Migraine treatment has evolved into the scientific arena, but it seems still controversial whether migraine is primarily a vascular or a neurological dysfunction. Irrespective of this controversy, the levels of serotonin (5-hydroxytryptamine, 5-HT), a vasoconstrictor and a central neurotransmitter, seem to decrease during migraine (with associated carotid vasodilatation) whereas an i.v. infusion of 5-HT can abort migraine. In fact, 5-HT as well as ergotamine, dihydroergotamine and other antimigraine agents invariably produce vasoconstriction in the external carotid circulation. The last decade has witnessed the advent of sumatriptan and second generation triptans (e.g. zolmitriptan, rizatriptan, naratriptan), which belong to a new class of drugs, the 5-HT1B / 1D / 1F receptor agonists. Compared to sumatriptan, the second-generation triptans have a higher oral bioavailability and longer plasma half-life. In line with the vascular and neurogenic theories of migraine, all triptans produce selective carotid vasoconstriction (via 5-HT1B receptors) and presynaptic inhibition of the trigeminovascular inflammatory responses implicated in migraine (via 5-HT1D / 5-ht1F receptors). Moreover, selective agonists at 5-HT1D (PNU-142633) and 5-ht1F (LY344864) receptors inhibit the trigeminovascular system without producing vasoconstriction. Nevertheless, PNU-142633 proved to be ineffective in the acute treatment of migraine, whilst LY344864 did show some efficacy when used in doses which interact with 5-HT1B receptors. Finally, although the triptans are effective antimigraine agents producing selective cranial vasoconstriction, efforts are being made to develop other effective antimigraine alternatives acting via the direct blockade of vasodilator mechanisms (e.g. antagonists at CGRP receptors, antagonists at 5-HT7 receptors, inhibitors of nitric oxide biosynthesis, etc). These alternatives will hopefully lead to fewer side effects.

The recent developments in the management of spinal cord injury (SCI) have led to a reduction in mortality and in the consequences, resulting from incomplete spinal cord damage in those who survive. In this respect, it is noteworthy that SCI not only results in paraplegia or tetraplegia, but also in systemic, cardiovascular and metabolic alterations secondary to autonomic dysfunction. After SCI there is a decrease in sympathetic discharge and an increase in parasympathetic drive, resulting in profound changes in arterial blood pressure and heart rate. When SCI is induced in experimental animals, an immediate hypotension occurs (acute phase) which has been attributed to an autonomic imbalance involving a predominance of parasympathetic activity. Subsequently, an episodic hypertension may develop (chronic phase) as a part of a condition denominated autonomic dysreflexia. This hypertension is caused by afferent stimulation below the level of injury and can be so severe that sometimes may lead to cerebral haemorrhage, seizures, and death. In the light of the above lines of evidence, experimental SCI may provide an ideal model to study the nature of cardiovascular mechanisms following traumatic injury. Thus, the present review will deal with an update of the possible cardiovascular complications associated to SCI (including spinal shock, autonomic dysreflexia, deep venous thrombosis, and risk for coronary heart disease). This will be discussed within the context of the development of drugs with potential therapeutic usefulness in the acute and chronic stages of SCI.

The antimigraine drugs methysergide, ergotamine and dihydroergotamine (DHE) produce selective vasoconstriction in the external carotid bed of vagosympathectomized dogs anaesthetized with pentobarbital and artificially respired, but the receptors involved have not yet been completely characterized. Since the above drugs display affinity for several binding sites, including alpha-adrenoceptors and several 5-HT1 and 5-HT2 receptor subtypes, this study has analysed the mechanisms involved in the above responses. Intracarotid (i.c.) infusions during 1 min of methysergide (31-310 microg min(-1)), ergotamine (0.56-5.6 microg min(-1)) or DHE (5.6-31 microg min(-1)) dose-dependently reduced external carotid blood flow (ECBF) by up to 46+/-4, 37+/-4 and 49+/-5%, respectively. Blood pressure and heart rate remained unchanged. The reductions in ECBF by methysergide were abolished and even reversed to increases in animals pre-treated with GR127935 (10 microg kg(-1), i.v.). The reductions in ECBF by ergotamine and DHE remained unchanged in animals pre-treated (i.v.) with prazosin (300 microg kg(-1)), but were partly antagonized in animals pre-treated with either GR127935 (10 or 30 microg kg(-1)) or yohimbine (1000 microg kg(-1)). Pre-treatment with a combination of GR127935 (30 microg kg(-1)) and yohimbine (1000 microg kg(-1)) abolished the responses to both ergotamine and DHE. The above doses of antagonists were shown to produce selective antagonism at their respective receptors. These results suggest that the external carotid vasoconstrictor responses to methysergide primarily involve 5-HT1B/1D receptors, whereas those to ergotamine and DHE are mediated by 5-HT1B/1D receptors as well as alpha2-adrenoceptors.

