Mechanisms of blockade by the novel migraine prophylactic agent, dotarizine, of various brain and peripheral vessel contractility.
The novel antimigraineur, dotarizine, inhibited 5-HT (5 hydroxytryptamine)-evoked contractions of rabbit vertebral, aorta, femoral and mesenteric arteries, with IC(50)s of 1.35, 1.40, 0.52 and 1.09 microM, respectively. Flunarizine had little effect on these contractions, while ketanserin was more potent (IC(50)s of 0.17 microM for vertebral, 0.22 microM for aorta, 0.05 microM for femoral and 0.03 microM for mesenteric arteries). At 10 microM, 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 microM flunarizine. Contractions of rabbit aorta elicited by noradrenaline, angiotensin II or prostaglandin F(2alpha) were not affected by 10 microM dotarizine or flunarizine. Ketanserin shifted to the right, in parallel, the concentration-response curves for 5-HT in rabbit aorta; however, dotarizine caused a non-competitive type of blockade, increasing the maximum 5-HT contraction at 30 nM and decreasing it at 3 and 30 microM. K(+)-evoked contractions of rabbit aorta were halved by 3 microM dotarizine in a voltage-independent manner; flunarizine caused a delayed-type, non-reversible post-drug blockade, and exhibited some voltage-dependence. Blockade by nifedipine was voltage-dependent and fully reversible. Ca(2+)-evoked contractions of depolarised bovine middle cerebral arteries were blocked by 1--3 microM dotarizine in a non-surmountable manner. Contraction of these vessels evoked by electrical stimulation was blocked 50% and 70% by 1 and 3 microM dotarizine, respectively. Dotarizine (1--3 microM) also inhibited to a similar extent the K(+)-evoked [(3)H]noradrenaline release from cultured rat sympathetic neurones. These data suggest that the mechanism of blockade by dotarizine of cerebral vessels contractility has three components: (i) presynaptic inhibition of noradrenaline release; (ii) blockade of postsynaptic vascular 5-HT receptors; (iii) blockade of Ca(2+)entry into the vascular smooth muscle cell cytosol. The compound does not affect the vascular receptors for noradrenaline, angiotensin II or prostaglandin F(2alpha).
Ruiz-Nuño
A
A
Departamento de Farmacología, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, 28029 Madrid, Spain.
Villarroya
M
M
Cano-Abad
M
M
Rosado
A
A
Balfagón
G
G
López
M G
MG
García
A G
AG
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001808:Blood Vessels / Q000187:drug effects* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002417:Cattle; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D004558:Electric Stimulation; D004594:Electrophysiology; D005444:Flunarizine / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000502:physiology; D008881:Migraine Disorders / Q000517:prevention & control*; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D001559:Benzhydryl Compounds; D002121:Calcium Channel Blockers; D010879:Piperazines; D012702:Serotonin Antagonists; D014665:Vasodilator Agents; D012701:Serotonin; C083946:dotarizine; D005444:Flunarizine; D009638:Norepinephrine