5-hydroxytryptamine receptors in the human cardiovascular

Pharmacology & Therapeutics 111 (2006) 674–706www.elsevier.com/locate/pharmthera

Associate editor: P. Molenaar

5-Hydroxytryptamine receptors in the human cardiovascular system

Alberto J. Kaumann a,⁎, Finn Olav Levy b,c

a Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, UKb Department of Pharmacology, University of Oslo, P.O. Box 1057 Blindern, 0316 Oslo, Norway

c Center for Heart Failure Research, University of Oslo, 0407 Oslo, Norway

Abstract

The human cardiovascular system is exposed to plasma 5-hydroxytryptamine (5-HT, serotonin), usually released from platelets. 5-HT canproduce harmful acute and chronic effects. The acute cardiac effects of 5-HT consist of tachycardia (preceded on occasion by a brief reflexbradycardia), increased atrial contractility and production of atrial arrhythmias. Acute inotropic, lusitropic and arrhythmic effects of 5-HT onhuman ventricle become conspicuous after inhibition of phosphodiesterase (PDE) activity. Human cardiostimulation is mediated through 5-HT4

receptors. Atrial and ventricular PDE3 activity exerts a protective role against potentially harmful cardiostimulation.Chronic exposure to high levels of 5-HT (from metastatic carcinoid tumours), the anorectic drug fenfluramine and its metabolites, as well as

the ecstasy drug 3,4-methylenedioxymethamphetamine (MDMA) and its metabolite 3,4-methylenedioxyamphetamine (MDA) are associated withproliferative disease and thickening of cardiac valves, mediated through 5-HT2B receptors. 5-HT2B receptors have an obligatory physiological rolein murine cardiac embryology but whether this happens in humans requires research. Congenital heart block (CHB) is, on occasion, associatedwith autoantibodies against 5-HT4 receptors.

Acute vascular constriction by 5-HT is usually shared by 5-HT1B and 5-HT2A receptors, except in intracranial arteries which constrict onlythrough 5-HT1B receptors. Both 5-HT1B and 5-HT2A receptors can mediate coronary artery spasm but only 5-HT1B receptors appear involved incoronary spasm of patients treated with triptans or with Prinzmetal angina. 5-HT2A receptors constrict the portal venous system includingoesophageal collaterals in cirrhosis. Chronic exposure to 5-HT can contribute to pulmonary hypertension through activation of constrictor 5-HT1B

receptors and proliferative 5-HT2B receptors, and possibly through direct intracellular effects.© 2006 Elsevier Inc. All rights reserved.

Keywords: 5-HT receptors; Human heart and blood vessels; Receptor polymorphisms; Cardiovascular disease

⁎ CorrespondingE-mail address

0163-7258/$ - seedoi:10.1016/j.phar

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6752. Molecular biology of 5-hydroxytryptamine receptors relevant to the human cardiovascular system 676

2.1. The 5-HT1 group of receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6762.2. The 5-HT2 group of receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6762.3. The 5-HT3 receptor: a ligand-gated ion channel . . . . . . . . . . . . . . . . . . . . . . 6762.4. The 5-HT4 receptor—a tale of splice variants . . . . . . . . . . . . . . . . . . . . . . . 6772.5. 5-HT5 and 5-HT6 receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6782.6. The 5-HT7 receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678

3. Cardiac 5-hydroxytryptamine receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6783.1. Heart rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679

3.1.1. Bradycardia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6793.1.2. Tachycardia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679

author. Tel.: +44 1223 333810.: [email protected] (A.J. Kaumann).

front matter © 2006 Elsevier Inc. All rights reserved.mthera.2005.12.004

mailto:[email protected]

http://dx.doi.org/10.1016/j.pharmthera.2005.12.004

675A.J. Kaumann, F.O. Levy / Pharmacology & Therapeutics 111 (2006) 674–706

3.2. Heart force . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6803.2.1. Atrium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6803.2.2. Ventricle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681

4. Vascular 5-hydroxytryptamine receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6814.1. Human arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681

4.1.1. Vasoconstriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6814.1.2. Vasorelaxation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683

4.2. Veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6844.2.1. Pulmonary veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6844.2.2. Hand veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6844.2.3. Saphenous veins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6844.2.4. Umibilical veins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 684

5. 5-Hydroxytryptamine receptors and cardiovascular disease . . . . . . . . . . . . . . . . . . . . . 6855.1. Genetic mutations and polymorphisms in 5-hydroxytryptamine receptors

possibly relevant to the human cardiovascular system . . . . . . . . . . . . . . . . . . . . 685
5.1.1. Polymorphisms in 5-HT1 receptors . . . . . . . . . . . . . . . . . . . . . . . . . 6855.1.2. Polymorphisms in 5-HT2 receptors . . . . . . . . . . . . . . . . . . . . . . . . . 6865.1.3. Polymorphisms in the 5-HT3 receptor. . . . . . . . . . . . . . . . . . . . . . . . 6875.1.4. Polymorphisms in the 5-HT4 receptor. . . . . . . . . . . . . . . . . . . . . . . . 6875.1.5. Polymorphisms in the 5-HT7 receptor. . . . . . . . . . . . . . . . . . . . . . . . 687
5.2. Heart disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6875.2.1. Physiological role of 5-hydroxytryptamine . . . . . . . . . . . . . . . . . . . . . 6875.2.2. Pathological role of 5-hydroxytryptamine . . . . . . . . . . . . . . . . . . . . . . 688

5.3. Vascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6925.3.1. Coronary spasm: different role of 5-HT1B and 5-HT2A receptors . . . . . . . . . . 6925.3.2. Pulmonary hypertension: role of 5-HT1B and 5-HT2B receptors . . . . . . . . . . 6935.3.3. Raynaud's vasospasm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6935.3.4. Migraine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6945.3.5. Portal hypertension and 5-HT2A receptors revisited . . . . . . . . . . . . . . . . . 694

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696

Table 1Functional effects mediated through the different 5-HT receptors in the humancardiovascular system

5-HT receptor Human cardiovascular function References

5-HT1A Renal vascular dilation? Verbeuren et al., 19915-HT1B Vasoconstriction Kaumann et al., 1993

Cerebral arteriolar dilation Elhusseiny & Hamel, 20015-HT1D Vascular nerve endings? Verheggen et al., 1998, 20045-HT1E Unknown5-HT1F Unknown5-HT2A Vasoconstriction Kaumann et al., 1993

Platelet aggregation De Clerck et al., 19845-HT2B Valvulopathy Fitzgerald et al., 2000

Vasodilation? Glusa & Pertz, 2000Embryology? Nebigil et al., 2000aPulmonary hypertension? Launay et al., 2002

5-HT2C Unknown5-HT3A/5-HT3B

Reflex bradycardia? Mohr et al., 1987Pain? Fu & Longhurst, 2002

5-HT4 Cardiostimulation Kaumann & Sanders, 1998Brattelid et al., 2004a, 2004b

Pulmonary vein dilation? Cocks & Arnold, 19925-HT5A Unknown5-HT6 Unknown5-HT7 Vascular relaxation? Schoeffter et al., 1996

Effects for which the documentation is uncertain or where there is nodocumentation in man are indicated with a question mark.

1. Introduction

Serotonin (5-hydroxytryptamine, 5-HT) exerts its multi-plicity of physiological effects through an unsurpasseddiversity of receptors (Hoyer et al., 1994, 2002). At least14 different 5-HT receptors, each encoded by a separate gene,are known in man and their roles in the human cardiovascularsystem summarised in Table 1. For some of these receptors,additional diversity is achieved through alternative splicing,RNA editing or posttranslational modifications. Furthermore,polymorphic variants and mutants of serotonin receptors arebeing unraveled, resulting in possible interindividual differ-ences in their response to serotonin (Göthert et al., 1998;Sanders-Bush et al., 2003).

A multitude of effects of 5-HT have been demonstrated onthe cardiovascular system. Some of these effects are mediatedthrough actions of 5-HT in the central nervous system, whereas5-HT also has multiple and diverse effects through directinteraction with 5-HT receptors in different parts of thecardiovascular system. In each of these, for example differentblood vessels or different parts of the heart, the physiologicaleffects of 5-HT depend on the 5-HT receptors involved, theintracellular signals evoked through these receptors, and theircellular localisation. The aim of this review is to present a

676 A.J. Kaumann, F.O. Levy / Pharmacology & Therapeutics 111 (2006) 674–706

comprehensive overview of the current knowledge about thediverse effects of 5-HT on the human cardiovascular system,with emphasis on the direct, peripheral effects, as opposed toeffects through the central nervous system, and to describe howthis knowledge translates into understanding and hypothesesregarding the involvement of 5-HT and 5-HT receptors in thepathogenesis and treatment of human cardiovascular disease.Particular emphasis will be put on the role of 5-HT in heartdisease and blood vessel disorders. We will also survey possibleeffects of polymorphic 5-HT receptor variants and mutants forhuman cardiovascular function.

2. Molecular biology of 5-hydroxytryptaminereceptors relevant to the human cardiovascular system

The 14 different 5-HT receptors are divided into 7 groups (5-HT1 through 5-HT7) based on molecular structure, signaltransduction properties and pharmacological properties (Hoyeret al., 1994, 2002).

2.1. The 5-HT1 group of receptors

The 5-HT1 group consists of 5 different receptors, 5-HT1A,5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F. These receptors allcouple via the G protein Gi with inhibition of adenylyl cyclaseas their primary signaling mechanism (Raymond et al., 2001).The genes encoding these receptors do not contain intronswithin the open reading frame, and therefore splice variants donot exist within this group. The 5-HT1A receptor is mainlylocated in the CNS, and except for a possible role in rat renalvasorelaxation (Verbeuren et al., 1991), there is no evidence fordirect cardiovascular effects mediated through this receptor.Furthermore, evidence for localisation of this receptor in theheart or blood vessels is also lacking. In contrast, the 5-HT1B

receptor is widely distributed in the cardiovascular system. The5-HT1B receptor, also previously known as 5-HT1Dβ (Hartig etal., 1992, 1996; Hoyer et al., 2002) is found on both endothelialcells and smooth muscle cells of several human vessels (Ullmeret al., 1995) including coronary and pulmonary artery (Fig. 2).The 5-HT1B receptor is mainly implicated in vasoconstriction(reviewed by Kaumann et al., 1993). The cardiovascular role ofthe 5-HT1D receptor (also previously known as 5-HT1Dα) is lessclear. Messenger RNA for 5-HT1D is generally less abundantthan for 5-HT1B, and is not found in endothelial cells or smoothmuscle cells from human blood vessel (Ullmer et al., 1995).However, the presence of this receptor in vascular nerves in theadventitial tissue may explain why we detected 5-HT1D mRNAin human temporal and occipital arteries, while no function ofthis receptor in contraction or relaxation of these arteries couldbe demonstrated (Verheggen et al., 1998, 2004). The 5-HT1B

receptors contribute to the vasocontriction elicited by 5-HT andtriptans in a variety of human arteries (Section 4.1.1) and veins(Section 4.2). Both 5-HT1B and 5-HT1D receptors are targetedby triptans, used to alleviate migraine attacks. 5-HT1B receptorsmediate both triptan-evoked vasoconstriction (for reviews, seeKaumann et al., 1993; Hall et al., 2004) and vasodilation(Elhusseiny & Hamel, 2001). The effects of triptans through the

5-HT1D receptor are believed to represent neuronal effects (e.g.inhibition of release of inflammatory neuropeptides; Goadsby etal., 2002).

