title: Pharmacological profile of the mechanisms involved in the external carotid vascular effects of the antimigraine agent isometheptene in anaesthetised dogs.
abstract: The present study set out to investigate the external carotid vascular effects of isometheptene in vagosympathectomised dogs, anaesthetised with pentobarbital. One-minute intracarotid (intra-arterial; i.a.) infusions of isometheptene (10, 30, 100 and 300 microg/min) produced dose-dependent decreases in external carotid blood flow, without affecting blood pressure or heart rate. The vasoconstrictor responses to 100 microg/min and 300 microg/min of isometheptene were clearly attenuated in animals pretreated with reserpine (5,000 microg/kg). Moreover, after prazosin (an alpha1-adrenoceptor antagonist; 100 microg/kg), the responses to isometheptene remained unaltered in untreated as well as reserpine-pretreated dogs. In contrast, the responses to isometheptene were attenuated by rauwolscine (an alpha2-adrenoceptor antagonist; 300 microg/kg) in untreated animals, and were practically abolished in reserpine-pretreated dogs. Further investigation into the specific alpha2-adrenoceptor subtypes, using selective antagonists, showed that BRL44408 (alpha2A) and MK912 (alpha2C) markedly attenuated this response, while imiloxan (alpha2B) was ineffective. The involvement of 5-HT1B and 5-HT1D receptors seems highly unlikely since antagonists at 5-HT1B (SB224289) and 5-HT1D (BRL15572) receptors (both at 300 microg/kg) were ineffective. On this basis, it is concluded that isometheptene-induced canine external carotid vasoconstriction is mediated by both indirect (a tyramine-like action) and direct (acting at receptors) mechanisms, which mainly involve alphaA- and alpha2C-adrenoceptors, while the involvement of alpha1-adrenoceptors seems rather limited.
authors.affiliation: Department of Pharmacology, Erasmus University Medical Centre Rotterdam, The Netherlands.
authors.forename: E W
authors.initials: EW
authors.lastname: Willems
authors.forename: L F
authors.initials: LF
authors.lastname: Valdivia
authors.forename: P R
authors.initials: PR
authors.lastname: Saxena
authors.forename: C M
authors.initials: CM
authors.lastname: Villalón
mesh_terms: D000758:Anesthesia; D000818:Animals; D002342:Carotid Artery, External / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D008744:Methylamines / Q000737:chemistry / Q000494:pharmacology*; D008881:Migraine Disorders / Q000188:drug therapy; D023421:Models, Animal; D015394:Molecular Structure; D011224:Prazosin / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012110:Reserpine / Q000494:pharmacology; D013562:Sympathectomy; D013566:Sympathomimetics / Q000737:chemistry / Q000494:pharmacology*; D014628:Vagotomy; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D008744:Methylamines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011985:Receptors, Serotonin; D013566:Sympathomimetics; D014662:Vasoconstrictor Agents; D012110:Reserpine; D011224:Prazosin; C008192:isometheptene