Carlos M. Villalón

Cardiovascular responses produced by 5-hydroxytriptamine: a pharmacological update on the receptors/mechanisms involved and therapeutic implications

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-HT1, 5-HT2, 5-HT3, 5-HT4, 5-ht5A/5B, and 5-HT7 receptors as well as by a tyramine-like action or unidentified mechanisms. It is noteworthy that 5-HT6 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-HT3 receptors located on sensory vagal nerve endings in the heart. Other bradycardic mechanisms include cardiac sympatho-inhibition by prejunctional 5-HT1B/1D receptors and, in the case of the rat, an additional 5-ht5A/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-HT2A (rat), 5-HT3 (dog), 5-HT4 (pig, human), and 5-HT7 (cat) receptors; (2) adrenomedullary 5-HT2 (dog) and prejunctional sympatho-excitatory 5-HT3 (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-HT1A and 5-HT2 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-HT3 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-HT2A 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-HT1B receptors. The late vasodepressor response may involve three different mechanisms: (1) direct vasorelaxation by activation of 5-HT7 receptors located on vascular smooth muscle; (2) inhibition of the vasopressor sympathetic outflow by sympatho-inhibitory 5-HT1A/1B/1D receptors; and (3) release of endothelium-derived relaxing factor (nitric oxide) by 5-HT2B and/or 5-HT1B/1D receptors. Furthermore, central administration of 5-HT can cause both hypotension (mainly mediated by 5-HT1A receptors) and hypertension (mainly mediated by 5-HT2 receptors). The increasing availability of new compounds with high affinity and selectivity for the different 5-HT receptor subtypes makes it possible to develop drugs with potential therapeutic usefulness in the treatment of some cardiovascular illnesses including hypertension, migraine, some peripheral vascular diseases, and heart failure.

Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy

The last decade has witnessed a tremendous progress in the acute therapy of migraine, with sumatriptan, belonging to a new class of drugs, now known as 5-HT(1B/1D/1F) receptor agonists, leading the way. The undoubted success of sumatriptan stimulated the development of new triptans as well as other suitable pharmacological tools and experimental models to probe into complex migraine mechanisms. In this review, we discuss the main experimental models for migraine, against the background of the disease pathophysiology and 5-HT receptors considered most important for migraine therapy. We believe that the use of these migraine models will provide even better treatment for migraine patients in the next millennium.

The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs

Migraine is a highly prevalent neurovascular disorder that can be provoked by infusion of calcitonin gene-related peptide (CGRP). CGRP, a neuropeptide released from activated trigeminal sensory nerves, dilates intracranial and extracranial blood vessels and centrally modulates vascular nociception. On this basis, it has been proposed that: (i) CGRP may play an important role in the pathophysiology of migraine; and (ii) blockade of CGRP receptors may abort migraine. With the advent of potent and selective CGRP receptor antagonists, the importance of CGRP in the pathophysiology of migraine and the therapeutic principle of CGRP receptor antagonism were clearly established. Indeed, both olcegepant (BIBN4096BS, given intravenously) and telcagepant (MK-0974, given orally) have been shown to be safe, well tolerated and effective acute antimigraine agents in phase I, phase II, and for telcagepant phase III, studies. However, recent data reported elevated liver transaminases when telcagepant was dosed twice daily for three months for the prevention of migraine rather than acutely. The potential for a specific acute antimigraine drug, without producing vasoconstriction or vascular side effects and with an efficacy comparable to triptans, is enormous. The present review will discuss the role of CGRP in the pathophysiology of migraine and the various treatment modalities that are currently available to target this neuropeptide.

Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends

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.

5-Hydroxytryptamine: a chameleon in the heart.

5-HT has profound effects on cardiac rate and force in a variety of animal species, including humans. The main initial response to 5-HT is a short-lasting bradycardia, mediated via a Bezold-Jarisch-like reflex, and initiated by stimulation of 5-HT3 receptors present on cardiac vagal afferents. Once this bradycardia is suppressed, 5-HT induces cardiac stimulation which, true to its chameleonic nature described here by Pramod Saxena and Carlos Villalón, is mediated by different mechanisms and receptors in different species. In several species, including humans, coronary vasodilatation is mediated by 5-HT1-like receptors, while both 5-HT1-like and 5-HT2 receptors mediate vasoconstriction. This knowledge may lead to a better assessment of the possible role of 5-HT in cardiovascular pathologies and to the development of selective 5-HT receptor agonists and antagonists for therapeutic usefulness in heart failure, coronary vasospasm and to avoid potential cardiac side-effects.