The 5-HT1E receptor will not be further discussed in thisreview as there is no evidence of cardiovascular location oreffects of this receptor. The 5-HT1F receptor on the other handmay potentially be involved in the anti-migraine effect of atleast some of the triptans. However, this postulated effect isbelieved to result from inhibition of neurogenic inflammationbut not from vasoconstriction (Goldstein et al., 2001). The 5-HT1F-selective agonist LY334370 (Ki =0.5 nM; Wainscott et al.,2005) does not significantly constrict large cerebral arteriesfrom the temporo-parietal region (Shepheard et al., 1999) andthere was no correlation between the affinity of several agonistsfor 5-HT1F receptors and contraction of the human middlemeningeal artery (Razzaque et al., 1999).

Recent evidence suggests that the molecularly elusive so-called 5-HT1P receptor found in the gut (Gershon, 2005) mayrepresent an oligomeric form of the 5-HT1B receptor throughinteraction with either the D2 dopamine receptor (heterooligo-mers) or other 5-HT1B receptors (homooligomers; Liu &Gershon, 2005). As yet, there is no evidence for this receptorin the human cardiovascular system.

2.2. The 5-HT2 group of receptors

This receptor class contains 3 members, 5-HT2A, 5-HT2B and5-HT2C (Hoyer et al., 1994, 2002). These receptors coupleprimarily via the G proteins Gq or G11 to activation ofphospholipase (PL) C. As all the 5-HT2 receptor genes containintrons, additional receptor diversity due to alternative splicingis possible. To date though, only non-functional truncatedvariants of 5-HT2A (Guest et al., 2000) and 5-HT2C (Sanders-Bush et al., 2003; Flomen et al., 2004) have been demonstrated,whereas there is not yet any real evidence for alternativesplicing of human 5-HT2B receptors (Bonhaus et al., 1995; Kimet al., 2000). The 5-HT2A receptor is widespread in the humancardiovascular system. It is present on arterial smooth muscle(Ullmer et al., 1995) and mediates vasoconstriction (reviewedby Kaumann et al., 1993; Sections 4.1.1 and 4.2), whereas it isabsent on endothelial cells (Ullmer et al., 1995). It is alsopresent on platelets and facilitates platelet aggregation (DeClerck et al., 1984; De Chaffoy de Courcelles et al., 1985). The5-HT2B receptor mediates mitogenic signaling and may beinvolved in pulmonary hypertension (Section 5.3.2) as well asvalvulopathy (Section 5.2.2.5). Coupling of the 5-HT2B

receptor to the G protein G13 could also play a role (Deraet etal., 2005; Section 5.1.2.2). The 5-HT2C receptor has not beenfound in the cardiovascular system.

2.3. The 5-HT3 receptor: a ligand-gated ion channel

The 5-HT3 receptor is the only serotonin receptor which isnot a G protein-coupled receptor, but belongs to the Cys-loopfamily of receptors (Kelley et al., 2003). It is a pentamericligand-gated cation channel similar to the nicotinic acetylcho-line and GABAA receptors (Boess et al., 1995). Until recently, 2


human 5-HT3 receptor subunits had been cloned, 5-HT3A

(Belelli et al., 1995; Miyake et al., 1995) and 5-HT3B (Davies etal., 1999). However, 5 subunits of the human 5-HT3 receptorhave now been cloned, adding to the molecular complexity ofthis receptor family (Niesler et al., 2003). Although it is notformally proven whether the native pentameric 5-HT3 receptoris a homopentamer or a heteropentamer, results from expressionof recombinant subunits indicate that heteromeric complexesare more consistent with the properties of the native receptors(Davies et al., 1999; Dubin et al., 1999). There is also evidencefor alternatively spliced human 5-HT3 receptors (Brüss et al.,1998). In the heart, the 5-HT3 receptor is mainly believed to belocated on afferent vagal and sympathetic neurons, mediatingreflex bradycardia (Section 3.1.1) and pain (Section 5.2.2.3),

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Fig. 1. Human 5-HT4 receptor splice variants. Asterisks denote expression in humanterminal tail b (Bender et al., 2000).

respectively. 5-HT3 receptors could also mediate a possiblereflex vasodilation in the human forearm. Blauw et al. (1988)showed that infusion of 5-HT into the radial artery of healthyvolunteers elicited forearm vasodilation, assessed with venousplethysmography, that was prevented by the 5-HT3/5-HT4

antagonist tropisetron. However, direct vasodilation through 5-HT4 receptors has not been ruled out.

2.4. The 5-HT4 receptor—a tale of splice variants

The 5-HT4 receptor is positively coupled to the Gs protein/adenylyl cyclase system and, thus, cAMP formation (Langlois &Fischmeister, 2003). The human 5-HT4 receptor exists inmultiple splice variants (Fig. 1), which are identical up to Leu-

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heart. “h” indicates the extra exon “h”, so far only found in association with C-


358, followed by different C-terminal tails. These are named 5-HT4(a), 5-HT4(b), etc., with the 5-HT4(i) splice variant as the mostrecent addition to the list (Brattelid et al., 2004a). A splicevariant with an internal insertion of 42 nt corresponding to 14extra amino acids in the second extracellular domain was alsodescribed and was called 5-HT4(hb) because it was only found incombination with the 5-HT4(b) C-terminal tail (Bender et al.,2000). In the human cardiovascular system, 5-HT4 receptors arepresent in cardiac atria (reviewed by Kaumann& Sanders, 1998;Sections 3.1 and 3.2.1) and ventricles (Brattelid et al., 2004b;Section 3.2.2), where they mediate increases in contractility. 5-HT4 receptors may also be expressed on human endothelial cells(Ullmer et al., 1995) but their function is still unknown. Theimplications to cardiac function of this plethora of splice variantsremain unresolved, partly because of a lack of tools to addressthis question. Recent work suggests different coupling of 5-HT4

(b) receptors, compared to 5-HT4(a) receptors (Pindon et al.,2002) or 5-HT4(d) receptors (Castro et al., 2005); possibleimplications for cardiac arrhythmias are discussed in Section5.2.2.1. Other work, so far only with the mouse 5-HT4(a)

receptor, indicates that the 5-HT4 receptor can also activate G13,resulting in activation of members of the Rho family of smallGTPases (Ponimaskin et al., 2002). This may open new avenuesof possible effects mediated through this receptor, perhaps alsoin the cardiovascular system. So far, antibodies specific forthe different splice variants have not been available topossibly determine the relative expression of the splicevariants at the protein level. In the heart, this expression isalso very low (b4 fmol mg protein−1 in human right atrium;Kaumann et al., 1996) and difficult to measure in bindingassays. Therefore, the relative expression of the differentsplice variants has only been inferred from quantitative RT-PCR studies. Although such studies with absolute quantifi-cation of message levels have not been performed, the studyof Medhurst et al. (2001) has been interpreted to indicate thatthe 5-HT4(b) splice variant is the dominant splice variant in allhuman tissues examined, including human heart.

The nomenclature of the 5-HT4 splice variants is confusing,especially since the human 5-HT4(g) variant was initially and isstill sometimes called 5-HT4(e). This is because of parallel andindependent discovery of novel 5-HT4 splice variants in mouse,rat and man in the late 1990s, following the original discoveryof the rat 5-HT4(a) (initially called 5-HT4S) and 5-HT4(b)

(initially called 5-HT4L) by Gerald et al. (1995). The human 5-HT4(c) and 5-HT4(d) variants were cloned by Blondel et al.(1998). However, in parallel and independently, Claeysen et al.(1998) cloned 2 novel rodent splice variants and initially calledthem 5-HT4(c) (cloned from both mouse and rat, with 13 aa afterthe common sequence including Leu-358) and 5-HT4(d) (clonedfrom mouse; 5 aa after Leu-358), and they also cloned a longerhuman splice variant they called 5-HT4(e) (20 aa after Leu-358).To avoid confusion a revised nomenclature has unofficiallybeen adopted where the 5-HT4(c) and 5-HT4(d) names arereserved for the human splice variants cloned by Blondel et al.(1998), and therefore the rodent 5-HT4(c) and 5-HT4(d) wererenamed to 5-HT4(e) and 5-HT4(f), respectively. Thus, thehuman variant originally called 5-HT4(e) had to be renamed to 5-

HT4(g). This is the nomenclature used to name the exons in andsplice variants derived from the human 5-HT4 gene as clonedand published by Bender et al. (2000). The gene containsone continuous exon encompassing sequence correspondingto the C-terminal tail of the rodent 5-HT4(e) and 5-HT4(f) andthe human 5-HT4(g) splice variants, but to our knowledge,mRNA encoding human 5-HT4(e) and 5-HT4(f) has not yetbeen demonstrated. However, due to and reinforcing thisoriginal confusion, some papers were published about thehuman 5-HT4(g) splice variant using the original name 5-HT4(e)

(e.g. Claeysen et al., 1999; Mialet et al., 2000a; Bozon et al.,2002; Di Scala et al., 2004).

2.5. 5-HT5 and 5-HT6 receptors

So far, the human 5-HT5A receptor is still considered aputative receptor, as there is not yet any evidence to confirm thatthis receptor is expressed in an endogenous setting (Grailhe etal., 2001). Concerning the 5-HT6 receptor, there is no evidenceto support a role for this receptor in the cardiovascular system.These receptors will therefore not be further described in thisreview.

2.6. The 5-HT7 receptor

The 5-HT7 receptor couples positively to Gs protein therebyactivating the adenylyl cyclase. The human 5-HT7 receptorexists in 3 splice variants with different C-termini, 5-HT7(a), 5-HT7(b), and 5-HT7(d) (Heidmann et al., 1997; Jasper et al.,1997). So far, no pharmacological or functional differenceshave been demonstrated between these 3 human splice variants(Krobert et al., 2001; Krobert & Levy, 2002). Also, recombi-nantly expressed human 5-HT7 receptors behave as if they arepreassociated with G protein in the absence of ligand (Bruheimet al., 2003) and express the unusual property of apparentlystealing signaling capacity from other Gs-coupled receptors(Andressen et al., 2006), but the physiological and humancardiovascular significance of this is as yet unknown. A recentreport, studying cells transfected with the mouse 5-HT7(a)

receptor as well as mouse hippocampal neurons, indicates thatthe 5-HT7 receptor may also activate G12, resulting intranscriptional activation through Rho family small GTPases(Kvachnina et al., 2005). In the human cardiovascular system,mRNA for the 5-HT7 receptor has been found in coronaryarteries (Bard et al., 1993) and on vascular smooth musclewhere it may mediate relaxation (Ullmer et al., 1995), whereasevidence for human cardiac functions of the 5-HT7 receptor islacking (Section 4.1.2).

3. Cardiac 5-hydroxytryptamine receptors

Human cardiac 5-HT receptors are depicted in Fig. 2.Functional cardiostimulant 5-HT4 receptors have been de-scribed in right atrium (Kaumann et al., 1990), left atrium(Sanders & Kaumann, 1992) and in right and left ventricle(Brattelid et al., 2004b). Human cardiac 5-HT4 receptorsmediate arrhythmias (Kaumann, 1994; Kaumann & Sanders,

Fig. 2. Location of 5-HT receptor subtypes in the human heart. Evidence for human sinoatrial 5-HT4 receptors, pulmonary vein 5-HT4 receptors and vagal 5-HT3

receptors is indirect but direct functional evidence has been provided in porcine, sheep and rat models, respectively.


