Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 374, Issue 3, pp 163–175 | Cite as

Effects of current and prospective antimigraine drugs on the porcine isolated meningeal artery

  • Suneet Mehrotra
  • Saurabh Gupta
  • Ingrid M. Garrelds
  • Carlos M. Villalón
  • Pramod R. Saxena
  • Ad J. J. C. Bogers
  • Antoinette MaassenVanDenBrink
Original Article

Abstract

Vasoconstriction to agonists at serotonin (5-hydroxytryptamine; 5-HT) receptors and α-adrenoceptors, as well as vasodilatation induced by α-CGRP, have been well described in the porcine carotid circulation in vivo. The present study sets out to investigate the effects of current and prospective antimigraine drugs on porcine meningeal artery segments in vitro. Sumatriptan, ergotamine, dihydroergotamine, isometheptene and clonidine failed to contract the meningeal artery, but 5-HT, noradrenaline and phenylephrine induced concentration-dependent contractions. The contractions to 5-HT were competitively antagonized by the 5-HT2A receptor antagonist ketanserin, whilst those to noradrenaline were antagonized by α1-(prazosin), α2-(rauwolscine and yohimbine) and α2C/2B-(OPC-28326) adrenoceptor antagonists. Whilst dobutamine and salbutamol were ineffective, α-CGRP produced concentration-dependent relaxations that were antagonized by the CGRP1 receptor antagonist olcegepant. In agreement with their lack of contractile effect, sumatriptan and ergotamine failed to influence forskolin-stimulated cyclic AMP accumulation in the porcine meningeal artery; in contrast, both compounds decreased forskolin-stimulated cyclic AMP accumulation in the human isolated saphenous vein, where they induced contractions. Finally, using RT-PCR, we could demonstrate the presence of mRNAs encoding for several 5-HT receptors (5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A and 5-HT7) and adrenoceptors (α1A, α1B, α1D, α2A, α2B, α2C, β1 and β2), as well as that for the calcitonin receptor like receptor, a component of the CGRP1 receptor. These results suggest that: (i) the porcine meningeal artery may not be involved in the vasoconstriction of the carotid vascular bed elicited by antimigraine drugs in anaesthetized pigs, and (ii) the mismatch between the presence of receptor mRNA and the lack of response to sumatriptan, dobutamine and salbutamol implies that mRNAs for the 5-HT1B receptor and β1- and β2-adrenoceptors are probably unstable, or that their density is too low for being translated as receptor protein in sufficient quantities.

Keywords

Adrenoceptors Ergot alkaloids Human saphenous vein 5-Hydroxytryptamine 5-HT receptors Migraine Noradrenaline Porcine meningeal artery Sumatriptan 

Notes

Acknowledgements

We would like to thank the pharmaceutical companies for their kind donations of the compounds used in this investigation.

