A61603-induced contractions of the porcine meningeal artery are mediated by alpha1- and alpha2-adrenoceptors.

It has recently been shown that A61603 (N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]methane sulphonamide), a potent alpha(1A)-adrenoceptor agonist, decreased carotid artery conductance in anaesthetized pigs by a novel non-adrenergic mechanism. In this study, we set out to pharmacologically characterize A61603-induced contractions of the porcine isolated meningeal artery. While the maximum contractile responses of the artery were similar, A61603 (E(max): 183 +/- 23% of 100 mM KCl; pEC(50): 7.25 +/- 0.18) was more potent than noradrenaline (E(max): 156 +/- 16%; pEC(50): 5.75 +/- 0.17) or phenylephrine (E(max): 163 +/- 20%; pEC(50): 5.63 +/- 0.02). Prazosin (pA(2): 9.36 +/- 0.23) and, to a lesser extent, rauwolscine (pK(b): 6.36 +/- 0.38) and yohimbine (pK(b): 7.30 +/- 0.15) antagonised the contractions to A61603. The 5-HT(1B) (GR127935; N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide) and 5-HT(2) (ritanserin) receptor antagonists failed to affect the responses to A61603, but methiothepin, which, in addition, has a high affinity for alpha-adrenoceptors, proved an effective antagonist. The A61603-induced responses were suppressed by the cAMP stimulator forskolin, but not by the protein kinase C inhibitor chelerythrine. Our results suggest that the contraction of porcine isolated meningeal artery by A61603 is mediated via mainly alpha(1)-(probably alpha(1A)) and, to a lesser extent, alpha(2)-adrenoceptors, involving the adenylyl cyclase, but not the diacylglycerol pathway.

The Role of 5-Hydroxytryptamine in the Pathophysiology of Migraine and its Relevance to the Design of Novel Treatments.

BACKGROUND: Migraine is a highly prevalent neurovascular disorder. OBJECTIVE: Of the many factors that have been implicated over the years, 5-hydroxytryptamine (5-HT; serotonin) has long been involved in the pathophysiology of migraine. Certainly, some lines of evidence suggest: (i) a 5-HT depletion from blood platelets resulting in cranial extracerebral vasodilatation; and (ii) the effectiveness of an intravenous (i.v.) infusion of 5-HT to abort migraine in some patients. More direct evidence comes from some drugs that influence 5-HT release and/or interact (as agonists or antagonists) with 5-HT receptors to treat this disorder. Indeed, the development of sumatriptan and second generation triptans in the 1990's led to discover that these drugs produce selective cranial extracerebral vasoconstriction (via 5-HT1B receptors) and inhibition of the trigeminovascular system responses implicated in migraine (via 5-HT1D/5-HT1F receptors). Although the triptans represent the current mainstay of acute antimigraine treatment, a number of patients do not respond well to the triptans and are contraindicated in patients with cardiovascular pathologies. CONCLUSION: This mini-review outlines further developments in the design of novel (non-vasoconstrictor) antimigraine treatments acting via 5-HT receptors, including selective agonists at 5-HT1D and 5-HT1F receptors, agonists at 5-HT1B/1D receptors combined with other properties as well as antagonists at 5-HT2B/2C, 5-HT3 and 5-HT7 receptors. It also touches upon the recent development of antagonists and antibodies at calcitonin gene-related peptide (CGRP) and its receptors, which produce a direct blockade of the CGRPergic vasodilator mechanisms involved in migraine. These alternative pharmacological approaches will hopefully lead to less side-effects.

Effects of female sex hormones on responses to CGRP, acetylcholine, and 5-HT in rat isolated arteries.

BACKGROUND: Female sex hormones are implicated in the modulation of reactivity of a wide range of blood vessels under physiological as well as pathological conditions. Migraine, a neurovascular syndrome, is 3 times more prevalent in women during their reproductive period than in men. OBJECTIVE: This study sets out to investigate the effects of the female sex steroids, 17beta-estradiol and progesterone (separately and in combination) on vasoactive responses to calcitonin gene-related peptide (CGRP), acetylcholine, and 5-hydroxytryptamine (5-HT) in rat isolated mesenteric, caudal, and basilar arteries. METHODS: Female Sprague-Dawley rats were ovariectomized (Day 0) and 7 days later subcutaneously implanted with pellets releasing over a 21-day period 17beta-estradiol (0.25 mg), progesterone (50 mg), their combination, or placebo. On days 25-28, the animals were killed, arteries isolated and mounted in Mulvany myographs, and cumulative concentration response curves to CGRP, acetylcholine, and 5-HT were constructed. RESULTS: The relaxant responses to CGRP were significantly potentiated in mesenteric and caudal arteries from rats treated with 17beta-estradiol as compared to the placebo-treated rats. Acetylcholine-induced relaxations were potentiated in the caudal artery from rats treated with the combination of 17beta-estradiol and progesterone, as compared to that from placebo-treated rats. The 5-HT-induced contractions in the 3 arteries were not significantly different in efficacy or potency. CONCLUSION: Our results show that 17beta-estradiol potentiates CGRP-induced relaxations in the mesenteric and caudal arteries, while the combination treatment enhances acetylcholine-induced relaxations in the caudal artery. Although these in vitro experiments have been carried out in rats and a direct extrapolation to migraine in humans is not possible, our results may provide a new avenue to study the effects of sex steroids on vascular reactivity.