title: Cranioselectivity of sumatriptan revisited: pronounced contractions to sumatriptan in small human isolated coronary artery.
abstract: BACKGROUND
  Initial concerns about the coronary side-effect potential of the anti-migraine drug sumatriptan and second-generation triptans initiated cranioselectivity studies using proximal human coronary arteries. However, myocardial ischaemia may originate from both large and small human coronary arteries.
  
  
  METHODS
  We investigated the contractions to sumatriptan in proximal (internal diameter 2-3 mm), distal (internal diameter 1,000-1,500 μm) and small (internal diameter 500-1,000 μm) human epicardial coronary arteries and compared these with contractions in the human middle meningeal artery. Concentration response curves to sumatriptan in human coronary arteries were constructed in the absence or presence of the 5-hydroxytryptamine1B (5-HT1B) receptor antagonist SB224289 and the 5-HT1D receptor antagonist BRL15572. The effect of sumatriptan on increased cyclic adenosine monophosphate (cAMP) levels induced by forskolin in proximal and distal coronary artery segments was investigated using a biochemical assay. Western blotting was used to analyse the 5-HT1B receptor density in the human arteries.
  
  
  RESULTS
  Contractions in the proximal human coronary artery were significantly smaller than those in the human meningeal artery, as we showed previously. In contrast, contractions to sumatriptan in distal and small human coronary arteries were not different from those in the human meningeal artery. The 5-HT1B receptor antagonist SB224289, but not the 5-HT1D receptor antagonist BRL15572, inhibited the contraction induced by sumatriptan in the coronary arteries. Moreover, in distal, but not in proximal, coronary arteries, sumatriptan inhibited the increase in cAMP levels induced by forskolin. Contrary to our expectations, the 5-HT1B receptor expression was more pronounced in the proximal human coronary artery than in the distal and small human coronary artery.
  
  
  CONCLUSIONS
  Based on functional experiments in distal and small human coronary arteries, contractions to sumatriptan are not as cranioselective as previously assumed. However, the vast clinical experience with sumatriptan and other triptans has proven that these drugs are cardiovascularly safe when contraindications are taken into account.
authors.affiliation: Department of Internal Medicine, Division of Pharmacology, Erasmus Medical Centre, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: Kayi Y
authors.initials: KY
authors.lastname: Chan
authors.forename: Sieneke
authors.initials: S
authors.lastname: Labruijere
authors.forename: Martha B
authors.initials: MB
authors.lastname: Ramírez Rosas
authors.forename: René
authors.initials: R
authors.lastname: de Vries
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.forename: Alexander H J
authors.initials: AH
authors.lastname: Danser
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Villalón
authors.forename: Antoon
authors.initials: A
authors.lastname: van den Bogaerdt
authors.forename: Clemens
authors.initials: C
authors.lastname: Dirven
authors.forename: Antoinette
authors.initials: A
authors.lastname: MaassenVanDenBrink
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001713:Biphenyl Compounds / Q000494:pharmacology; D002648:Child; D005576:Colforsin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008576:Meningeal Arteries / Q000187:drug effects / Q000502:physiology; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D010881:Piperidones / Q000494:pharmacology; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology; D018170:Sumatriptan / Q000494:pharmacology*; D046509:Tissue Culture Techniques; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001713:Biphenyl Compounds; D010879:Piperazines; D010881:Piperidones; C108518:SB 22489G; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D013141:Spiro Compounds; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D005576:Colforsin; D018170:Sumatriptan; D000242:Cyclic AMP; C108532:BRL 15572