1994; Pau et al., 2003; Brattelid et al., 2004b). Activation of 5-HT3 receptors, presumably located at epicardial afferent sensorynerve endings of the vagus, can probably cause reflexbradycardia (Mohr et al., 1987). Activation of 5-HT3 receptors,located at epicardial sympathetic afferent C fibers, couldpossibly transmit ischaemic anginal pain (Fu & Longhurst,2002). Activation of 5-HT1B and 5-HT2A receptors of coronaryarteries could elicit vascular constriction and spasm, therebyindirectly producing life-threatening arrhythmias and cardiode-pression (Kaumann et al., 1993, 1994). Cardiac valvular 5-HT2B

receptors have been identified and appear involved in valvularcardiopathies caused by 5-HT in carcinoids (Møller et al., 2003),fenfluramine (Fitzgerald et al., 2000), ergot derived dopamineagonists (Horvath et al., 2004) and 3,4-methylenedioxymetham-phetamine (MDMA, ‘Ecstacy’) (Setola et al., 2003).

3.1. Heart rate

Intravenously administered 5-HT can both decrease (Harriset al., 1960) and increase (Hollander et al., 1957; Le Mesurier etal., 1959; Parks et al., 1960) heart rate in man.

3.1.1. Bradycardia5-HT-induced bradycardia in man is accompanied by

hypotension (Harris et al., 1960) and probably producedthrough activation of 5-HT3 receptors located at epicardialafferent vagal nerve endings. In the cat the intrapericardialinjection of 5-HT elicits reflex bradycardia (i.e. the Bezold-Jarisch reflex) and hypotension accompanied by inhibition ofefferent renal sympathetic nerve activity (Mohr et al., 1987).These effects are prevented by either vagotomy or greatlyattenuated with the administration of MDL72222 (Mohr et al.,1987), a 5-HT3-selective blocker (Fozard, 1984). By releasing

5-HT from platelets through TXA2 receptor simulation(Hamberg et al., 1975), the tromboxane A2 agonist U-46619also elicits the Bezold-Jarisch reflex and produces hypoten-sion in the rabbit; the 5-HT3 receptor-selective antagonisttropisetron prevents these effects, consistent with activation ofepicardial vagal 5-HT3 receptors (Wacker et al., 2003).Decreases in heart rate have been observed during arterio-graphic examinations (Eckberg et al., 1974; Perez-Gomez &Garcia-Aguado, 1977) and Prinzmetal angina (Perez-Gomezet al., 1979) but it is not clear whether a 5-HT-evokedBezold-Jarisch reflex is involved.

3.1.2. Tachycardia5-HT produces dose-dependent tachycardia in healthy

volunteers (Le Mesurier et al., 1959), plausibly through 5-HT4 receptors as argued before (Kaumann & Sanders, 1998). Insupport for a 5-HT4 nature of human sinoatrial 5-HT receptors isa double blind randomised study reporting small tachycardiacaused by cisapride (Bateman, 1986). Cisapride is a partialagonist, with respect to 5-HT, that enhances contractility oftrabeculae isolated from human atria (Kaumann et al., 1991).The tachycardia elicited by 5-HT and cisapride were mimickedat 5-HT4 receptors of the sinoatrial node of newborn piglets(Kaumann, 1990). It is possible that the human sinoatrialtachycardia evoked by 5-HT is mediated through cyclic AMPgenerated through 5-HT4 receptors and subsequent activation ofthe pacemaker current If. If channels are permeable for both Na+

and K+ and activated by hyperpolarisation at membranepotentials too negative to contribute to the pacemaker actionpotential. 5-HT activates the channels by causing a shift to lessnegative potentials, thereby hastening diastolic depolarisationso that tachycardia ensues. Although direct proof for thismechanism is lacking for human sinoatrial cells, evidence for 5-


HT-evoked stimulation of If has been found on human atrialmyocytes (Pino et al., 1998; Workman & Rankin, 1998).

3.2. Heart force

3.2.1. AtriumIn human atrium, mRNA for 5-HT4(a) (Claeysen et al., 1997;

Blondel et al., 1998; Bach et al., 2001) and 5-HT4(b) receptors(Van den Wyngaert et al., 1997; Blondel et al., 1998; Bach et al.,2001), as well as 5-HT4(g) (Mialet et al., 2000a, Brattelid et al.,2004a) and 5-HT4(i) receptors (Brattelid et al., 2004a) werefound with RT-PCR (Fig. 1). The corresponding binding affinityof 5-HT, 5-MeOT, 5-carboxamidotryptamine (5-CT), tropise-tron, SB203186, SB207710, GR113808, renzapride, cisapride,GR125487 and prucalopride for recombinant 5-HT4(a), 5-HT4(b),5-HT4(g) and 5-HT4(i) receptors was not different for these4 splice variants (Brattelid et al., 2004a; Krobert et al., 2005).Furthermore, the binding affinities of several of these ligandsfor recombinant 5-HT4(a) and 5-HT4(b) receptors correlatedclosely (Bach et al., 2001) with both binding affinities obtainedfor 5-HT4 receptors of human atrium (Kaumann et al., 1996)and affinity estimates obtained from the blockade of humanatrial 5-HT4 receptors by antagonists or partial agonists(Kaumann & Sanders, 1998; Krobert et al., 2005). It wouldappear therefore uncertain which 5-HT4 receptor splice variantscontribute mainly to the effects of 5-HT and related ligands inhuman atrium. However, recent work has revealed subtlecoupling differences of some splice variants (Pindon et al.,2002; Castro et al., 2005) which will be discussed in Section5.2.2.1.

Human atrial 5-HT4 receptors, identified in 1989 (Kaumannet al., 1989a), mediate positive inotropic and lusitropic effects of5-HT, cyclic AMP elevation and activation of cyclic AMP-dependent protein kinase (PKA) in right (Kaumann et al., 1990)and left (Sanders & Kaumann, 1992) atrium. The partialagonists renzapride and cisapride also cause positive inotropiceffects through the cyclic AMP/PKA pathway (Kaumann et al.,1991). The PKA activation through human atrial 5-HT4

receptors suggested phosphorylation of L-type Ca2+ channels(Kaumann et al., 1990, 1991) which was verified by Ouadid etal. (1992) and Jahnel et al. (1993). The hastened relaxation (i.e.lusitropic effects) observed with 5-HT through atrial 5-HT4

receptors probably occurs through PKA-dependent phosphor-ylation of phospholamban, thereby removing the inhibitoryeffect of non-phosphorylated phospholamban on the Ca2+-ATPase (SERCA), thus augmenting its pumping activity.Cytoplasmic Ca2+ is then reduced and contractile proteinsrelax, and more Ca2+ becomes available in the sarcoplasmicreticulum for release. Troponin I may also be phosphorylated byPKA thereby reducing the sensitivity of troponin for Ca2+ andcontributing to relaxation.

5-HT causes an up to 6-fold increase in L-type Ca2+ channelcurrent through 5-HT4 receptors, with an obligatory involve-ment of PKA, in atrial myocytes from patients in sinus rhythm(Ouadid et al., 1992) but 5-HT-evoked increases in L-type Ca2+

current are smaller in atrial myocytes from failing hearts(Ouadid et al., 1995). The increased L-type Ca2+ current may

cause myocyte Ca2+ overload, thereby facilitating the appear-ance of arrhythmias (Kaumann, 1994). 5-HT also enhances thehyperpolarisation-activated pacemaker current If through 5-HT4

receptors in human atrium (Pino et al., 1998; Lonardo et al.,2005), which would be expected to facilitate spontaneousimpulse formation or ectopic activity. Experimental arrhythmiashave been reported with 5-HT in human atrium; the arrhythmiasare suppressed by blockade of 5-HT4 receptors and thereforemediated through 5-HT4 receptors (Kaumann & Sanders,1994). The incidence of 5-HT-evoked arrhythmias is inverselyrelated to the rate at which atrial trabeculae are paced (Kaumann& Sanders, 1994). 5-HT can also elicit arrhythmic contractions(Sanders et al., 1995) and pro-arrhythmic electrophysiologicalevents (delayed after depolarisations) (Pau et al., 2003) inhuman atrial myocytes. Increases in L-type Ca2+ current (Pau etal., 2005a), associated with positive inotropic effects (Krobert etal., 2005), have also been observed with the partial 5-HT4

receptor agonist prucalopride, a gastrokinetic agent (Prins et al.,2000). However, prucalopride did neither elicit arrhythmiccontractions (Krobert et al., 2005) nor produce pro-electro-physiological changes (Pau et al., 2005a), presumably becausethe increase of L-type Ca2+ current was smaller than theincrease caused by 5-HT (Pau et al., 2005a). Small increases ofL-type Ca2+ current, compared to 5-HT, have also beenobserved with the partial agonist ML10302 (Blondel et al.,1997) on human atrial myocytes.

The inotropic and cAMP-elevating effects of 5-HT (Sanderset al., 1995), as well as the arrhythmic inotropic (Kaumann &Sanders, 1994) and electrophysiological (Pau et al., 2003)effects of 5-HT, are enhanced in atrial trabeculae and myocytesobtained from patients chronically treated with β-blockers. β2-Adrenoceptors (Kaumann et al., 1989b; Hall et al., 1990) andH2 histamine receptors (Sanders et al., 1996), both coupled toGs protein, also mediate enhanced inotropic and arrhythmicresponses (Kaumann & Sanders, 1993; Sanders et al., 1996) inatrial trabeculae obtained from patients chronically treated withβ-blockers selective for β1-adrenoceptors. One possiblemechanism for the greater human atrial inotropic andarrhythmic responsiveness through 5-HT4 receptors, β2-adre-noceptors and H2 receptors in β1-selective blocker-treatedpatients could be related to their promiscuous coupling to Gi

protein (Kilts et al., 2000). Recombinant 5-HT4(b) receptors, butnot 5-HT4(a) receptors, have been found not only to couple toGαs protein but also to Gαi/o proteins (Pindon et al., 2002).Consistent with dual coupling to Gαs and Gαi/o proteins, Castroet al. (2005) reported that 5-HT causes a greater increase in L-type Ca2+ current in rat myocytes transfected with human 5-HT4(b) receptors in the presence of pertussis toxin (PTX, thatinactivates Gi/o protein) than in the absence of PTX, suggestingthat this receptor isoform can couple to both Gs and Gi/o

proteins. In contrast, PTX-treatment did not modify the effectsof 5-HT through transfected 5-HT4(d) receptors, suggesting thatthis isoform only couples to Gs but not Gi/o proteins (Castro etal., 2005). Gi protein has been proposed to have a protective roleagainst β-adrenoceptor-mediated arrhythmias because treat-ment of rats with PTX induces isoprenaline to consistently elicitautomaticity in rat ventricular preparations (Grimm et al.,


1998). It is well known that in human heart failure Gi proteinsare increased (Neumann et al., 1988; Feldman et al., 1988).Chronic β-adrenoceptor blockade with metoprolol in patientswith heart failure is known to decrease PTX-sensitive Gαi

protein activity (Sigmund et al., 1996), thereby probablyreducing the Gi-evoked inhibition of adenylyl cyclase, thusallowing greater cAMP/PKA signals, including inotropiccardiostimulation and arrhythmias. The enhanced cAMP signal,increased inotropic responses and arrhythmias caused by 5-HTthrough 5-HT4 receptors in human atrial trabeculae (Kaumann& Sanders, 1994; Sanders et al., 1995) and myocytes (Sanderset al., 1995; Pau et al., 2003) obtained from patients treatedchronically with β-blockers, are consistent with this interpre-tation. However, more experimental evidence is required tosupport or reject this hypothesis.

Recombinant 5-HT4(d) and 5-HT4(g) receptors can formconstitutive homodimers and 5-HT4(d) receptors heterodimerswith recombinant β2-adrenoceptors that are not affected byligands with agonist or antagonist properties (Berthouze et al.,2005). Formation of heterodimers could plausibly be related tothe atrial hyperresponsiveness through β2-adrenoceptors (Kau-mann et al., 1989b; Hall et al., 1990) and 5-HT4 receptors(Sanders et al., 1995) of patients chronically treated with β-blockers. However, 5-HT4(d) receptors appear to be expressed ingut but not heart (Mialet et al., 2000b) and dimerisation of othersplice variants, expressed in human heart (Fig. 1), remains to bedemonstrated.

