Drake WM, Ajayi SR, Lowe SR, Mirtella A, Bartlett TJ, Clark AJL (1999) Desensitisation of CGRP and adrenomedullin receptors in SK-N-MC cells: implications for the RAMP hypothesis. Endocrinology 140:533–537CrossRefPubMedGoogle Scholar
  9. Durham PL, Russo AF (1999) Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J Neurosci 19:3423–3429PubMedGoogle Scholar
  10. Edvinsson L, Alm R, Shaw D, Rutledge RZ, Koblan KS, Longmore J, Kane SA (2002) Effect of the CGRP receptor antagonist BIBN4096BS in human cerebral, coronary and omental arteries and in SK-N-MC cells. Eur J Pharmacol 434:49–53CrossRefPubMedGoogle Scholar
  11. Evans BN, Rosenblatt MI, Mnayer LO, Oliver KR, Dickerson IM (2000) CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptor. J Biol Chem 275:31438–31443CrossRefPubMedGoogle Scholar
  12. Goadsby PJ, Edvinsson L (1993) The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol 33:48–56Google Scholar
  13. Goadsby PJ, Edninsson L, Ekman R (1990) Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 28:183–187Google Scholar
  14. Hilairet S, Belanger C, Bertrand J, Laperriere A, Foord SM, Bouvier M (2001) Agonist-promoted internalization of a ternary complex between calcitonin receptor-like receptor, receptor activity-modifying protein 1 (RAMP1), and β-arrestin. J Biol Chem 276:42182–42190CrossRefPubMedGoogle Scholar
  15. Jansen I (1992) Characterization of calcitonin gene-related peptide (CGRP) receptors in guinea pig basilar artery. Neuropeptides 21:73–79CrossRefPubMedGoogle Scholar
  16. Jansen I, Uddman R, Hocherman M, Ekman R, Jensen K, Olesen J, Stiernholm P, Edvinsson L (1986) Localization and effects of neuropeptide Y, vasoactive intestinal polypeptide, substance P, and calcitonin gene-related peptide in human temporal arteries. Ann Neurol 20:496–501CrossRefPubMedGoogle Scholar
  17. Jansen I, Mortensen A, Edvinsson L (1992) Characterization of calcitonin gene-related peptide receptors in human cerebral vessels. Vasomotor responses and cAMP accumulation. Ann N Y Acad Sci 57:435–440Google Scholar
  18. Jansen-Olesen I, Gulbenkian S, Valença A, Antunes JL, Wharton J, Polak JM, Edvinsson L (1995) The peptidergic innervation of the human superficial temporal artery: immunohistochemistry, ultrastructure, and vasomotility. Peptides 16:275–287CrossRefPubMedGoogle Scholar
  19. Jansen-Olesen I, Jørgensen L. Engel U, Edvinsson L (2003) In-depth characterization of CGRP receptors in human intracranial arteries. Eur J Pharmacol 481:207–216CrossRefPubMedGoogle Scholar
  20. Juaneda C, Dumond Y, Quirion R (2000) The molecular pharmacology of CGRP and related peptide receptor subtypes. Trends Pharmacol Sci 21:432–438Google Scholar
  21. Kaumann AJ (1990) Piglet sinoatrial 5-HT receptors resemble human atrial 5-HT4-like receptors. Naunyn-Schmiedebergs Arch Pharmacol 342:619–622PubMedGoogle Scholar
  22. Lance JW (1992) History of involvement of 5-HT in primary headache. In: Olesen J, Saxena PR (eds) 5-hydroxytryptamine mechanisms in primary headaches, vol 2. Raven, New York, pp 19–28Google Scholar
  23. Mallee JJ, Salvatore CA, LeBourdelles B, Oliver KV, Longmore J, Koblan KS, Kane SA (2002) Receptor activity-modifying protein 1 determines the species selectivity of non-peptide CGRP receptor antagonists. J Biol Chem 277:14294–14298CrossRefPubMedGoogle Scholar
  24. McLatchie LM, Fraser NJ, Main MJ, Wise A, Brown J, Thompson N, Solari R, Lee MG, Foord SM (1998) RAMPS regulate the transport and ligand specificity of the calcitonin receptor-like receptor. Nature 393:333–339CrossRefPubMedGoogle Scholar
  25. Moreno MJ, Abounader R, Hebert E, Doods H, Hamel E (2002a) Efficacy of the non-peptide CGRP receptor antagonist BIBN4096BS in blocking CGRP-induced dilations in human and bovine cerebral arteries: potential implications in acute migraine treatment. Neuropharmacology 42:568–576Google Scholar