The vasodilator effects of 5‐hydroxytryptamine (5‐HT) in the external carotid bed of anaesthetized dogs with intact sympathetic tone are mediated by prejunctional sympatho‐inhibitory 5‐HT_1B/1D receptors and postjunctional 5‐HT receptors. The prejunctional vasodilator mechanism is abolished after vagosympathectomy which results in the reversal of the vasodilator effect to vasoconstriction. The blockade of this vasoconstrictor effect of 5‐HT with the 5‐HT_1B/1D receptor antagonist, GR 127935, unmasks a dose‐dependent vasodilator effect of 5‐HT, but not of sumatriptan. Therefore, the present study set out to analyse the pharmacological profile of this postjunctional vasodilator 5‐HT receptor in the external carotid bed of vagosympathectomized dogs pretreated with GR 127935 (20 μg kg⁻¹, i.v.). One‐minute intracarotid (i.c.) infusions of 5‐HT (0.330 μg min⁻¹), 5‐carboxamidotryptamine (5‐CT; 0.010.3 μg min⁻¹), 5‐methoxytryptamine (1100 μg min⁻¹) and lisuride (31000 μg min⁻¹) resulted in dose‐dependent increases in external carotid blood flow (without changes in blood pressure or heart rate) with a rank order of agonist potency of 5‐CT>>5‐HT5‐methoxytryptamine>lisuride, whereas cisapride (1001000 μg min⁻¹, i.c.) was practically inactive. Interestingly, lisuride (mean dose of 85±7 μg kg⁻¹, i.c.), but not cisapride (mean dose of 67±7 μg kg⁻¹, i.c.), specifically abolished the responses induced by 5‐HT, 5‐CT and 5‐methoxytryptamine, suggesting that a common site of action may be involved. In contrast, 1 min i.c. infusions of 8‐OH‐DPAT (33000 μg min⁻¹) produced dose‐dependent decreases, not increases, in external carotid blood flow and failed to antagonize (mean dose of 200±33 μg kg⁻¹, i.c.) the agonist‐induced vasodilator responses. The external carotid vasodilator responses to 5‐HT, 5‐CT and 5‐methoxytryptamine were not modified by intravenous (i.v.) pretreatment with either saline, (±)‐pindolol (4 mg kg⁻¹) or ritanserin (100 μg kg⁻¹) plus granisetron (300 μg kg⁻¹), but were dose‐dependently blocked by i.v. administration of methiothepin (10 and 30 μg kg⁻¹, given after ritanserin plus granisetron), mesulergine (10 and 30 μg kg⁻¹), metergoline (1 and 3 mg kg⁻¹), methysergide (1 and 3 mg kg⁻¹) or clozapine (0.3 and 1 mg kg⁻¹). Nevertheless, the blockade of the above responses, not significant after treatment with the lower of the two doses of metergoline and mesulergine, was nonspecific after administration of the higher of the two doses of methysergide and clozapine. Based upon the above rank order of agonist potencies and the antagonism produced by a series of drugs showing high affinity for the cloned 5‐ht₇ receptor, our results indicate that the 5‐HT receptor mediating external carotid vasodilatation in GR 127935‐pretreated vagosympathectomized dogs is operationally similar to the putative 5‐HT₇ receptor mediating relaxation of vascular and non‐vascular smooth muscles (e.g. rabbit femoral vein, canine coronary artery, rat systemic vasculature and guinea‐pig ileum) as well as tachycardia in the cat. British Journal of Pharmacology (1997) 120, 1319–1327; doi:10.1038/sj.bjp.0701020