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

Abstract 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 μM, respectively. Flunarizine had little effect on these contractions, while ketanserin was more potent (IC 50 s of 0.17 μM for vertebral, 0.22 μM for aorta, 0.05 μM for femoral and 0.03 μM for mesenteric arteries). At 10 μM, 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 μM flunarizine. Contractions of rabbit aorta elicited by noradrenaline, angiotensin II or prostaglandin F 2α  were not affected by 10 μM 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 μM. K + -evoked contractions of rabbit aorta were halved by 3 μM 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 μM dotarizine in a non-surmountable manner. Contraction of these vessels evoked by electrical stimulation was blocked 50% and 70% by 1 and 3 μM dotarizine, respectively. Dotarizine (1–3 μM) 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 2α .