Abstract
It has previously been suggested that ergotamine produces external carotid vasoconstriction in vagosympathectomised dogs via 5-HT1B/1D receptors and α2-adrenoceptors. The present study has reanalysed this suggestion by using more selective antagonists alone and in combination. Fifty-two anaesthetised dogs were prepared for ultrasonic measurements of external carotid blood flow. The animals were divided into thirteen groups (n=4 each) receiving an i.v. bolus injection of, either physiological saline (0.3 ml/kg; control), or the antagonists SB224289 (300 μg/kg; 5-HT1B), BRL15572 (300 µg/kg; 5-HT1D), rauwolscine (300 µg/kg; α2), SB224289 + BRL15572 (300 µg/kg each), SB224289 + rauwolscine (300 µg/kg each), BRL15572 + rauwolscine (300 µg/kg each), rauwolscine (300 µg/kg) + prazosin (100 µg/kg; α1), SB224289 (300 µg/kg) + prazosin (100 µg/kg), SB224289 (300 µg/kg) + rauwolscine (300 µg/kg) + prazosin (100 µg/kg), SB224289 (300 µg/kg) + prazosin (100 µg/kg) + BRL44408 (1,000 µg/kg; α2A), SB224289 (300 µg/kg) + prazosin (100 µg/kg)+ imiloxan (1,000 µg/kg; α2B), or SB224289 (300 µg/kg) + prazosin (100 µg/kg) + MK912 (300 µg/kg; α2C). Each group received consecutive 1-min intracarotid infusions of ergotamine (0.56, 1, 1.8, 3.1, 5.6, 10 and 18 µg/min), following a cumulative schedule. In saline-pretreated animals, ergotamine induced dose-dependent decreases in external carotid blood flow without affecting arterial blood pressure or heart rate. These control responses were: unaffected by SB224289, BRL15572, rauwolscine or the combinations of SB224289 + BRL15572, BRL15572 + rauwolscine, rauwolscine + prazosin, SB224289 + prazosin, or SB224289 + prazosin + imiloxan; slightly blocked by SB224289 + rauwolscine; and markedly blocked by SB224289 + rauwolscine + prazosin, SB224289 + prazosin + BRL44408 or SB224289 + prazosin + MK912. Thus, the cranio-selective vasoconstriction elicited by ergotamine in dogs is predominantly mediated by 5-HT1B receptors as well as α2A/2C-adrenoceptor subtypes and, to a lesser extent, by α1-adrenoceptors.
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References
Baxter GS (1996) Novel discriminatory ligands for 5-HT2B receptors. Behave Brain Rees 73:149–152
Bylund DB, Iceberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP, Molinoff PB, Ruffolo RR Jr, Trendelenburg U (1994) International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol Rev 46:121–136
Den Boer MO, Heiligers JP, Saxena PR (1991) Carotid vascular effects of ergotamine and dihydroergotamine in the pig: no exclusive mediation via 5-HT1-like receptors. Br J Pharmacol 104:183–189
Devedjian JC, Esclapez F, Denis-Pouxviel C, Paris H (1994) Further characterization of human α2-adrenoceptor subtypes: [3H]RX821002 binding and definition of additional selective drugs. Eur J Pharmacol 252:43–49
De Vries P, Apaydin S, Villalón CM, Heiligers JP, Saxena PR (1997) Interactions of GR127935, a 5-HT1B/D receptor ligand, with functional 5-HT receptors. Naunyn-Schmiedebergs Arch Pharmacol 355:423–430
De Vries P, Sanchez Lopez A, Centurión D, Heiligers JP, Saxena PR, Villalón CM (1998a) The canine external carotid vasoconstrictor 5-HT1 receptor: blockade by 5-HT1B (SB224289), but not by 5-HT1D (BRL15572) receptor antagonists. Eur J Pharmacol 362:69–72