References

  1. Abrahamsen J (1991) Accumulation and release of adrenaline, and the modulation by adrenaline of noradrenaline release from rabbit blood vessels in vitro. Pharmacol Toxicol 69(Suppl 3):1–40PubMedCrossRefGoogle Scholar
  2. Akerman S, Goadsby PJ (2005) Topiramate inhibits trigeminovascular activation: an intravital microscopy study. Br J Pharmacol 146:7–14PubMedCrossRefGoogle Scholar
  3. Arulmani U, Heiligers JPC, Garrelds IM, Sanchez-Lopez A, Willems EW, Villalón CM, Saxena PR (2004) Effects of sumatriptan on capsaicin-induced carotid haemodynamic changes and CGRP release in anaesthetized pigs. Cephalalgia 24:717–727PubMedCrossRefGoogle Scholar
  4. Arunlakshana O, Schild HO (1959) Some quantitative uses of drug antagonists. Br J Pharmacol 14:48–58Google Scholar
  5. Batenburg WW, Popp R, Fleming I, De Vries R, Garrelds IM, Saxena PR, Danser AHJ (2004) Bradykinin-induced relaxation of coronary microarteries: S-nitrosothiols as EDHF? Br J Pharmacol 142:125–135PubMedCrossRefGoogle Scholar
  6. Bhalla P, Sharma HS, Wurch T, Pauwels PJ, Saxena PR (2000) Molecular cloning, sequence analysis and pharmacological properties of the porcine 5-HT1D receptor. Br J Pharmacol 131:949–957PubMedCrossRefGoogle Scholar
  7. Bhalla P, Sharma HS, Ma X, Wurch T, Pauwels PJ, Saxena PR (2001) Molecular cloning, pharmacological properties and tissue distribution of the porcine 5-HT1B receptor. Br J Pharmacol 133:891–901PubMedCrossRefGoogle Scholar
  8. Bou J, Domenech T, Puig J, Heredia A, Gras J, Fernandez-Forner D, Beleta J, Palacios JM (2000) Pharmacological characterization of almotriptan: an indolic 5-HT receptor agonist for the treatment of migraine. Eur J Pharmacol 410:33–41PubMedCrossRefGoogle Scholar
  9. Burstein R, Levy D, Jakubowski M (2005) Effects of sensitization of trigeminovascular neurons to triptan therapy during migraine. Rev Neurol (Paris) 161:658–660Google Scholar
  10. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate- phenol-chloroform extraction. Anal Biochem 162:156–159PubMedCrossRefGoogle Scholar
  11. Cocks TM, Kemp BK, Pruneau D, Angus JA (1993) Comparison of contractile responses to 5-hydroxytryptamine and sumatriptan in human isolated coronary artery: synergy with the thromboxane A2-receptor agonist, U46619. Br J Pharmacol 110:360–368PubMedGoogle Scholar
  12. De Vries P, Villalón CM, Heiligers JPC, Saxena PR (1998) Characterization of 5-HT receptors mediating constriction of porcine carotid arteriovenous anastomoses; involvement of 5-HT1B/1D and novel receptors. Br J Pharmacol 123:1561–1570PubMedCrossRefGoogle Scholar
  13. De Vries P, Villalón CM, Saxena PR (1999a) Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy. Eur J Pharmacol 375:61–74PubMedCrossRefGoogle Scholar
  14. De Vries P, Willems EW, Heiligers JPC, Villalón CM, Saxena PR (1999b) Investigation of the role of 5-HT1B and 5-HT1D receptors in the sumatriptan-induced constriction of porcine carotid arteriovenous anastomoses. Br J Pharmacol 127:405–412PubMedCrossRefGoogle Scholar
  15. Den Boer MO, Somers JA, Saxena PR (1992) Lack of effect of the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine on arteriovenous anastomotic shunting in the dura mater of the pig. Br J Pharmacol 107:577–583Google Scholar
  16. Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W (2000) Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol 129:420–423PubMedCrossRefGoogle Scholar
  17. Edvinsson L, Gulbenkian S, Barroso CP, Cunha e Sa M, Polak JM, Mortensen A, Jorgensen L, Jansen-Olesen I (1998) Innervation of the human middle meningeal artery: immunohistochemistry, ultrastructure, and role of endothelium for vasomotility. Peptides 19:1213–1225PubMedCrossRefGoogle Scholar