Mediation of 5-hydroxytryptamine-induced tachycardia in the pig by the putative 5-HT4 receptor

Intravenous bolus Injections of 5‐hydroxytryptamine (5‐HT; 3, 10 and 30 μg kg−1), 5‐methoxytryptamine (5‐MeO‐T; 3, 10 and 30 μg kg−1), renzapride (BRL 24924; 3, 10, 30 and 100μgkg−1) and isoprenaline (0.03, 0.1 and 0.3 μg kg−1) to anaesthetized pigs increased heart rate by, respectively, 22 ± 3, 44 ± 3 and 65 ± 4 beats min−1 (5‐HT; n = 17); 12 ± 1, 26 ± 2 and 44 ± 4 beats min−1 (5‐MeO‐T; n = 15), 5 ± 2, 11 ± 2, 18 ± 4 and 37 ± 5 beats min−1 (renzapride; n = 8) and 17 ± 2, 46 ± 3 and 75 ± 3 beats min−1 (isoprenaline; n = 13). The responses to 5‐HT, 5‐MeO‐T and renzapride were antagonized by ICS 205–930 (1 and 3 mg kg−1, i.v.), which did not modify the increases in heart rate by isoprenaline. Renzapride showed tachyphylaxis and attenuated the responses to 5‐HT. These findings indicate that 5‐HT elicits tachycardia in the pig by acting on a novel receptor, either similar or identical to the 5‐HT4 receptor identified in mouse brain colliculi.

Role of 5‐HT1‐like receptors in the reduction of porcine cranial arteriovenous anastomotic shunting by sumatriptan

1 The new tryptamine derivative sumatriptan (GR43175) is effective in the treatment of migraine. Since several antimigraine agents reduce cranial arteriovenous anastomotic blood flow in the anaesthetized pig, we have investigated the carotid haemodynamic effects of sumatriptan. 2 Sumatriptan (10, 30, 100 and 300 μg kg−1, i.v.) reduced total common carotid blood flow, exclusively by affecting its arteriovenous anastomotic fraction; the capillary fraction even increased with the highest doses. 3 These reductions in the carotid arteriovenous anastomotic (‘shunt’) blood flow were mediated by a 5‐HT1‐like receptor, as methiothepin, but not ketanserin, antagonized the responses to sumatriptan. 4 Sumatriptan increased the difference in oxygen saturation between arterial and jugular venous blood, which is likely to be a consequence of the reduction of the carotid shunt blood flow. 5 The selective reduction in arteriovenous anastomotic blood flow produced by sumatriptan may reflect its antimigraine action, thought to involve vasoconstriction of those cranial vessels, be they ‘shunt’ vessels or not, which are distended and inflamed during a migraine attack.

Role of endothelium in the vasodilating effect of progestins and androgens on the rat thoracic aorta

1. In the rat thoracic aorta, contractions induced by noradrenaline were inhibited by the steroids progesterone, pregnanolone, testosterone and 5 alpha- and 5 beta-dihydrotestosterone. 2. Removal of endothelium did not prevent relaxation to the steroids, suggesting that the vasodilating effect of steroids occurred on the smooth muscle cells. 3. gamma-Aminobutyric acid (GABA) did not modify noradrenaline-induced contraction. Thus, the vasodilation elicited by steroids is not apparently mediated by GABA receptors. 4. On the basis that noradrenaline opens receptor-operated calcium channels to induce contraction, we suggest that relaxation by steroids involves a blockade of this type of channels.

Cardiovascular Alterations After Spinal Cord Injury: An Overview

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.

Basic mechanisms of migraine and its acute treatment.

Migraine is a neurovascular disorder characterized by recurrent unilateral headaches accompanied by nausea, vomiting, photophobia and phonophobia. Current theories suggest that the initiation of a migraine attack involves a primary event in the central nervous system (CNS), probably involving a combination of genetic changes in ion channels and environmental changes, which renders the individual more sensitive to environmental factors; this may, in turn, result in a wave of cortical spreading depression (CSD) when the attack is initiated. Genetically, migraine is a complex familial disorder in which the severity and the susceptibility of individuals are most likely governed by several genes that vary between families. Early PET studies have suggested the involvement of a migraine active region in the brainstem. Migraine headache is associated with trigeminal nerve activation and calcitonin gene-related peptide (CGRP) release from the trigeminovascular system. Administration of triptans (5-HT(1B/1D) receptor agonists) causes the headache to subside and the levels of CGRP to normalize. Moreover, administration of CGRP receptor antagonists aborts the headache. Recent immunohistochemical and pharmacological results suggest that the trigeminal system has receptors for CGRP; further, 5-HT(1B/1D) receptors, which inhibit the action of CGRP in pain transmission when activated, have been demonstrated. This offers an explanation for the treatment response. The present review provides an updated analysis of the basic mechanisms involved in the pathophysiology of migraine and the various pharmacological approaches (including 5-HT(1B/1D) receptor agonists, CGRP receptor antagonists and glutamate receptor antagonists) that have shown efficacy for the acute treatment of this disorder.