De Vries P, Villalón CM, Heiligers JP, Saxena PR (1998b) Characterization of 5-HT receptors mediating constriction of porcine carotid arteriovenous anastomoses; involvement of 5-HT1B/1D and novel receptors. Br J Pharmacol 123:1561–1570
De Vries P, Willems EW, Heiligers JPC, Villalón CM, Saxena PR (1999) Investigations of the role of 5-HT1B and 5-HT1D receptors in the sumatriptan-induced constriction of porcine carotid arteriovenous anastomoses. Br J Pharmacol 127:405–412
Ennis MD, Ghazi NB, Hoffman RL, Smith MW, Shatter SK, Lawson CF, Imp WB, Pretender JF, Swenson KA, Lewis RA, Hall ED, Sutter DM, Harris LT, McCall RB (1998) Isochroman-6-carboxamides as highly selective 5-HT1D agonists: potential new treatment for migraine without cardiovascular side effects. J Med Chem. 41:2180–2183
Gaster LM, Blarney FE, Davies S, Duckworth DM, Ham P, Jenkins S, Jennings AJ, Joiner GF, King FD, Mulholland KR, Wyman PA, Hagan JJ, Hatcher J, Jones BJ, Middlemiss DN, Price GW, Riley G, Roberts C, Routledge C, Selkirk J, Slade PD (1998) The selective 5-HT1B receptor inverse agonist 1’-methyl-5-[[2’-methyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydro-spiro[furo[2,3-f]indole-3,4’-piperidine] (SB-224289) potently blocks terminal 5-HT autoreceptor function both in vitro and in vivo. J Med Chem 41:1218–1235
Glusa E, Roos A (1996) Endothelial 5-HT receptors mediate relaxation of porcine pulmonary arteries in response to ergotamine and dihydroergotamine. Br J Pharmacol 119:330–334
Hagan JJ, Slade PD, Gaster L, Jeffrey P, Hatcher JP, Middlemiss DN (1997) Stimulation of 5-HT1B receptors causes hypothermia in the guinea pig. Eur J Pharmacol 331:169–174
Hieble JP, Bondinell WE, Ruffolo RJ (1995) α- and β-Adrenoceptors: from the gene to the clinic. I. Molecular biology and adrenoceptor subclassification. J Med Chem 38:3415–3444
Hoyer D (1988) Functional correlates of serotonin 5-HT1 recognition sites. J Rec Res 8:59–81
Kleinman LI, Radford EP (1964) Ventilation standards for small mammals. J Appl Physiol 19:360–362
Leysen JE, Gommeren W (1984) In vitro receptor binding profile of drugs used in migraine. In: Amery WK, van Nueten JM, Wauquier A (eds) The pharmacological basis of migraine therapy. Pitman, London, pp 255–266
Price GW, Burton MJ, Collin LJ, Duckworth M, Gaster L, Gothert M, Jones BJ, Roberts C, Watson JM, Middlemiss DN (1997) SB-216641 and BRL-15572—compounds to pharmacologically discriminate h5-HT1B and h5-HT1D receptors. Naunyn-Schmiedebergs Arch Pharmacol 356:312–320
Saxena PR, De Vlaam-Schluter GM (1974) Role of some biogenic substances in migraine and relevant mechanism in antimigraine action of ergotamine—studies in an experimental model for migraine. Headache 13:142–163
Saxena PR, Tfelt-Hansen P (2000) Triptans, 5-HT1B/1D receptor agonists in the acute treatment of migraine. In: Olesen J, Tfelt-Hansen P, Welch KMA (eds) The headaches. Lippincott Williams & Wilkins, Philadelphia, pp 411–438
Skingle M, Beattie DT, Scopes DIT, Starkey SJ, Connor HE, Feniuk W, Tyers MB (1996) GR127935: a potent and selective 5-HT1D receptor antagonist. Behav Brain Res 73:157–161
Steel RGD, Torrie JH (1980) Principles and procedures of statistics. A biomedical approach. McGraw Hill Kogakusha, Tokyo
Terrón JA, Ramírez-San Juan E, Hong E, Villalón CM (1996) Role of α1-adrenoceptors in the reduction of external carotid blood flow induced by buspirone and ipsapirone in the dog. Life Sci 58:63–73