  18. 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 434:49–53PubMedCrossRefGoogle Scholar
  19. Goadsby PJ (2005) Migraine pathophysiology. Headache 45(Suppl 1):S14–S24PubMedCrossRefGoogle Scholar
  20. Guimarães S, Moura D (2001) Vascular adrenoceptors: an update. Pharmacol Rev 53:319–356PubMedGoogle Scholar
  21. Gupta S, Mehrotra S, Avezaat CJJ, Villalón CM, Saxena PR, MaassenVanDenBrink A (2006a) Characterisation of CGRP receptors in the human isolated middle meningeal artery. Life Sci 79:265–271PubMedCrossRefGoogle Scholar
  22. Gupta S, Mehrotra S, Villalón CM, Garrelds IM, de Vries R, van Kats JP, Sharma HS, Saxena PR, MaassenVanDenBrink A (2006b) Characterisation of CGRP receptors in human and porcine isolated coronary arteries: evidence for CGRP receptor heterogeneity. Eur J Pharmacol 530:107–116PubMedCrossRefGoogle Scholar
  23. Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PPA (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 46:157–203PubMedGoogle Scholar
  24. Jansen I, Edvinsson L, Mortensen A, Olesen J (1992) Sumatriptan is a potent vasoconstrictor of human dural arteries via a 5-HT1-like receptor. Cephalalgia 12:202–205PubMedCrossRefGoogle Scholar
  25. Kapoor K, Arulmani U, Heiligers JPC, Garrelds IM, Willems EW, Doods H, Villalón CM, Saxena PR (2003) Effects of the CGRP receptor antagonist BIBN4096BS on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Br J Pharmacol 140:329–338PubMedCrossRefGoogle Scholar
  26. Leysen JE, Awouters F, Kennis L, Laduron PM, Vandenberk J, Janssen PA (1981) Receptor binding profile of R 41 468, a novel antagonist at 5-HT2 receptors. Life Sci 28:1015–1022PubMedCrossRefGoogle Scholar
  27. Longmore J, Razzaque Z, Shaw D, Davenport AP, Maguire J, Pickard JD, Schofield WN, Hill RG (1998) Comparison of the vasoconstrictor effects of rizatriptan and sumatriptan in human isolated cranial arteries: immunohistological demonstration of the involvement of 5-HT1B-receptors. Br J Clin Pharmacol 46:577–582PubMedCrossRefGoogle Scholar
  28. MaassenVanDenBrink A, Bax WA, Ferrari MD, Zijlstra FJ, Bos E, Saxena PR (1996) Augmented contraction of the human isolated coronary artery by sumatriptan: a possible role for endogenous thromboxane. Br J Pharmacol 119:855–862Google Scholar
  29. MaassenVanDenBrink A, Reekers M, Bax WA, Ferrari MD, Saxena PR (1998) Coronary side-effect potential of current and prospective antimigraine drugs. Circulation 98:25–30PubMedGoogle Scholar
  30. MaassenVanDenBrink A, Van den Broek RWM, De Vries R, Upton N, Parsons AA, Saxena PR (2000a) The potential anti-migraine compound SB-220453 does not contract human isolated blood vessels or myocardium; a comparison with sumatriptan. Cephalalgia 20:538–545PubMedCrossRefGoogle Scholar
  31. MaassenVanDenBrink A, Van den Broek RWM, De Vries R, Bogers AJJC, Avezaat CJJ, Saxena PR (2000b) Craniovascular selectivity of eletriptan and sumatriptan in human isolated blood vessels. Neurology 55:1524–1530PubMedGoogle Scholar
  32. Mehrotra S, Gupta S, Villalón CM, Saxena PR, MaassenVanDenBrink A (2005) Effects of current and prospective antimigraine drugs in the porcine isolated meningeal artery. Cephalalgia 25:886Google Scholar
  33. Muller-Schweinitzer E (1983) Vascular effects of ergot alkaloids: a study on human basilar arteries. Gen Pharmacol 14:95–102PubMedGoogle Scholar
