The complexity of cardiovascular responses produced by 5-hydroxytryptamine (5-HT, serotonin), including bradycardia or tachycardia, hypotension or hypertension, and vasodilatation or vasoconstriction, has been explained by the capability of this monoamine to interact with different receptors in the central nervous system (CNS), on the autonomic ganglia and postganglionic nerve endings, on vascular smooth muscle and endothelium, and on the cardiac tissue. Depending, among other factors, on the species, the vascular bed under study, and the experimental conditions, these responses are mainly mediated by 5-HT(1), 5-HT(2), 5-HT(3), 5-HT(4), 5-ht(5A/5B), and 5-HT(7) receptors as well as by a tyramine-like action or unidentified mechanisms. It is noteworthy that 5-HT(6) receptors do not seem to be involved in the cardiovascular responses to 5-HT. Regarding heart rate, intravenous (i.v.) administration of 5-HT usually lowers this variable by eliciting a von Bezold-Jarisch-like reflex via 5-HT(3) receptors located on sensory vagal nerve endings in the heart. Other bradycardic mechanisms include cardiac sympatho-inhibition by prejunctional 5-HT(1B/1D) receptors and, in the case of the rat, an additional 5-ht(5A/5B) receptor component. Moreover, i.v. 5-HT can increase heart rate in different species (after vagotomy) by a variety of mechanisms/receptors including activation of: (1) myocardial 5-HT(2A) (rat), 5-HT(3) (dog), 5-HT(4) (pig, human), and 5-HT(7) (cat) receptors; (2) adrenomedullary 5-HT(2) (dog) and prejunctional sympatho-excitatory 5-HT(3) (rabbit) receptors associated with a release of catecholamines; (3) a tyramine-like action mechanism (guinea pig); and (4) unidentified mechanisms (certain lamellibranch and gastropod species). Furthermore, central administration of 5-HT can cause, in general, bradycardia and/or tachycardia mediated by activation of, respectively, 5-HT(1A) and 5-HT(2) receptors. On the other hand, the blood pressure response to i.v. administration of 5-HT is usually triphasic and consists of an initial short-lasting vasodepressor response due to a reflex bradycardia (mediated by 5-HT(3) receptors located on vagal afferents, via the von Bezold-Jarisch-like reflex), a middle vasopressor phase, and a late, longer-lasting, vasodepressor response. The vasopressor response is a consequence of vasoconstriction mainly mediated by 5-HT(2A) receptors; however, vasoconstriction in the canine saphenous vein and external carotid bed as well as in the porcine cephalic arteries and arteriovenous anastomoses is due to activation of 5-HT(1B) receptors. The late vasodepressor response may involve three different mechanisms: (1) direct vasorelaxation by activation of 5-HT(7) receptors located on vascular smooth muscle; (2) inhibition of the vasopressor sympathetic outflow by sympatho-inhibitory 5-HT(1A/1B/1D) receptors; and (3) release of endothelium-derived relaxing factor (nitric oxide) by 5-HT(2B) and/or 5-HT(1B/1D) receptors. Furthermore, central administration of 5-HT can cause both hypotension (mainly medi...

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.

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Background and purpose: Resistance blood vessels are innervated by sympathetic and primary sensory nerves, which modulate vascular tone through the release of noradrenaline and calcitonin gene-related peptide (CGRP), respectively. Moreover, electrical stimulation of the perivascular sensory outflow in pithed rats results in vasodepressor responses which are mainly mediated by CGRP release. The present study has investigated the role of a 2 -adrenoceptors in the inhibition of these vasodepressor responses. Experimental approach: 144 pithed male Wistar rats were pretreated with hexamethonium (2 mg kg À1 min À1 ) followed by i.v. continuous infusions of either methoxamine (15 and 30 mg kg À1 min À1 ) or clonidine (3, 10 and 30 mg kg À1 min À1 ). Under these conditions, electrical stimulation (0.56-5.6 Hz; 50 V and 2 ms) of the spinal cord (T 9 -T 12 ) resulted in frequencydependent decreases in diastolic blood pressure. Key results: The infusion of clonidine (10 mg kg À1 min À1 ), as compared to those of methoxamine (15 or 30 mg kg À1 min À1 ), inhibited the vasodepressor responses to electrical stimulation without affecting those to i.v. bolus injections of a-CGRP (0.1-1 mg kg À1 ). This inhibition by clonidine was: (i) antagonized by 300 mg kg À1 rauwolscine (a 2A/2B/2C ), 300 and 1000 mg kg À1 BRL44408 (a 2A ), or 10 and 30 mg kg À1 MK912 (a 2C ); and (ii) unaffected by 1 ml kg À1 saline, 100 mg kg À1 BRL44408, 3000 and 10000 mg kg À1 imiloxan (a 2B ) or 3 mg kg À1 MK912. Conclusions and implications:The inhibition produced by 10 mg kg À1 min À1 clonidine on the vasodepressor (perivascular) sensory outflow in rats may be mainly mediated by prejunctional a 2A /a 2C -adrenoceptors.

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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.

1 Continuous infusions of 5-hydroxytryptamine (5-HT) inhibit the tachycardiac responses to preganglionic (C 7 -T 1 ) sympathetic stimulation in pithed rats pretreated with desipramine. The present study identified the pharmacological profile of this inhibitory action of 5-HT. 2 The inhibition induced by intravenous (i.v.) continuous infusions of 5-HT (5.6 mg kg À1 min À1) on sympathetically induced tachycardiac responses remained unaltered after i.v. treatment with saline or the antagonists GR 127935 (5-HT 1B/1D ), the combination of WAY 100635 (5-HT 1A ) plus GR 127935, ritanserin (5-HT 2 ), tropisetron (5-HT 3/4 ), LY215840 (5-HT 7 ) or a cocktail of antagonists/inhibitors consisting of yohimbine (a 2 ), prazosin (a 1 ), ritanserin, GR 127935, WAY 100635 and indomethacin (cyclooxygenase), but was abolished by methiothepin (5-HT 1/2/6/7 and recombinant 5-ht 5A/5B ). These drugs, used in doses high enough to block their respective receptors/mechanisms, did not modify the sympathetically induced tachycardiac responses per se. 3 I.v. continuous infusions of the agonists 5-carboxamidotryptamine (5-CT; 5-HT 1/7 and recombinant 5-ht 5A/5B ), CP 93,129 (r5-HT 1B ), sumatriptan (5-HT 1B/1D ), PNU-142633 (5-HT 1D ) and ergotamine (5-HT 1B/1D and recombinant 5-ht 5A/5B ) mimicked the above sympatho-inhibition to 5-HT. In contrast, the agonists indorenate (5-HT 1A ) and LY344864 (5-ht 1F ) were inactive. Interestingly, 5-CT-induced cardiac sympatho-inhibition was abolished by methiothepin, the cocktail of antagonists/ inhibitors, GR 127935 or the combination of SB224289 (5-HT 1B ) plus BRL15572 (5-HT 1D ), but remained unchanged when SB224289 or BRL15572 were given separately. 4 Therefore, 5-HT-induced cardiac sympatho-inhibition, being unrelated to 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-ht 6 , 5-HT 7 receptors, a 1/2 -adrenoceptor or prostaglandin synthesis, seems to be primarily mediated by (i) 5-HT 1 (probably 5-HT 1B/1D ) receptors and (ii) a novel mechanism antagonized by methiothepin that, most likely, involves putative 5-ht 5A/5B receptors.

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