title: Assessment of anti-migraine potential of a novel alpha-adrenoceptor agonist S19014: effects on porcine carotid and regional haemodynamics and human coronary artery.
abstract: Taking into account the drawbacks associated with the use of triptans, attempts are being made to explore other avenues for the treatment of migraine. Recently, it has been shown that both alpha1- and alpha2-adrenoceptors mediate the constriction of porcine carotid arteriovenous anastomoses, which has effectively served as an experimental model predictive of anti-migraine activity. The present study investigated the effects of a novel alpha-adrenoceptor agonist S19014 (spiro[(1,3-diazacyclopent-1-ene)-5 : 2'-(4',5'-dimethylindane)] fumarate) on carotid and systemic haemodynamics in anaesthetized pigs, and on human isolated coronary arteries. Increasing doses of S19014 (1-30 micro g/kg, i.v.) produced a dose-dependent initial short-lasting vasopressor response and a decrease of total carotid blood flow and conductance. The carotid blood flow and conductance changes were exclusively due to constriction of carotid arteriovenous anastomoses (capillary blood flow increased) and were accompanied by an increase in arterio-jugular venous oxygen saturation difference. Whereas prazosin (100 micro g/kg, i.v.) was ineffective, rauwolscine (300 micro g/kg, i.v.) attenuated the responses to S19014. The compound did not much affect the distribution of cardiac output to peripheral organs when compared with the vehicle group. Furthermore, S19014 only slightly contracted the human isolated coronary artery and its contractions, contrary to those of sumatriptan, were not increased in blood vessels pre-contracted with U46619. These results suggest that (i) the systemic and carotid vascular effects of S19014 are mainly mediated by alpha2-adrenoceptors, and (ii) S19014 could be effective in the treatment of migraine with an improved cardiovascular tolerance.
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute 'COEUR', Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Kapoor
authors.forename: E W
authors.initials: EW
authors.lastname: Willems
authors.forename: A
authors.initials: A
authors.lastname: Maassen VanDenBrink
authors.forename: J P C
authors.initials: JP
authors.lastname: Heiligers
authors.forename: A A
authors.initials: AA
authors.lastname: Cordi
authors.forename: C
authors.initials: C
authors.lastname: Vayssettes-Courchay
authors.forename: T J
authors.initials: TJ
authors.lastname: Verbeuren
authors.forename: C M
authors.initials: CM
authors.lastname: Villalón
authors.forename: P R
authors.initials: PR
authors.lastname: Saxena
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000328:Adult; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy* / Q000503:physiopathology; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: D000316:Adrenergic alpha-Agonists; D007189:Indans; D011942:Receptors, Adrenergic, alpha; D013141:Spiro Compounds; C495412:spiro((1,3-diazacyclopent-1-ene)-5 : 2'-(4',5'-dimethylindan)) fumarate