  34. Nyborg NC, Baandrup U, Mikkelsen EO, Mulvany MJ (1987) Active, passive and myogenic characteristics of isolated rat intramural coronary resistance arteries. Pflugers Arch 410:664–670PubMedCrossRefGoogle Scholar
  35. Olesen J, Diener H-C, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM, Group BBCPoCS (2004) Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 350:1104–1110PubMedCrossRefGoogle Scholar
  36. Orito K, Kishi M, Imaizumi T, Nakazawa T, Hashimoto A, Mori T, Kambe T (2001) α2-adrenoceptor antagonist properties of OPC–28326, a novel selective peripheral vasodilator. Br J Pharmacol 134:763–770PubMedCrossRefGoogle Scholar
  37. Roon KI, MaassenVanDenBrink A, Ferrari MD, Saxena PR (1999) Bovine isolated middle cerebral artery contractions to antimigraine drugs. Naunyn-Schmiedeberg’s Arch Pharmacol 360:591–596CrossRefGoogle Scholar
  38. Sahin-Erdemli I, Hoyer D, Stoll A, Seiler MP, Schoeffter P (1991) 5-HT1-like receptors mediate 5-hydroxytryptamine-induced contraction of guinea-pig isolated iliac artery. Br J Pharmacol 102:386–390PubMedGoogle Scholar
  39. Saxena PR (1978) Arteriovenous shunting and migraine. Res Clin Stud Headache 6:89–102PubMedGoogle Scholar
  40. Saxena PR, Koedam NA, Heiligers JPC, Hof RP (1983) Ergotamine-induced constriction of cranial arteriovenous anastomoses in dogs pretreated with phentolamine and pizotifen. Cephalalgia 3:71–81PubMedCrossRefGoogle Scholar
  41. Saxena PR, De Vries P, Wang W, Heiligers JPC, MaassenVanDenBrink A, Bax WA, Yocca FD (1997) Effects of avitriptan, a new 5-HT 1B/1D receptor agonist, in experimental models predictive of antimigraine activity and coronary side-effect potential. Naunyn-Schmiedeberg’s Arch Pharmacol 355:295–302CrossRefGoogle Scholar
  42. Schmuck K, Ullmer C, Kalkman HO, Probst A, Lubbert H (1996) Activation of meningeal 5-HT2B receptors: an early step in the generation of migraine headache? Eur J Neurosci 8:959–967PubMedCrossRefGoogle Scholar
  43. Schoeffter P, Pfeilschifter J, Bobirnac I (1995) 5-Hydroxytryptamine 5-HT1B receptors inhibiting cyclic AMP accumulation in rat renal mesangial cells. Naunyn-Schmiedeberg’s Arch Pharmacol 351:35–39CrossRefGoogle Scholar
  44. Sharma HS, Maulik N, Gho BC, Das DK, Verdouw PD (1996) Coordinated expression of heme oxygenase-1 and ubiquitin in the porcine heart subjected to ischemia and reperfusion. Mol Cell Biochem 157:111–116PubMedCrossRefGoogle Scholar
  45. Silberstein SD, McCrory DC (2003) Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache 43:144–166PubMedCrossRefGoogle Scholar
  46. Sun B, Lockyer S, Li J, Chen R, Yoshitake M, Kambayashi JI (2001) OPC-28326, a selective femoral vasodilator, is an α2C-adrenoceptor-selective antagonist. J Pharmacol Exp Ther 299:652–658PubMedGoogle Scholar
  47. Tadipatri S, Van Heuven-Nolsen D, Feniuk W, Saxena PR (1991) Analysis of the 5-HT receptors mediating contractions in the rabbit isolated renal artery. Br J Pharmacol 104:887–894PubMedGoogle Scholar
  48. Tfelt-Hansen P, De Vries P, Saxena PR (2000a) Triptans in migraine: a comparative review of pharmacology, pharmacokinetics and efficacy. Drugs 60:1259–1287PubMedCrossRefGoogle Scholar
  49. Tfelt-Hansen P, Saxena PR, Dahlöf C, Pascual J, Lainez M, Henry P, Diener H-C, Schoenen J, Ferrari MD, Goadsby PJ (2000b) Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 123:9-18PubMedCrossRefGoogle Scholar
  50. Tom B, Dendorfer A, De Vries R, Saxena PR, Danser AHJ (2002) Bradykinin potentiation by ACE inhibitors: a matter of metabolism. Br J Pharmacol 137:276-284PubMedCrossRefGoogle Scholar