3.2.2. VentriclemRNA for 5-HT4(a), 5-HT4(b), 5-HT4(g) and 5-HT4(i)

receptors has been detected with RT-PCR in human ventricle(Bach et al., 2001; Brattelid et al., 2004a, 2004b). However,demonstration of a functional role for human ventricular 5-HT4

receptors has proved elusive until recently. Early reportsclaimed that, unlike human atrium, 5-HT does not increasecontractile force in human ventricular preparations (Jahnel etal., 1992; Schoemaker et al., 1993). Similar to the situation inman, 5-HT exerts positive chronotropic and inotropic effects(Kaumann, 1990; Parker et al., 1995) through porcine atrial 5-HT4 receptors but apparently not through porcine ventricular 5-HT4 receptors (Lorrain et al., 1992; Saxena et al., 1992;Schoemaker et al., 1992). Human atrial 5-HT4 receptors areexpressed at a density considerably lower than the density ofβ1- and β2-adrenoceptors (Kaumann et al., 1996) and mediatecAMP signals that are smaller than those of β-adrenoceptorstimulation (Kaumann et al., 1990, 1991; Sanders & Kaumann,1992; Sanders et al., 1995). Conceivably the density of 5-HT4

receptors in human ventricle is even lower than in human atriumand cAMP hydrolysis by phosphodiesterases (PDE) mayprevent the release of sufficient catalytic units of PKAnecessary for the phosphorylation of proteins involved incardiostimulation. Accordingly, functional 5-HT4 receptorswere uncovered in human and porcine ventricular trabeculaein the presence of the non-selective PDE inhibitor isobutyl-methyl-xanthine (IBMX; Brattelid et al., 2004b). 5-HT usually,but not always, caused small increases of contractile force (8%of the maximum effect of isoprenaline mediated through β-

adrenoceptors) in right ventricular trabeculae. 5-HT causedconsistent positive inotropic effects (46% vs. isoprenaline) andalso lusitropic effects (25% vs. isoprenaline) in left ventriculartrabeculae. In 3 of 11 patients 5-HT elicited arrhythmicventricular contractions. 5-HT even produced small increasesin contractility of left ventricular trabeculae, on occasion, in theabsence of IBMX. All 5-HT effects were prevented orantagonised by GR113808, consistent with mediation through5-HT4 receptors (Brattelid et al., 2004b).

As demonstrated in human ventricle, 5-HT also causedpositive inotropic effects in ventricular trabeculae of new-bornpiglets (16% vs. isoprenaline) and adult pigs (32% vs.isoprenaline) in the presence of IBMX. The effects of 5-HTwere antagonised competitively by either SB207710 orGR113808, consistent with mediation through 5-HT4 receptors(Brattelid et al., 2004b). 5-HT, in the presence of IBMX,increased PKA activity by 20% and 39% compared toisoprenaline in ventricle from new-born or adult pigs respec-tively, consistent with the greater inotropic effects in adults. The5-HT-evoked PKA signal was prevented by SB207710,consistent with mediation through 5-HT4 receptors (Brattelidet al., 2004b). These results support the use of porcine ventricleas an experimental model for human ventricular 5-HT4

receptors.

4. Vascular 5-hydroxytryptamine receptors

4.1. Human arteries

4.1.1. Vasoconstriction5-HT receptor subtypes mediating vasoconstriction were

identified with the help of subtype-selective antagonists and bycomparison with the pharmacology of recombinant receptors.Messenger RNA for both 5-HT1B and 5-HT2A receptors hasbeen detected in smooth muscle cells of human aorta andpulmonary artery (Ullmer et al., 1995). Useful antagonists astools have been the 5-HT2A-selective ketanserin (Van Nueten etal., 1981), 5-HT1B-selective SB224289 (Roberts et al., 1997)and 5-HT1D-selective BRL15572 (Price et al., 1997).

Following the proposal that human arterial vasoconstrictionby 5-HT is mediated by coexisting 5-HT1B and 5-HT2A

receptors (Kaumann et al., 1993), evidence for this has beenaccumulating for coronary artery (Kaumann et al., 1993, 1994),pulmonary artery (Morecroft et al., 1999), temporal artery(Verheggen et al., 1996, 1998) and occipital artery (Verheggenet al., 2004). It is likely that 5-HT-induced contractions ofhuman mesenteric artery (Kaumann et al., 1993), internalmammary artery (Yildiz et al., 1996a), umbilical artery (Lovrenet al., 1999), omental artery (Wallerstedt et al., 1996) anduterine artery (Karlsson et al., 1997) are also mediated throughboth 5-HT1B and 5-HT2A receptors. However, intracranialarteries appear to contract exclusively through 5-HT1B receptors(Hamel & Bouchard, 1991; Hamel et al., 1993).

4.1.1.1. Coronary arteries. Human coronary artery can bothconstrict and relax in response to intracoronary 5-HT but thedilator response disappears in patients with stable coronary


artery disease (Golino et al., 1991; McFadden et al., 1991). Theselective blocker of 5-HT2A receptors ketanserin was used bothclinically and as a pharmacological tool. The constrictorresponse evoked by 5-HT is mediated through ketanserin-sensitive and ketanserin-insensitive 5-HT receptors (Godfraindet al., 1992; McFadden et al., 1992).

Analysis of the antagonism of 5-HT-induced contractions ofendothelium-denuded epicardial coronary arteries from 28patients with terminal heart failure by ketanserin (100–1000nM) yielded patient-dependent results (Kaumann et al., 1994).Ketanserin shifted concentration–effect curves to 5-HT to avariable extent and reduced the maximum effect (Emax) of 5-HTon average by 29% (range 0–89%), consistent with mediationthrough 5-HT2A receptors. The ketanserin-resistant componentof the 5-HT curves was shifted 2 log units by methiothepin (100nM), an antagonist with similar affinity for 5-HT1B and 5-HT1D

receptors. The affinity of ketanserin for recombinant 5-HT1D

and 5-HT1B receptors was studied simultaneously and found tobe ∼100-fold higher for 5-HT1D-receptors (pKi =7.1). It wastherefore proposed that the 5-HT receptors resistant toketanserin but sensitive to methiothepin were 5-HT1B receptors(Kaumann et al., 1994). In line with this conclusion,immunoreactivity for 5-HT1B receptors, but not for 5-HT1D

receptors, was found within the smooth muscle wall of humancoronary arteries (Nilsson et al., 1999a). Consistent with the co-function of both 5-HT2A and 5-HT1B receptors, theircorresponding mRNA was also detected (Ishida et al., 1999;Bouchelet et al., 2000; Van den Broek et al., 2002).

The triptan sumatriptan causes contractions of variablestrength of human isolated coronary arteries in a patient-dependent manner (Kaumann et al., 1994; MaassenVanDen-Brink et al., 1996). Ketanserin failed to antagonise sumatriptan-induced contractions (Connor et al., 1989; Chester et al., 1990;Kaumann et al., 1994) but the contractions are blocked by the 5-HT1B/1D receptor antagonists methiothepin (Chester et al.,1990; Kaumann et al., 1994) and GR55562 (MaassenVanDen-Brink et al., 2000). Because 5-HT1B receptors but not 5-HT1D

receptors have been detected in the smooth muscle of humancoronary (Nilsson et al., 1999a) and because 5-HT appears tocontract in part or mostly through 5-HT1B receptors (Kaumannet al., 1994), it appears likely that sumatriptan-evokedcontractions are mediated through 5-HT1B receptors, but directevidence with 5-HT1B-selective blockers is not yet available.Comparison of the 5-HT1B receptor-mediated Emax of 5-HTwith the Emax of sumatriptan on a coronary artery from the samepatient suggests that sumatriptan is a full agonist, compared to5-HT, through 5-HT1B receptors (Kaumann et al., 1993, 1994).The contractions of isolated human coronary arteries by thetriptans naratriptan, zolmitriptan, rizatriptan, avitriptan (Maas-senVanDenBrink et al., 1998a), eletriptan (Van den Broek et al.,2000), frovatriptan (Parsons et al., 1998), and almotriptan (Bouet al., 2001) are probably also mediated through 5-HT1B

receptors, but verification, that is whether the effects areblocked by a 5-HT1B-selective antagonist, is still missing.

4.1.1.2. Pulmonary arteries. 5-HT, infused through a catheterjust beyond the pulmonary valve, can cause unequivocal rises in

pulmonary pressure (Harris et al., 1960). 5-HT causescontractile responses of spirally cut preparations of the humanpulmonary artery (Houghton & Phillips, 1973). Sumatriptancauses pressor responses in the human pulmonary circulation(McIntyre et al., 1992) and constricts rings of the large humanpulmonary artery (MacLean et al., 1996; Cortijo et al., 1997),suggesting an involvement of 5-HT1B or 5-HT1D receptors. The5-HT-evoked constriction is partially antagonised by the 5-HT2A-selective antagonist ritanserin and the 5-HT1B/1D blockerGR127935 (Cortijo et al., 1997), consistent with an involve-ment of 5-HT2A receptors and 5-HT1B and/or 5-HT1D receptors.Binding sites for [3H]5-CT were also detected in humanpulmonary artery, consistent with the existence of 5-HT1B and/or 5-HT1D receptors (Cortijo et al., 1997). 5-HT-inducedcontractions of human small (250–300 μm i.d.) muscularpulmonary arteries are mediated through 5-HT1B receptors atlow 5-HT concentrations (≤30 nM) and through 5-HT2A

receptors at higher 5-HT concentrations, and mRNA for both 5-HT2A and 5-HT1B receptors is expressed (Morecroft et al.,1999). Sumatriptan was a full agonist with respect to 5-HT, theeffects were blocked by 5-HT1B-selective SB224289 but not by5-HT1D-selective BRL15572 (Morecroft et al., 1999).

4.1.1.3. Internal mammary arteries. 5-HT-induced contrac-tions of the human internal mammary artery are partiallyblocked by ketanserin, consistent with mediation through 5-HT2A receptors (Conti et al., 1990; Godfraind et al., 1992;Yildiz et al., 1996a). The nature of the ketanserin-resistantcomponent of 5-HT-induced contractions is unknown but couldbe 5-HT1B because sumatriptan causes small contractions in70% of the arteries studied (Yildiz et al., 1996a). Thesumatriptan-evoked contractions become more consistent andpronounced in arteries whose basal tone had been slightlyenhanced by either elevated K+ or angiotensin (Yildiz et al.,1996b).

4.1.1.4. Mesenteric arteries. Ketanserin antagonises partially5-HT-induced contractions of the human mesenteric artery,reducing the maximum response by 41%, consistent withmediation through 5-HT2A receptors. The ketanserin-resistantcomponent was antagonised by methiothepin and presumablymediated through 5-HT1B receptors (Kaumann et al., 1993).Similarly, 5-HT-induced contractions were partially antago-nised by either ketanserin or the 5-HT1B/5-HT1D antagonistGR127935 (Gul et al., 2003). In addition, sumatriptan contractsthe mesenteric artery through ketanserin-resistant butGR127935-sensitive receptors (Gul et al., 2003). The suspected5-HT1B nature of these receptors should still be verified with a5-HT1B-selective antagonist.

