title: Comparison of contractile responses to donitriptan and sumatriptan in the human middle meningeal and coronary arteries.
abstract: Donitriptan is a potent, high efficacy agonist at 5-HT(1B/1D) receptors. We investigated the contractile effects of donitriptan and sumatriptan on human isolated blood vessels of relevance to therapeutic efficacy in migraine (middle meningeal artery) and coronary adverse events (coronary artery). Furthermore, using the concentration-response curves in the middle meningeal artery, we predicted the plasma concentration needed for the therapeutic effect of donitriptan. Both donitriptan and sumatriptan contracted the middle meningeal artery with similar apparent efficacy (E(max): 103+/-8% and 110+/-12%, respectively), but the potency of donitriptan (pEC(50): 9.07+/-0.14) was significantly higher than that of sumatriptan (pEC(50): 7.41+/-0.08). In the coronary artery, the contraction to donitriptan was biphasic with a significantly higher maximal response (E(max): 29+/-6%) than sumatriptan (E(max): 14+/-2%; pEC(50): 5.71+/-0.16), yielding two distinct pEC(50) values (8.25+/-0.16 and 5.60+/-0.24). Incubation with the 5-HT(2) receptor antagonist ketanserin (10 microM) eliminated the low affinity component of the concentration-response curve of donitriptan and the resultant E(max) and pEC(50) were 9+/-2% and 7.33+/-0.21, respectively. Ketanserin was without effect on the sumatriptan-induced contraction. Based on the middle meningeal artery contraction, concentrations (C(max)) of donitriptan that may be expected to have a therapeutic efficacy equivalent to that of 50 and 100 mg sumatriptan are predicted to be around 2.5 and 4.3 nM, respectively. Such concentrations are likely to induce only a small coronary artery contraction of 2.9+/-1.5% and 3.8+/-2.0%, respectively; these are not different from those by C(max) concentrations of sumatriptan (1.7+/-0.4% or 2.2+/-0.4%). The present results suggest that, like sumatriptan, donitriptan exhibits cranioselectivity and would be effective in aborting migraine attacks with a similar coronary side-effect profile as sumatriptan.
authors.affiliation: Department of Pharmacology, Erasmus University Medical Centre Rotterdam, Post Box 1738, 3000 DR, Rotterdam, The Netherlands.
authors.forename: Rémon W M
authors.initials: RW
authors.lastname: van den Broek
authors.forename: Antoinette
authors.initials: A
authors.lastname: MaassenVanDenBrink
authors.forename: Paul G H
authors.initials: PG
authors.lastname: Mulder
authors.forename: Ad J J C
authors.initials: AJ
authors.lastname: Bogers
authors.forename: Cees J J
authors.initials: CJ
authors.lastname: Avezaat
authors.forename: Gareth W
authors.initials: GW
authors.lastname: John
authors.forename: Pramod R
authors.initials: PR
authors.lastname: Saxena
mesh_terms: D000328:Adult; D000368:Aged; D003331:Coronary Vessels / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008576:Meningeal Arteries / Q000187:drug effects*; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009570:Nitriles / Q000097:blood / Q000494:pharmacology*; D010879:Piperazines / Q000097:blood / Q000494:pharmacology*; D011237:Predictive Value of Tests; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000097:blood / Q000494:pharmacology*; D013373:Substance P / Q000494:pharmacology; D018170:Sumatriptan / Q000097:blood / Q000494:pharmacology*; D014363:Tryptamines; D014662:Vasoconstrictor Agents / Q000097:blood / Q000494:pharmacology*
chemical_list: C470302:HTR1B protein, human; D009570:Nitriles; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; D014662:Vasoconstrictor Agents; D013373:Substance P; C120143:donitriptan; D018170:Sumatriptan