  51. Valdivia LF, Centurión D, Perusquia M, Arulmani U, Saxena PR, Villalón CM (2004) Pharmacological analysis of the mechanisms involved in the tachycardic and vasopressor responses to the antimigraine agent, isometheptene, in pithed rats. Life Sci 74:3223–3234PubMedCrossRefGoogle Scholar
  52. Van den Broek RWM, Bhalla P, MaassenVanDenBrink A, De Vries R, Sharma HS, Saxena PR (2002) Characterization of sumatriptan-induced contractions in human isolated blood vessels using selective 5-HT1B and 5-HT1D receptor antagonists and in situ hybridization. Cephalalgia 22:83–93PubMedCrossRefGoogle Scholar
  53. Van Esch JH, Tom B, Dive V, Batenburg WW, Georgiadis D, Yiotakis A, Van Gool JM, De Bruijn RJ, De Vries R, Danser AHJ (2005) Selective angiotensin-converting enzyme C-domain inhibition is sufficient to prevent angiotensin I-induced vasoconstriction. Hypertension 45:120–125PubMedGoogle Scholar
  54. Verdouw PD, Duncker DJ, Saxena PR (1984) Poor vasoconstrictor response to adrenergic stimulation in the arteriovenous anastomoses present in the carotid vascular bed of young Yorkshire pigs. Arch Int Pharmacodyn Ther 272:56–70PubMedGoogle Scholar
  55. Verheggen R, Wojtas K, Webel M, Hoffmann S, Kaumann AJ (2005) BIBN4096BS and CGRP8-37 antagonize the relaxant effects of α-CGRP more than those of β-CGRP in human extracranial arteries. Naunyn-Schmiedeberg’s Arch Pharmacol 371:383–392CrossRefGoogle Scholar
  56. Villalón CM, Centurión D, Valdivia LF, De Vries P, Saxena PR (2003) Migraine: pathophysiology, pharmacology, treatment and future trends. Curr Vasc Pharmacol 1:71–84PubMedCrossRefGoogle Scholar
  57. Weinstein JS, Grossman W, Weintraub RM, Thurer RL, Johnson RG, Morgan KG (1989) Differences in α-adrenergic responsiveness between human internal mammary arteries and saphenous veins. Circulation 79:1264–1270PubMedGoogle Scholar
  58. Willems EW, Trion M, De Vries P, Heiligers JPC, Villalón CM, Saxena PR (1999) Pharmacological evidence that α1-and α2-adrenoceptors mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Br J Pharmacol 127:1263–1271PubMedCrossRefGoogle Scholar
  59. Willems EW, Heiligers JPC, De Vries P, Kapoor K, Tom B, Villalón CM, Saxena PR (2001a) α1-adrenoceptor subtypes mediating vasoconstriction in the carotid circulation of anaesthetized pigs: possible avenues for antimigraine drug development. Cephalalgia 21:110–119PubMedCrossRefGoogle Scholar
  60. Willems EW, Valdivia LF, Saxena PR, Villalón CM (2001b) Pharmacological profile of the mechanisms involved in the external carotid vascular effects of the antimigraine agent isometheptene in anaesthetised dogs. Naunyn-Schmiedeberg’s Arch Pharmacol 364:27–32CrossRefGoogle Scholar
  61. Willems EW, Valdivia LF, Villalón CM, Saxena PR (2003) Possible role of α-adrenoceptor subtypes in acute migraine therapy. Cephalalgia 23:245–257PubMedCrossRefGoogle Scholar
  62. Yildiz O, Cicek S, Ay I, Tatar H, Tuncer M (1996) 5-HT1-like receptor-mediated contraction in the human internal mammary artery. J Cardiovasc Pharmacol 28:6–10PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Suneet Mehrotra
    • 1
  • Saurabh Gupta
    • 1
  • Ingrid M. Garrelds
    • 1
  • Carlos M. Villalón
    • 2
  • Pramod R. Saxena
    • 1
  • Ad J. J. C. Bogers
    • 3
  • Antoinette MaassenVanDenBrink
    • 1
  1. 1.Department of Pharmacology, Cardiovascular Research Institute “COEUR”, Erasmus MCUniversity Medical Center RotterdamRotterdamThe Netherlands
  2. 2.Departamento de FarmacobiologíaMéxico D.F.Mexico
  3. 3.Thoracic Surgery, Erasmus MCUniversity Medical Center RotterdamRotterdamThe Netherlands

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