title: The anti-migraine 5-HT(1B/1D) agonist rizatriptan inhibits neurogenic dural vasodilation in anaesthetized guinea-pigs.
abstract: These studies investigated the pharmacology of neurogenic dural vasodilation in anaesthetized guinea-pigs. Following introduction of a closed cranial window the meningeal (dural) blood vessels were visualized using intravital microscopy and the diameter constantly measured using a video dimension analyser. Dural blood vessels were constricted with endothelin-1 (3 microg kg(-1), i.v.) prior to dilation of the dural blood vessels with calcitonin gene-related peptide (CGRP; 1 microg kg(-1), i.v.) or local electrical stimulation (up to 300 microA) of the dura mater. In guinea-pigs pre-treated with the CGRP receptor antagonist CGRP((8-37)) (0.3 mg kg(-1), i.v.) the dilator response to electrical stimulation was inhibited by 85% indicating an important role of CGRP in neurogenic dural vasodilation in this species. Neurogenic dural vasodilation was also blocked by the 5-HT(1B/1D) agonist rizatriptan (100 microg kg(-1)) with estimated plasma levels commensurate with concentrations required for anti-migraine efficacy in patients. Rizatriptan did not reverse the dural dilation evoked by CGRP indicating an action on presynaptic receptors located on trigeminal sensory fibres innervating dural blood vessels. In addition, neurogenic dural vasodilation was also blocked by the selective 5-HT(1D) agonist PNU-142633 (100 microg kg(-1)) but not by the 5-HT(1F) agonist LY334370 (3 mg kg(-1)) suggesting that rizatriptan blocks neurogenic vasodilation via an action on 5-HT(1D) receptors located on perivascular trigeminal nerves to inhibit CGRP release. This mechanism may underlie one of the anti-migraine actions of the triptan class exemplified by rizatriptan and suggests that the guinea-pig is an appropriate species in which to investigate the pharmacology of neurogenic dural vasodilation.
authors.affiliation: Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK. david_williamson@merck.com
authors.forename: D J
authors.initials: DJ
authors.lastname: Williamson
authors.forename: R G
authors.initials: RG
authors.lastname: Hill
authors.forename: S L
authors.initials: SL
authors.lastname: Shepheard
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
mesh_terms: D000758:Anesthesia; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002839:Chromans / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004388:Dura Mater / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008576:Meningeal Arteries / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D008881:Migraine Disorders / Q000517:prevention & control; D010446:Peptide Fragments / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D014363:Tryptamines; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C108218:4-fluoro-N-(3-(1-methyl-4-piperidinyl)-1H-indol-5-yl)benzamide; D001549:Benzamides; D002839:Chromans; C470302:HTR1B protein, human; D007211:Indoles; D010446:Peptide Fragments; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014230:Triazoles; D014363:Tryptamines; C058636:calcitonin gene-related peptide (8-37); C093622:rizatriptan; D015740:Calcitonin Gene-Related Peptide; C401885:PNU 142633F