4.1.1.5. Omental arteries. The contractile effects of 5-HT,sumatriptan and other agonists were studied on omental arteries,obtained from patients undergoing abdominal surgery (Waller-stedt et al., 1996). With the help of ketanserin and methiothepinWallerstedt et al. (1996) concluded that the effects of 5-HT aremediated through both 5-HT1- and 5-HT2A-receptors and theeffects of sumatriptan through 5-HT1 receptors. The likelihood


that 5-HT1 receptors are 5-HT1B receptors needs to be verifiedwith the use of a 5-HT1B-selective antagonist.

4.1.1.6. Umbilical arteries. The human umbilical arterycontracts with 5-HT through both 5-HT1-like and 5-HT2

receptors (MacLennan et al., 1989). More recently mRNA forboth 5-HT1B and 5-HT2A receptors but not for 5-HT1D receptorshas been detected in human umbilical artery (Lovren et al.,1999). Ketanserin and the 5-HT1B/D antagonist GR127935 bothantagonised partially 5-HT-induced contractions, consistentwith mediation through both 5-HT2A and 5-HT1B receptors(Lovren et al., 1999). Sumatriptan caused inconsistent smallcontractions. However, marked contractions to sumatriptan,resistant to ketanserin, were observed by precontracting thevessels with other vasoactive agents, consistent with mediationthrough 5-HT1B receptors (Lovren et al., 1999). The 5-HT1B

nature of these receptors needs to be verified with the use of a 5-HT1B-selective antagonist.

4.1.1.7. Uterine arteries. Early work, obtained from uterinepreparations devoid of endothelium, reported that 5-HT-inducedcontractions were antagonised by ketanserin and spiperone andtherefore mediated through 5-HT2A receptors (Fontes Ribeiro etal., 1991). Later, Karlsson et al. (1997) found that the 5-HT-induced contractions were antagonised more by methiothepinthan by ketanserin and that sumatriptan evoked modestcontractions. Therefore, both 5-HT1-like and 5-HT2A receptorsfunction in the human uterine artery. Whether the 5-HT1-like

receptors are of 5-HT1B nature still must await experimentalverification with a 5-HT1B-selective antagonist.

4.1.1.8. Extracranial arteries. Both human temporal arteries(Verheggen et al., 1996, 1998) and occipital arteries (Verheggenet al., 2004) contract with 5-HT through both 5-HT2A and 5-HT1B receptors. 5-HT-induced contractions were partiallyantagonised by 5-HT2A-selective ketanserin and 5-HT1B-selective SB224289 and 5-HT-induced contractions resistantto one antagonist were blocked by the other. The 5-HT1D-selective antagonist BRL15772 did not affect 5-HT-inducedcontractions. Sumatriptan also contracted both temporal(Verheggen et al., 1998) and occipital arteries (Verheggen etal., 2004) through 5-HT1B receptors, sensitive to antagonism bySB224289 but not to ketanserin and BRL15572. These findingsagree with the detection of mRNA for 5-HT1B (Verheggen et al.,1998, 2004) and 5-HT2A receptors (Verheggen et al., 2004) inboth human temporal and occipital arteries. mRNA for 5-HT1D

receptors was also detected in both temporal and occipitalarteries but is probably located in nerve endings and unrelated to5-HT-induced contractions (Verheggen et al., 1998, 2004).

4.1.1.9. Intracranial arteries. Hamel et al. (1993) found 5-HT1B mRNA transcripts in human cerebral arteries andsuggested that 5-HT1B receptors mediate the constrictor effectsof sumatriptan on human basilar artery observed by Parsons etal. (1989). The mediation through 5-HT1B receptors of thecontractile effects of 5-HT and sumatriptan, as well as othertriptans, on cerebral arteries has since been confirmed by several

authors (Nilsson et al., 1999b; Razzaque et al., 1999; Van denBroek et al., 2002). 5-HT1B receptor immunoreactivity waspresent in smooth muscle of human cerebral arteries (Nilsson etal., 1999b; Razzaque et al., 2002). A participation of 5-HT1D

and 5-HT1F receptors in the contractile effects of 5-HT andsumatriptan on human cerebral arteries was excluded by severalauthors (Razzaque et al., 1999; Bouchelet et al., 2000). Themediation of the contractile effects of 5-HT and sumatriptanthrough 5-HT1B receptors but not 5-HT1D receptors has beenconfirmed with antagonism by the 5-HT1B-selective antagonistSB224289 and lack of antagonism by the 5-HT1D-selectiveBRL15572 (Van den Broek et al., 2002).

4.1.2. VasorelaxationBased on the cellular localisation of mRNA for 5-HT

receptors, Ullmer et al. (1995) suggested that endothelial 5-HT1B, 5-HT2B and perhaps 5-HT4 receptors and smooth muscle5-HT7 receptors could be involved in human vascularrelaxation. Although several of these receptors mediaterelaxation in arteries of a variety of species (for literature seeElhusseiny & Hamel, 2001), direct evidence from human bloodvessels is scarce. For example, although 5-CT and 5-HTproduce increases in cyclic AMP levels through 5-HT7

receptors of smooth muscle cells, isolated from human uterineartery (Schoeffter et al., 1996), relaxation of this artery through5-HT7 receptors appears not to have been demonstrated. 5-HTcauses Ca2+ release from ryanodine channels through 5-HT2B

receptors in human pulmonary endothelial cells (Ullmer et al.,1996), which would be expected to activate NO synthase andrelease NO, which in turn would relax smooth muscle.Consistent with these events, porcine pulmonary artery relaxesvia 5-HT2B receptors (Glusa & Pertz, 2000), but evidence forrelaxation of human pulmonary artery through 5-HT2B

receptors is missing.

4.1.2.1. Cerebral arterioles. 5-HT1B mRNA was detected incerebral microvessels (Riad et al., 1998; Cohen et al., 1999),consistent with relaxation of perfused human intracorticalarterioles (47 μm average intraluminal diameter) by nanomolarsumatriptan concentrations, although contractions were alsoobserved at higher sumatriptan concentrations (≥10−7 M)(Elhusseiny & Hamel, 2001). Both the 5-HT1D-selective agonistPNU109291 and the 5-HT1F-selective agonist LY344864 failedto elicit relaxant or contractile effects of sumatriptan, despite thedetection of mRNA for 5-HT1D and 5-HT1F receptors inisolated microvessels (Cohen et al., 1999). The relaxant effectsof sumatriptan were prevented by Nω-nitro-L-arginine (L-NNA)which greatly enhanced sumatriptan-evoked contractions.These results are consistent with the concept that sumatriptancaused nitric oxide (NO)-mediated relaxation through endothe-lial 5-HT1B receptors and contraction through smooth muscle 5-HT1B receptors (Elhusseiny & Hamel, 2001). Interestingly, low5-HT concentrations (nanomolar) did not produce microvascu-lar relaxation but induced instead small contractions whichbecame considerably greater at ≥10−7 M. The absence ofmicrovascular relaxation by 5-HT reported by Elhusseiny andHamel (2001) could be due to a greater relaxant efficacy of


sumatriptan than of 5-HT as agonists on endothelial 5-HT1B

receptors. These authors also reported that the sumatriptan-evoked relaxation was inversely related to vessel size. As theblood vessel gets larger, the increase in muscle layers pushes theequilibrium towards agonist-evoked contractions, mediatedthrough smooth muscle 5-HT1B receptors (Riad et al., 1998;Elhusseiny & Hamel, 2001).

4.1.2.2. Umbilical arteries. Perfused umbilical arteries,prepared from uncomplicated full term pregnancies, relaxwith low (nanomolar) 5-HT concentrations and contract withhigher (≥10−7 M) concentrations (Haugen et al., 1997). Therelaxant component of 5-HT was only marginally reduced byNω-nitro-L-arginine methyl ester (L-NAME) or methylene blue.Methysergide (100 nM) prevented 5-HT-induced relaxationsand contractions. Because it is unlikely that endothelium-derived NO was involved, the participation of endothelial 5-HT1B and 5-HT2B receptors (Ullmer et al., 1995) was alsounlikely. Instead, methysergide may have antagonised smoothmuscle 5-HT7 receptors. The affinity of methysergide issufficiently high for 5-HT7 receptors (pKi≈7.6–7.8, Krobertet al., 2001), so that at least 80% of the 5-HT7 receptors wouldbe blocked with 100 nM methysergide, the concentrations usedby Haugen et al. (1997). The hypothetical mediation through 5-HT7 receptors needs to be verified with the use of an antagonistselective for 5-HT7 receptors.

4.1.2.3. Coronary arteries. Although 5-HT7 receptor mRNAhas been detected in human coronary arteries (Bard et al., 1993),functional evidence has eluded detection, so far. Unlike othertriptans, the 5-HT1B/D agonist flovatriptan causes markedlybiphasic effects at human endothelium-denuded coronaryarteries, contractions at low concentrations and relaxations athigh concentrations (Parsons et al., 1998; Comer, 2002). Thispattern may be related to agonistic effects of flovatriptan at 5-HT7 receptors. Flovatriptan stimulated adenylyl cyclase ofrecombinant 5-HT7 receptors as a full agonist with submicro-molar potency, while sumatriptan and naratriptan were onlypartial agonists with supramicromolar potency (Comer, 2002).Bell-shaped concentration–effect curves for 5-HT have alsobeen observed in coronary arteries of some patients but not inothers (Kaumann et al., 1994). More work is needed to assesswhether 5-HT7 receptors participate in relaxation at high agonistconcentrations.

4.1.2.4. Occipital arteries. Bell-shaped concentration–effectcurves for 5-HT were observed on occipital arteries, obtainedfrom patients undergoing brain surgery (Verheggen et al., 2004).The relaxations elicited by high 5-HT concentrations werepartially reduced by L-NAME suggesting release of NO fromendothelial cells. Ketanserin also prevented part of the 5-HT-induced relaxation. However, selective antagonists of 5-HT1B,5-HT1D, 5-HT2B, 5-HT4 and 5-HT7 receptors failed to affect the5-HT-induced relaxations, so that their nature remains unknown.

4.1.2.5. Renal arteries. Evidence for endothelium-dependentdilation of the perfused renal arterial bed of the rat by 5-HT, 5-

CT and 8-OH-DPAT in the presence of ritanserin (to block 5-HT2A receptors) and tropisetron (to block 5-HT3 receptors) hasbeen provided by Verbeuren et al. (1991). They showed that theagonist-mediated dilation was suppressed by the 5-HT1A

receptor-selective antagonist BMY7378 (Sharp et al., 1990)and decreased by inhibitors of the action of nitric oxide(haemoglobin, methylene blue and L-NNA). They concludedthat dilatory effects of the agonists were mediated by 5-HT1A

receptors. However, Ullmer et al. (1995) failed to detect 5-HT1A

mRNA in the rat renal artery. 5-HT1A receptors have beendetected with immunohistochemistry in the human kidneytubules but not in blood vessels (Raymond et al., 1993).Nevertheless, it may be worthwhile to investigate whether 5-HTcan dilate some arteries of human kidney and whether thisoccurs through 5-HT1A receptors.

4.2. Veins

4.2.1. Pulmonary veinsAlthough sheep pulmonary veins appear to relax with 5-HT

via 5-HT4 receptors (Cocks & Arnold, 1992), humanpulmonary veins contract with 5-HT (Houghton & Phillips,1973). As in human pulmonary arteries, both 5-HT1B and 5-HT2A receptors appear to mediate 5-HT-induced contractions ofhuman pulmonary veins (Cortijo et al., 1997).

4.2.2. Hand veins5-HT, sumatriptan and other agonists produced contractions

in isolated segments of human superficial hand veins (Bod-elsson et al., 1992). The contractile effects of the 5-HT2A-selective agonist α-methyl-5-HT were antagonised by ketan-serin, consistent with mediation through 5-HT2A receptors. Thesumatriptan-evoked contractions were resistant to blockade byketanserin but antagonised by methiothepin, consistent withmediation through 5-HT1-like receptors, possibly 5-HT1B

receptors, but this needs verification with a 5-HT1B-selectiveantagonist.

