Mechanisms of blockade by the novel migraine prophylactic agent, dotarizine, of various brain and peripheral vessel contractility

Citation
A. Ruiz-nuno et al., Mechanisms of blockade by the novel migraine prophylactic agent, dotarizine, of various brain and peripheral vessel contractility, EUR J PHARM, 411(3), 2001, pp. 289-299
Citations number
38
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
EUROPEAN JOURNAL OF PHARMACOLOGY
ISSN journal
0014-2999 → ACNP
Volume
411
Issue
3
Year of publication
2001
Pages
289 - 299
Database
ISI
SICI code
0014-2999(20010112)411:3<289:MOBBTN>2.0.ZU;2-X
Abstract
The novel antimigraineur, dotarizine, inhibited 5-HT (5 hydroxytryptamine)- evoked contractions of rabbit vertebral, aortal femoral and mesenteric arte ries, with IC(50)s of 1.35, 1.40, 0.52 and 1.09 muM, respectively. Flunariz ine had little effect on these contractions, while ketanserin was more pote nt (IC(50)s of 0.17 muM for vertebral, 0.22 muM for aorta, 0.05 muM for fem oral and 0.03 muM for mesenteric arteries). At 10 muM. dotarizine caused 40 % blockade of K+-evoked contractions of rabbit aorta, and 70% inhibition of 5-HT-evoked responses; these values were 30% and 20% for 10 muM flunarizin e. Contractions of rabbit aorta elicited by noradrenaline, angiotensin II o r prostaglandin F-2 alpha were not affected by 10 muM dotarizine or flunari zine. Ketanserin shifted to the right, in parallel. the concentration-respo nse curves for 5-HT in rabbit aorta: however, dotarizine caused a non-compe titive type of blockade, increasing the maximum 5-HT contraction at 30 nM a nd decreasing it at 3 and 30 muM. K+-evoked contractions of rabbit aorta we re halved by 3 muM dotarizine in a voltage-independent manner; flunarizine caused a delayed-type. non-reversible post-drug blockade. and exhibited som e voltage-dependence. Blockade by nifedipine was voltage-dependent and full y reversible. Ca2+-evoked contractions of depolarised bovine middle cerebra l arteries were blocked by 1-3 muM dotarizine in a non-surmountable manner. Contraction of these vessels evoked by electrical stimulation was blocked 50% and 70% by 1 and 3 muM dotarizine. respectively. Dotarizine (1-3 ELM) a lso inhibited to a similar extent the K+-evoked [H-3]noradrenaline release from cultured rat sympathetic neurones. These data suggest that the mechani sm of blockade by dotarizine of cerebral vessels contractility has three co mponents: (i) presynaptic inhibition of noradrenaline: release; (ii) blocka de of postsynaptic vascular 5-HT receptors; (iii) blockade of Ca2+ entry in to the vascular smooth muscle cell cytosol. The compound does not affect th e vascular receptors for noradrenaline, angiotensin II or prostaglandin F-2 alpha. (C) 1001 Elsevier Science B.V. All rights reserved.