  26. Moreno MJ, Terron JA, Stanimirovic DB, Doods H, Hamel E (2002b) Characterization of calcitonin gene-related peptide (CGRP) receptors and their receptor-activity-modifying proteins (RAMPs) in human brain microvascular and astroglial cells in culture. Neuropharmacology 42:270–280Google Scholar
  27. Olesen J, Diener H-C, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM, BIBN4096BS Clinical Proof of Concept Study Group (2004) Calcitonin-gene-related peptide receptor antagonist BIBN4096BS for the acute treatment of migraine. N Engl J Med 350:1104–1110CrossRefPubMedGoogle Scholar
  28. Poyner DR, Sexton PM, Marshall I, Smith DM, Quirion R, Born W, Muff R, Fischer JA, Foord SM (2002) International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol Rev 54:233–246CrossRefPubMedGoogle Scholar
  29. Saldanha G, Honho J, Plant G, Acheson J, Levy I, Anand P (1999) Decreased CGRP, but preserved Trk A immunoreactivity in nerve fibres in inflamed human superficial temporal arteries. J Neurol Neurosurg Psychiatry 66:390–392PubMedGoogle Scholar
  30. Sams A, Jansen-Olesen I (1998) Expression of calcitonin receptor-like receptor and receptor-activity-modifying proteins in human cranial arteries. Neurosci Lett 258:41–44CrossRefPubMedGoogle Scholar
  31. Sams A, Yenidunya A, Engberg J, Jansen-Olesen I (1999) Equipotent in vitro actions of alpha- and beta-CGRP on guinea pig basilar artery are likely to be mediated via CRLR derived CGRP receptors. Regul Pept 23:67–75CrossRefGoogle Scholar
  32. Uddman R, Edvinsson L, Jansen I, Stiernholm P, Jensen K, Olesen J, Sundler F (1986) Peptide-containing fibres in human extracranial tissue: a morphological basis for neuropeptide involvement in extracranial pain. Pain 27:391–399CrossRefPubMedGoogle Scholar
  33. Van Rossum D, Hanisch UK, Quirion R (1997) Neuroanatomical localization and functions of CGRP, related peptides and their receptors. Neurosci Biobehav Rev 21:649–678CrossRefPubMedGoogle Scholar
  34. Verheggen R, Freudenthaler S, Meyer-Dulheuer F, Kaumann AJ (1996) Participation of 5-HT1-like and 5-HT2A receptors in the contraction of human temporal artery by 5-hydroxytryptamine and related drugs. Br J Pharmacol 117:283–289Google Scholar
  35. Verheggen R, Bumann K, Kaumann AJ (2002) BIBN4096BS is a potent competitive antagonist of the relaxant effects of α-CGRP on human temporal artery: comparison with CGRP(8-37). Br J Pharmacol 136:120–126Google Scholar
  36. Verheggen R, Wotjas K, Bumann K, Kaumann AJ (2003) Relaxant effects of β-CGRP on human temporal artery. Comparison with α-CGRP and antagonism by BIBN4096BS and α-CGRP8-37. Naunyn-Schmiedebergs Arch Pharmacol 367[Suppl 1]:R37Google Scholar
  37. Verheggen R, Meier A, Werner I, Wienekamp A, Kruschat T, Brattelid T, Levy FO, Kaumann AJ (2004) Functional 5-HT receptors in human occipital artery. Naunyn-Schmiedebergs Arch Pharmacol 369:391–401CrossRefPubMedGoogle Scholar
  38. Wu D, Doods H, Arndt K, Schindler M (2002) Development and potential of non-peptide antagonists for calcitonin-gene-related peptide (CGRP) receptors: evidence for CGRP receptor heterogeneity. Biochem Soc Trans 30:468–473CrossRefPubMedGoogle Scholar
  39. Yoshimoto R, Mitsui-Saito M, Ozaki H, Karaki H (1998) Effects of adrenomedullin and calcitonin gene-related peptide on contractions of the rat aorta and porcine coronary artery. Br J Pharmacol 123:1645–1654Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Raphaela Verheggen
    • 1
  • Kordian Wojtas
    • 1
  • Martin Webel
    • 1
  • Steffi Hoffmann
    • 1
  • Alberto J. Kaumann
    • 2
  1. 1.Department of NeurosurgeryUniversity of GöttingenGöttingenGermany
  2. 2.Department of PhysiologyUniversity of CambridgeCambridgeUK

Personalised recommendations