4.2.3. Saphenous veinsEarly evidence suggested the co-function of 5-HT1 and 5-

HT2 receptors in human saphenous vein because ketanserinblocked the effects of high but not low 5-HT concentrations(Docherty & Hyland, 1986). These receptors have morerecently been demonstrated to be 5-HT1B and 5-HT2A receptors.Bax et al. (1992) confirmed that ketanserin antagonised thecontractile effects of high but not low 5-HT concentrations, andin addition failed to antagonise sumatriptan-evoked contrac-tions. 5-HT1B immunoreactivity was detected in smooth muscleof human saphenous vein (Razzaque et al., 2002) and thecontractile effects of sumatriptan were antagonised by 5-HT1B-selective SB224289 but hardly by 5-HT1D-selective BRL15572(Van den Broek et al., 2002).

4.2.4. Umibilical veins5-HT is a potent constrictor of human umbilical veins (Altura

et al., 1972). The 5-HT-induced contractions are in partantagonised by ketanserin, and high-affinity binding sites for


ketanserin (KD=0.3 nM) have been reported, consistent withmediation through 5-HT2A receptors (Rogines-Velo et al.,2002a). When basal venous tone is slightly enhanced by KCl,sumatriptan also elicited contractions that were antagonised bythe 5-HT1B/D blocker GR55562 in rings of human umbilicalveins (Rogines-Velo et al., 2002b), attributed to mediationthrough 5-HT1B receptors. This interpretation demands verifi-cation with the use of a selective 5-HT1B antagonist.

5. 5-Hydroxytryptaminereceptors and cardiovascular disease

5.1. Genetic mutations andpolymorphisms in 5-hydroxytryptamine receptorspossibly relevant to the human cardiovascular system

Several polymorphic variants of human serotonin receptorgenes have been reported. Polymorphisms located in theuntranslated regions (UTR) may give rise to altered levels ofreceptor expression, through altered levels of transcription (e.g.polymorphisms in the promoter region) or through alteredmRNA stability (e.g. polymorphisms in the 3′-UTR). Poly-morphisms (usually single nucleotide polymorphisms or SNPs)located in the open reading frame (coding region) may be silent,either by causing no amino acid change (synonymouspolymorphisms) or by causing an amino acid change withoutfunctional (physiological or pharmacological) consequences.Such mutations will not be discussed in detail here. Otherpolymorphisms cause an amino acid change (non-synonymouspolymorphisms) with functional (physiological or pharmaco-logical) consequences. Such polymorphisms with documentedor putative cardiovascular consequences will be the main topicof this section. Importantly, although not dealt with in detailhere, silent polymorphisms may also be associated with diseasein genetic linkage studies. This would normally indicate that thepolymorphic protein (e.g. the 5-HT receptor) is in linkagedisequilibrium with another polymorphism, which may becausally related to the disease.

When describing coding region SNPs in serotonin receptors,we will use a nomenclature like “A50V-5-HT1A”, where thenumber indicates the position of the polymorphic amino acidresidue, and the first and last 1-letter amino acid code indicatesthe more and less frequent polymorphic variant, respectively.The 2 alternative alleles would then typically be referred to asA50 and 50V. We will adhere to this nomenclature even in caseswhere there may be doubt about which allele is more frequent.

5.1.1. Polymorphisms in 5-HT1 receptors

5.1.1.1. Polymorphisms of 5-HT1A receptors. Of 13 potentialSNPs resulting in amino acid changes that were identified in thehuman 5-HT1A receptor, only 2, A50V-5-HT1A and L381F-5-HT1A, resulted in altered pharmacology (Del Tredici et al.,2004). From a pharmacological point of view, the A50V-5-HT1A is interesting. For example, the A50V amino acidsubstitution in transmembrane domain 1 resulted in a selectiveloss of detectable response to 5-HT and 5-CT, whereas other

agonists tested, including buspirone, lisuride and (+)8-OH-DPAT, exhibited efficacies similar to the wild-type receptor.This and other peculiarities of this mutant receptor suggest arole for transmembrane 1 of the 5-HT1A receptor in mediating 5-HT response. However, since there is no data indicating a rolefor the 5-HT1A receptor in the human cardiovascular system, itis premature to speculate about cardiovascular effects ofpolymorphic variants of this receptor.

5.1.1.2. Polymorphisms of the 5-HT1B receptor. A number of5-HT1B receptor polymorphisms have been identified, both inthe coding sequence and in the surrounding 5′-UTR and 3′-UTR (Sanders et al., 2002).

F124C-5-HT1B. A naturally occurring variant of the 5-HT1B

receptor was identified by Nöthen et al. (1994), in which 124-phenylalanine is substituted by cysteine. The incidence of the124C variant was 2% in the Caucasian population. Comparisonof the binding affinity for [3H]5-CT at recombinant receptors,transiently transfected into COS-7 cells at pmol mg protein−1

densities, yielded KD values of 8.8 nM for the F124 5-HT1B

receptor and 2.3 nM for the 124C variant (Brüss et al., 1999).Consistent with this finding, the affinity of 5-HT and severalligands, including sumatriptan, methysergide and dihydroer-gotamine, was also 2- to 3-fold higher for the 124C variant thanfor F124. However, the affinity of ketanserin was 2.4-fold lowerat 124C than F124. Brüss et al. (1999) suggested that the rarelyobserved sumatriptan-induced spasm of coronary arteries couldbe related to patients carrying the 124C polymorphism, therebyenhancing the constrictor potency of sumatriptan in thesearteries (Kaumann et al., 1994).

In transfected rat C-6 glioma cells, stably expressing1.0 pmol mg protein−1 F124 variant or 0.6 pmol mgprotein−1 124C variant, Kiel et al. (2000) found a 1.6-foldhigher binding affinity of [3H]5-CT at 124C. Kiel et al. (2000)also reported 2.6- to 3.8-fold greater potencies of 5-CT, 5-HTand sumatriptan as stimulants of [35S]GTPγS binding at 124Ccompared to F124, but lower maximum binding. The 5-HT1B-selective antagonist SB224289 decreased [35S]GTPγS bindingat both variants in the absence of agonists, but blockedsurmountably with a 2-fold higher affinity the effects of 5-CTat 124C compared to F124. Both 5-CT and sumatriptan werearound 2-fold more potent as inhibitors of forskolin-stimulatedadenylyl cyclase activity at 124C than F124 but thecorresponding intrinsic activities did not differ.

The work of Brüss et al. (1999) and Kiel et al. (2000) withrecombinant F124C variants would suggest a greater arterialconstrictor potency of 5-HTand sumatriptan on 124C than F1245-HT1B receptors. Analysing data from temporal arteries of 98patients, Verheggen et al. (submitted for publication) did notdetect an enhanced constrictor potency of the three heterozy-gous 124C patients compared to the 95 homozygous F124patients. However, Verheggen et al. (2006) found that in the 3patients with the 124C variant the 5-HT responses were mostlymediated through 5-HT1B receptors while in the 95 patientswith F124 the mediation of the 5-HT-induced contractions ismore evenly shared by both coexisting 5-HT1B and 5-HT2A

receptors. Verheggen et al. (submitted for publication) have


interpreted their results by the finding that the 124C 5-HT1B

receptor couples less tightly to Gi protein than the F124 5-HT1B

receptor (Kiel et al., 2000). It has been shown that Gi-coupledreceptors can synergise with Gq-coupled receptors throughdonation of βγ unit, thereby activating phospholipase Cβ(Chan et al., 2000). It is plausible that such synergy also existsfor the contractile 5-HT responses mediated through 5-HT1B

receptors, coupled to Gi protein, and 5-HT2A receptors, coupledto Gq protein. The synergy could be decreased when the 124C5-HT1B receptor, in addition to the F124 5-HT1B receptor,coexists with the 5-HT2A receptor in arterial smooth musclecells in heterozygous individuals. Since the 124C 5-HT1B

receptor is less tightly coupled to Gi protein than the F124 5-HT1B receptor (Kiel et al., 2000), fewer βγ units would becomeavailable to stimulate phospholipase Cβ.

5-HT1B promoter polymorphisms. A promoter polymor-phism (A-161T) in the 5-HT1B receptor gene was independentlyidentified by several groups (Cigler et al., 2001; Sanders et al.,2001; Sun et al., 2002). The frequency of the −161T allelevaries between 0 and 33% in different ethnic groups (Sanders etal., 2001) and this allele was shown in reporter gene assays tolead to more efficient (up to about doubled) transcriptionalactivity in carcinoma cell lines (Sun et al., 2002). Conversely,Duan et al. (2003) found in reporter gene assays in neuronal celllines that a haplotype containing the -161T allele reversed theenhanced transcriptional activity observed by the -261G variantat the T-261G polymorphic site. They concluded that -261Ggenerates a new AP2 binding site, while the alleles A-161 and-161T display different binding characteristics to AP1. Changesin 5-HT1B transcriptional activity could be relevant for 5-HT1B-mediated vasoconstriction. Whereas we are not aware of anyreports on such possible associations for the A-161T polymor-phism, MaassenVanDenBrink et al. (1998b) looked forassociations of the T-261G polymorphism as well as G861C(synonymous polymorphism) with clinical response to suma-triptan in migraine patients, but did not find different allelefrequencies between groups of patients with different clinicalresponse.

Other 5-HT1B polymorphisms. Three other 5-HT1B codingregion variants have been detected, which appear at lowerfrequencies (minor allele frequency less than 1%) (Sanders etal., 2001). These are F219L (conservative amino acid change)in transmembrane domain (TM) 5, I367V (conservativeamino acid change) in TM7 and E374L (acidic to basicamino acid change) in the intracellular C-terminal domain.Based on comparison with analogous receptors (orthologs) inother mammals, Sanders et al. (2001) concluded that each ofthese 3 variants probably represents a tolerable change interms of receptor function. However, studies using, forexample, site-directed mutagenesis to investigate the pharma-cological properties and their cardiovascular relevance of eachvariant receptor to validate this conclusion are lacking. Oneother variant, A772G, was also detected and reported as asilent change (Sun et al., 2002), although it would bepredicted to result in a non-conservative amino acid change(Thr258Ala, hydrophilic neutral to hydrophobic) (Sanders etal., 2002).

5.1.2. Polymorphisms in 5-HT2 receptors

5.1.2.1. Polymorphisms in the 5-HT2A receptor. Given thatthe 5-HT2A receptor plays important roles in the humancardiovascular system, both in blood vessel contraction andplatelet aggregation, effects of mutations in this receptor oncardiovascular function could be expected. To date, at least 16SNPs in the 5-HT2A receptor gene have been described, ofwhich 9 are in the promoter, 2 are synonymous coding-regionpolymorphisms and 5 are non-synonymous coding-regionpolymorphisms and thus give a change in the receptor protein(Erdmann et al., 1996a; Ozaki et al., 1996; Spurlock et al., 1998;Cargill et al., 1999; Sanders-Bush et al., 2003).

T102C, A-1438G, 5-HT2A receptor expression and disease.Polymorphisms in the 5-HT2A promoter could be relevant forcardiovascular function if these lead to altered receptortranscription. The promoter polymorphism which has beenmost thoroughly investigated is the A-1438G polymorphism,which is in almost complete linkage disequilibrium (i.e. almostcomplete genetic linkage) with the synonymous T102Cpolymorphism, so that A-1438 will almost always coexistwith T102 (Spurlock et al., 1998). Several association studieshave been performed and indicate an association of the 102Callele with schizophrenia and other neuropsychiatric disorders(Williams et al., 1997; Arranz et al., 1996, 1998). However,studies aimed at explaining this association with altered 5-HT2A

receptor expression due to the strong genetic linkage betweenT102C and A-1438G have so far resulted in conflicting results(Spurlock et al., 1998; Parsons et al., 2004).