Tfelt-Hansen P, Saxena PR, Dahlof C, Pascual J, Lainez M, Henry P, Diener H, Schoenen J, Ferrari MD, Goadsby PJ (2000) Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 123:9–18
Vargas HM, Gorman AJ (1995) Vascular alpha-1 adrenergic receptor subtypes in the regulation of arterial pressure. Life Sci 57:2291–2308
Vayssettes-Courchay C, Bouysset F, Cordi AA, Laubie M, Verbeuren TJ (1996) A comparative study of the reversal by different α2-adrenoceptor antagonists of the central sympatho-inhibitory effect of clonidine. Br J Pharmacol 117:587–593
Villalón CM, Terrón JA, Hong E (1993) Role of 5-HT1-like receptors in the increase in external carotid blood flow induced by 5-hydroxytryptamine in the dog. Eur J Pharmacol 240:9–20
Villalón CM, De Vries P, Rabelo G, Centurión D, Sánchez-López A, Saxena PR (1999) Canine external carotid vasoconstriction to methysergide, ergotamine and dihydroergotamine: a role of 5-HT1B/1D receptors and α2-adrenoceptors. Br J Pharmacol 126:385–394
Villalón CM, Sánchez-López A, Centurión D, Saxena PR (2001) Unravelling the pharmacological profile of the canine external carotid vasodilator “5-HT1-like” receptors: coexistence of sympathoinhibitory 5-HT1B receptors and postjunctional 5-HT7 receptors. Naunyn-Schmiedebergs Arch Pharmacol 363:73–80
Villalón CM, Centurión D, Valdivia LF, De Vries P, Saxena PR (2002) An introduction to migraine: from ancient treatment to functional pharmacology and antimigraine therapy. Proc West Pharmacol Soc 45:199–210
Villalón CM, Centurión D, Willems EW, Arulmani U, Saxena PR, Valdivia LF (2004) 5-HT1B receptors and α2A/2C-adrenoceptors mediate external carotid vasoconstriction to dihydroergotamine. Eur J Pharmacol 484:287–290
Wainscott DB, Sasso DA, Kursar JD, Baez M, Lucaites VL, Nelson DL (1998) [3H]Rauwolscine: an antagonist radioligand for the cloned human 5-hydroxytryptamine2b (5-HT2B) receptor. Naunyn-Schmiedebergs Arch Pharmacol 357:17–24
Willems EW, Valdivia LF, Ramírez-San Juan E, Saxena PR, Villalón CM (2001a) Pharmacological identification of the major subtypes of adrenoceptors involved in the canine external carotid vasoconstrictor effects of adrenaline and noradrenaline. Life Sci 69:143–153
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-Schmiedebergs Arch Pharmacol 364:27–32
Willems EW, Valdivia LF, Saxena PR, Villalón CM (2001c) The role of several α1- and α2-adrenoceptor subtypes mediating vasoconstriction in the canine external carotid circulation. Br J Pharmacol 132:1292–1298
Acknowledgements
The authors thank Mr. Arturo Contreras for his skilful technical assistance. We are also indebted to the pharmaceutical companies (see Drugs section) and CONACYT (México), for their support.
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In memoriam: Luis F. Valdivia died on 26 May 2004
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Valdivia, L.F., Centurión, D., Arulmani, U. et al. 5-HT1B receptors, α2A/2C- and, to a lesser extent, α1-adrenoceptors mediate the external carotid vasoconstriction to ergotamine in vagosympathectomised dogs. Naunyn-Schmiedeberg's Arch Pharmacol 370, 46–53 (2004). https://doi.org/10.1007/s00210-004-0947-0
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DOI: https://doi.org/10.1007/s00210-004-0947-0