On this background of studies on receptors in the CNS andassociations with neuropsychiatric disorders, it is interesting tonote that Yamada et al. (2000) found an association between theT102 allele and non-fatal myocardial infarction in a study of255 Japanese patients and as many matched controls. In a laterreport, the same group found that the A-1438 and the T102allele was associated with a hypersensitivity of platelets to 5-HT(Shimizu et al., 2003). Recently, Ozdener et al. (2005) found anincreased aggregation response to 5-HT in platelets frompatients homozygous for the T102 allele compared to thosecarrying the 102C allele. These reports are compatible with ahypothesis that increased transcriptional activity of the 5-HT2A

promoter through increased 5-HT2A expression in platelets andincreased liability to thrombotic events would be a predisposingfactor to myocardial infarction. However, in a study of 210Spanish patients with myocardial infarction before age 55compared to age-matched controls as well as 95 patients withmyocardial infarction after age 60 there was no association withthe T102C polymorphism (Coto et al., 2003). An unexplainedassociation between the T102C polymorphism and HDLcholesterol levels has also been reported (Choi et al., 2005).More studies of association between the T102C/A-1438Gpolymorphism and cardiovascular disease are warranted.

5-HT2A polymorphisms resulting in amino acid change. The5 known non-synonymous coding region polymorphisms in the5-HT2A receptor are (minor allele frequencies in parentheses)T25N (1%), I197V (1%), S421F (unknown), A447V (1%) andH452Y (9%) (Erdmann et al., 1996a; Ozaki et al., 1996; Cargill


et al., 1999; reviewed by Sanders-Bush et al., 2003). Sanders-Bush et al. (2003) reported preliminary data in a review paper toindicate that the variants I197V, A447V and H452Y alldisplayed reduced maximum phosphoinositide hydrolysisfollowing 5-HT treatment of NIH3T3 cells stably expressing5-HT2A variants. An early study comparing platelets fromheterozygous (H452/452Y) and homozygous (H452/H452)patients indicated that the 452Y variant resulted in a bluntedCa2+ signal in response to 5-HT (Ozaki et al., 1997). This wasfurther addressed by Hazelwood & Sanders-Bush (2004) whocompared the signaling function of H452 and 452Y human 5-HT2A receptors expressed in NIH3T3 cells and found that the452Y variant displayed a reduced ability to convey agonist-stimulation of both phospholipase C and phospholipase Dactivity, a loss of high-affinity agonist binding and altereddesensitisation properties. The S421F variant was examined inthe context of a systematic screen for serine residues involved in5-HT2A receptor desensitisation (Gray et al., 2003) and the 421Fvariant was found to display greatly attenuated agonist-mediated desensitisation. Thus, 5-HT2A receptor SNPs haveprofound functional consequences on 5-HT2A receptor functionand regulation and it is plausible to expect that further studieswill reveal relevance for cardiovascular disease.

5.1.2.2. Polymorphisms in the 5-HT2B receptor. A patientwith fenfluramine-associated primary pulmonary hypertensionwas found to carry a SNP (CNT) in the 5-HT2B receptor codingregion, resulting in premature termination (R393X) withremoval of the bulk of the intracellular C-terminal tail, includingthe palmitylation site (Blanpain et al., 2003). This mutation wasinitially characterised as a loss-of-function mutation, since thetruncated receptor when expressed in COS or CHO cells failedto activate inositol phosphate production and subsequent [Ca2+]iincrease, despite normal expression at the cell membrane andligand binding (Blanpain et al., 2003). This apparent loss offunction was not easily reconciled with the putative involve-ment of 5-HT2B receptor stimulation in the pathogenesis ofprimary pulmonary hypertension (Eickelberg et al., 2003).However, later work (Deraet et al., 2005) demonstrated thatwhile the 393X variant had indeed lost its ability to couple toGαq, it had gained efficacy in promoting 5-HT-stimulated cellproliferation through Gα13, associated with and possiblyresulting from an essential lack of 5-HT-induced internalisation(see also Section 5.3.2).

A double-mutant (R6G/E42G) of the 5-HT2B receptor,resulting from 2 linked SNPs, was associated with vulnerabilityto illegal drug abuse (Lin et al., 2004). Pharmacologicalcharacterisation and studies of possible association of thisdouble mutant receptor with cardiovascular disease iswarranted.

5.1.3. Polymorphisms in the 5-HT3 receptorSeveral polymorphisms have been found in the 5-HT3A

(Kaiser et al., 2004; Kurzwelly et al., 2004) and 5-HT3B

(Tremblay et al., 2003) genes, but there are as yet no studiesavailable to indicate important roles of such polymorphisms forthe sensitivity to reflex bradycardia or cardiac pain.

5.1.4. Polymorphisms in the 5-HT4 receptorWith the impressive amount of C-terminal splice variants

reported, genetic variation in the 5-HT4 receptor gene could leadnot only to altered transcription or pharmacological properties,but also to altered mRNA splicing. However, although reportson 5-HT4 receptor gene polymorphisms have began to appear(Ohtsuki et al., 2002; Suzuki et al., 2003), there is yet a lack ofdata to warrant conclusions about their cardiovascular signif-icance in, for example, arrhythmia or heart failure.

5.1.5. Polymorphisms in the 5-HT7 receptorTwo receptor variants (P279L and T92K) and one silent

(A1233G) polymorphism were identified in an early screen ofthe 5-HT7 receptor gene (Erdmann et al., 1996b). The 279Lvariant, with a proline to leucine change in the third intracellularloop of the receptor, showed a severely impaired ability tostimulate cAMP formation in transfected HEK293 cells, withmaximum values of only 9–11% of those seen with the P279variant (Kiel et al., 2003). If the 5-HT7 receptor is important invascular ralaxation, this could be of significance. However, asyet, no studies have addressed possible cardiovascular pheno-types associated with this variant. The T92K variant, with anamino acid change in the first transmembrane domain, wasfound to display reduced binding affinity and agonist potency ofseveral agonists, whereas the affinity of several antagonists wasunchanged (Brüss et al., 2005). The physiological andcardiovascular significance of this variant remains unexplored.Additional variants of 5-HT7 and other 5-HT receptors wererecently reported and warrant further studies (Glatt et al., 2004).

5.2. Heart disease

5.2.1. Physiological role of 5-hydroxytryptamine5-HT is the physiological excitatory neurotransmitter of

cardiac nerves in molluscs (Greenberg, 1960a) but the receptorshave a pharmacology (Greenberg, 1960b) that is unrelated to thepharmacology of 5-HT receptors occurring in mammalian heart.Evolution has replaced 5-HT by catecholamines as excitatoryneurotransmitters of cardiac nerves in higher species. Although5-HT also has excitatory effects in human adult myocardiumthese would be harmful (see below) and its physiological role isunknown. However, based mostly on work with murinemyocardium, it is plausible that 5-HT has a physiological rolein human cardiac embryogenesis as it appears to have in mice.5-HT is synthesised by tryptophan hydroxylase (Tph), Tph1 inenterochromaffin cells and the pineal gland and Tph2 inneurons (Côté et al., 2003). When the tph1 gene has beeninactivated in mice (tph1−/− mutant) some of these animalsdevelop cardiac dysfunction and heart failure without demon-strable structural alterations together with a 92% drop in plasma5-HT, due to lack of 5-HT synthesis by the enterochromaffincells. Côté et al. (2003) postulated that the lack of 5-HT wasdeleterious to heart function. However, the nature of theplausible function of 5-HT in maintaining normal cardiacfunction is unknown.

In mice the 5-HT2B receptor appears to have an obligatoryrole for normal cardiac embryogenesis. Genetic ablation of 5-


HT2B receptors causes partial lethality in midgestation andventricular trabeculation defects (Nebigil et al., 2000a).Midgestation mortality of the 5-HT2B knock-out mice hasbeen attributed to an impairment of the ability of the 5-HT2B ofwild-type mice to transduce mitogenic signals in fibroblasts(Nebigil et al., 2000b). In addition, 5-HT2B receptors haveantiapoptotic properties in murine cardiocytes (Nebigil et al.,2003). Whether these functions of the 5-HT2B receptors occur inthe developing human heart is unknown. Although 5-HT4

receptors mediate human cardiostimulation, cardiac dysfunctionhas not been reported in 5-HT4 knockout mice (Compan et al.,2004).

5.2.2. Pathological role of 5-hydroxytryptamineHarmful effects of 5-HT are due to platelet-released 5-HT

which can produce thrombogenesis, vascular spasm, mitogen-esis and proliferation of vascular smooth muscle cells. Theendocardium protects the myocardium by preventing plateletaggregation, but when the endocardium is damaged as forexample in dilated left atria of patients with heart diseaseplatelet aggregation and secretion is facilitated (Shah et al.,1989) and 5-HT can exert harmful effects on myocardial cells(Kaumann, 1994). Plasma levels of 5-HT, originated fromenterochomaffin cells, appear to be elevated in patients withcongestive heart failure (Chandra et al., 1994; Vizir & Berezin,2001). In addition, the human heart itself stores and perhapssynthesises 5-HT. Human left ventricular myocardium contains∼400 ng 5-HT g−1 (Sole et al., 1979) but its histologicallocalisation was unknown. Tryptophan hydroxylase and 5-HTimmunoreactivity has been demonstrated histochemically inneurons of cardiac ganglia of human transmural cardiac tissue,consistent with synthesis of 5-HT (Singh et al., 1999). 5-HT canbe captured by sympathetic nerve endings in human atrialtrabeculae, released with field stimulation and increasecontractility through 5-HT4 receptors, thus plausibly act as afalse neurotransmitter (Kaumann, 2000).

Polymorphic alterations of the 5-HT transporter (5-HTT)of platelets are associated with a higher risk of myocardialinfarction (Fumeron et al., 2002). The 5-HTT is encoded by asingle gene expressed in neurons, platelets, as well asendothelial, vascular and other cells. Human 5-HTT expres-sion is determined genetically by an insertion/deletionpolymorphism in the promoter region of the gene with long(L) and short (S) forms (Lesch et al., 1996). The L alleledoubles or triples the rate of 5-HTT gene transcriptioncompared to the S allele (Heils et al., 1996), reflected bygreater 5-HTT mRNA and protein levels and 5-HT uptakeinto lymphoblasts with the LL genotype compared to the SSand LS genotypes (Lesch et al., 1996). Individuals with theLL and LS genotypes had significantly higher blood 5-HTthan did those with the SS genotype (Hanna et al., 1998).Furthermore, because of greater 5-HT platelet storage, plateletactivation is greater in a group of clinically depressed patientswith the 5-HTT LL genotype than with other genotypes andthis may facilitate ischaemic heart disease (Whyte et al.,2001). Similar conclusions were made from a study withJapanese individuals in which the L allele of the 5-HTT was

associated with coronary heart disease in smokers (Arinami etal., 1999).

Conversely, the lower 5-HTT expression in platelets resultsin lower 5-HT uptake and less 5-HT available for release,thereby reducing the risk of platelet aggregation, thrombusformation and vascular spasm. As expected, patients with theSS 5-HTT genotype appear to have a lower risk of myocardialinfarction, delaying the age of onset, in particular amongsmokers (Coto et al., 2003). Antidepressants that are inhibitorsof 5-HT uptake by 5-HTT, thereby depleting platelet 5-HTstorage and reducing function (Hergovich et al., 2000), alsoreduce the incidence of myocardial infarction; increasingtransporter affinity correlates with greater protection (Sauer etal., 2003). Selective inhibitors of 5-HT uptake by 5-HTT furtherinhibit platelet function in patients with congestive heart failurealready on aspirin (Serebruany et al., 2003).

Platelet aggregation at ruptured atheromatous plaques occursthrough binding of von Willebrand factor and fibrinogen to theplatelet surface receptor, glycoprotein IIb/IIIa (Jang et al.,1994). A polymorphism of platelet glycoprotein IIIa gene, PIA2

(Newman et al., 1989) was found to be associated with acutecoronary thrombosis in a younger population with highprevalence of smokers (Weiss et al., 1996) but not in anotherstudy with a cohort of healthy men, mostly non-smokers(Ridker et al., 1997). However, the risk of myocardial infarctionappears to be increased with a combination of the unfavorableglycoprotein IIIa PIA polymorphism with the LL genotype ofthe 5-HTT (Schwartz et al., 2003).

5.2.2.1. Atrial fibrillation. The endogenously occurringagonists noradrenaline, adrenaline, histamine and 5-HT cantrigger experimental arrhythmias mediated through the Gs-protein-coupled β1-adrenoceptors, β2-adrenoceptors, histamineH2 receptors and 5-HT4 receptors respectively, in human atrialtrabeculae. The incidence of these arrhythmias is consistentlyenhanced in atrial trabeculae (Kaumann & Sanders, 1993;Kaumann & Sanders, 1994; Sanders et al., 1996) and myocytes(Pau et al., 2003), obtained from patients chronically treatedwith β1-selective blockers. The pro-arrhythmic effects of 5-HT,mediated through human atrial 5-HT4 receptors, are probablymainly related to Ca2+ overload (Kaumann, 1994), producedthrough an increase in L-type Ca2+ current (ICa,L). The effects of5-HT on ICa,L are as marked as those of isoprenaline (up to 6-fold increases in ICa,L; Ouadid et al., 1992; Jahnel et al., 1993).Matching increases of ICa,L by 5-HT and isoprenaline areassociated with cyclic AMP, PKA and inotropic signals of 5-HTonly approximately half as great as the corresponding signals ofisoprenaline (Kaumann et al., 1990). This paradox suggests thatPKA-catalysed phosphorylation of the L-type Ca2+ channel via5-HT4-receptors (Ouadid et al., 1992) is more efficient than viaβ-adrenoceptors. Alternatively, part of the isoprenaline-evokedcyclic AMP and PKA signals (Kaumann et al., 1990) could beunrelated to signals at the microscopic level of the L-type Ca2+

channels. However, the maximum inotropic signal of 5-HT isalso only half of that of isoprenaline, in line with the smallerbiochemical signals (Kaumann et al., 1990). This suggests thatCa2+-induced Ca2+ release is smaller through 5-HT4 receptors


than through β-adrenoceptors, although PKA-induced phos-phorylation of ryanodine RyR2 Ca2+ release channels andphospholamban could also be smaller. It is interesting in thiscontext that in atrial trabeculae of patients with chronic atrialfibrillation the contractile responses to 5-HT are nearlyabolished while still nearly maximum ICa,L signals could beelicited with 5-HT in atrial myocytes through 5-HT4 receptors,suggesting a marked impairment of Ca2+-induced Ca2+ release(Christ et al., 2005). However, a decrease in 5-HT potency asenhancer of ICa,L has also been observed in atrial myocytes frompatients with atrial fibrillation (Christ et al., 2005; Pau et al.,2005b), possibly due to 5-HT4 receptor desensitisation and/orgreater activity of PDE.

As suggested above (Section 3.2.1), the increased arrhythmic(Kaumann & Sanders, 1994; Sanders et al., 1995; Pau et al.,2003) responses to 5-HT through 5-HT4 receptors in atrialmyocardium of patients chronically treated with β1-adrenocep-tor-selective blockers, could be related to a decreased Gi proteinfunction. Consistent with a role of Gi protein, the inhibition of Gi

protein with PTX enhances the responses of a low 5-HTconcentration on the hyperpolarising current If (Lonardo et al.,2005). Because in addition to coupling to Gs, 5-HT4(b) receptors,but not coexisting 5-HT4(a) receptors (Bach et al., 2001), appearalso to couple to Gi (Pindon et al., 2002), the effects of 5-HTon Ifare consistent with mediation through 5-HT4(b) receptors inhuman atrial myocytes. The shift of the If activation curve by 5-HT and catecholamines toward less negative potentials has beenproposed to facilitate arrhythmias (Pino et al., 1998; Lonardo etal., 2005). The effects of adrenaline on If, mediated through β2-adrenoceptors, but not the effects of noradrenaline, mediatedthrough β1-adrenoceptors, are also enhanced by PTX (Lonardoet al., 2005), consistent with coupling of β2- but not β1-adrenoceptors to Gi protein. However, the incidence ofarrhythmias is not only higher through β2-adrenoceptors butalso through β1-adrenoceptors in atrial trabeculae from patientschronically treated with β1-selective blockers (Kaumann &Sanders, 1993; Kaumann et al., 1995). Therefore factorsunrelated to receptor-coupling to Gi protein appear to contributeto the arrhythmic hyperresponsiveness to noradrenaline. Gi

inhibition with PTX should also be investigated on the effects of5-HTon ICa,L and be compared with the effects of noradrenalineand adrenaline through β1- and β2-adrenoceptors.

Focal activity in human pulmonary veins often initiates(Haissaguerre et al., 1998) but can also maintain atrialfibrillation (Haissaguerre et al., 2004a) and isolation andelectrical ablation of pulmonary veins significantly terminatesthe arrhythmia (Haissaguerre et al., 2004b). Atrial myocardialsleeves extend into the pulmonary veins (Saito et al., 2001;Becker, 2004). Since functional 5-HT4 receptors have beendetected in human left atrium (Sanders & Kaumann, 1992), it isconceivable that the left atrial sleeves extending into thepulmonary veins may also possess 5-HT4 receptors. Activationof these receptors by 5-HT could conceivably initiate atrialfibrillation in some pulmonary veins and 5-HT4 receptorblockers would be expected to prevent the arrhythmias. Thishypothesis requires experimental testing. The more generalproposal for using 5-HT4 receptor-selective antagonists in atrial

fibrillation (Kaumann, 1994) still needs clinical verification.Due to the inotropic and electrophysiological changes of the 5-HT responses in atrial myocytes from patients with chronicatrial fibrillation, compared to myocytes from patients withsinus rhythm (Christ et al., 2005; Pau et al., 2005b), it isplausible that 5-HT4 receptor-selective blockers will be moreeffective in preventing the initiation of atrial fibrillation in somecases than aborting chronic fibrillation due to profoundremodelling (Wijffels et al., 1995; Nattel, 2002).

Experiments on porcine atrium are consistent with thehypothesis that 5-HT contributes to the generation of atrialfibrillation and flutter. The porcine left atrium possessesfunctional 5-HT4 receptors (Parker et al., 1995) and has beenused as a model for human 5-HT4 receptor-mediated atrialfibrillation (Rahme et al., 1999). The 5-HT4-selective antagonistRS100302 terminated electrically induced atrial fibrillation andflutter and reintroduced sinoatrial rhythm in porcine atria. Thethoracotomy and suturing of the mapping plaque to the porcineatrium might have caused 5-HT release and 5-HT4 receptoractivation (Rahme et al., 1999).

The inotropic effects of 5-HT on human atrium, mediatedthrough 5-HT4 receptors, can fade (Sanders & Kaumann, 1992),probably due to the hydrolysis of cyclic AMP by PDE(Kaumann & Levy, 2006). Fade of human atrial inotropicresponses to 5-HT was reduced by the selective PDE3 inhibitorcilostamide but not by the PDE4-selective inhibitor rolipram,consistent with PDE3-catalysed cyclic AMP hydrolysis (A.Galindo-Tovar & A. Kaumann, unpublished observation).PDE3 activity may prevent harmful cardiostimulation through5-HT4 receptors. The PDE3-selective inhibitor milrinone causesarrhythmias and increases mortality in heart failure (Packer etal., 1991). Conceivably, 5-HT4 receptor-mediated arrhythmiascould be one of the factors that contributed to the harmfuleffects of milrinone. Inotropic fade has also been observed with5-HT4 receptor partial agonists (Kaumann et al., 1991). Since 5-HT4 partial agonists are used in irritable bowel syndrome, theircombination with a PDE3 inhibitor should probably be avoided,to prevent the appearance of possible arrhythmias (Kaumann &Levy, 2006).

5.2.2.2. Heart failure. 5-HT released from platelets (Kau-mann, 1994) or as a false neurotransmitter from sympatheticnerve endings (Kaumann, 2000) could elicit harmful arrhyth-mias in heart failure. Consistent with this hypothesis are theexperimental arrhythmias observed on human atrial trabeculae(Kaumann & Sanders, 1994) and human ventricular trabeculaefrom failing hearts (Brattelid et al., 2004b). Since theexperimental arrhythmias are produced by 5-HT through 5-HT4 receptors, chronic administration of a 5-HT4 receptorblocker would be expected to prevent the arrhythmias triggeredby 5-HT (Kaumann, 1994).

5-HT can also enhance the contractility and hasten relaxationof human atrial and ventricular trabeculae through 5-HT4

receptors in preparations from failing hearts (Sanders &Kaumann, 1992; Brattelid et al., 2004b), thereby conceivablycreating an overdemand of oxygen in an already oxygen-starvedheart. As in 5-HT-evoked arrhythmias, 5-HT4 blockers should


provide some benefit in heart failure by preventing harmfulcardiostimulation (Qvigstad et al., 2005c).

Since ventricular effects of 5-HT become conspicuous in thepresence of non-selective inhibition of PDE with IBMX, it wasproposed that PDEs have a protective role against the potentiallyharmful effects of 5-HT (Brattelid et al., 2004b). To investigatewhich PDE isoenzymes are involved, preliminary experimentsshow that the selective PDE3 inhibitor milrinone, but not theselective PDE4 inhibitor rolipram, facilitates the appearance ofpositive inotropic and lusitropic responses to 5-HT in ventriculartrabeculae obtained from human failing hearts (E. Qvigstad, F.Afzal et al., unpublished data). These findings are consistentwith the attenuation by PDE3-selective cilostamide of the fade ofinotropic responses to 5-HT in human atrium (Section 5.2.2.1),suggesting that PDE3 is the isoenzyme that prevents unduecardiac overstimulation in human heart.

The positive inotropic, lusitropic and arrhythmic effects of 5-HT, mediated through 5-HT4 receptors, have been observed inhuman ventricular trabeculae from terminally failing hearts(Brattelid et al., 2004b). Although atria from rats with non-failing hearts express 5-HT4 mRNA (Gerald et al., 1995), 5-HTincreases atrial contractility through 5-HT2A receptors but notthrough 5-HT4 receptors in this species (Kaumann, 1991; Läeret al., 1998) and 5-HT does not affect ventricular contractility(Läer et al., 1998). However, myocardial infarction, induced bycoronary artery ligation, followed by heart failure, uncoversfunctional ventricular cardiostimulation through both 5-HT2A

and 5-HT4 receptors (Qvigstad et al., 2005a, 2005b). Three daysafter coronary ligation rats with acute heart failure exhibitincreases in contractility of the left ventricular papillary muscle,mainly mediated through 5-HT2A receptors, accompanied bymyosin light chain-2 phosphorylation (Qvigstad et al., 2005b)and a small increase in contractility through 5-HT4 receptors. Atpresent, however, there is no evidence for the existence andfunction of human myocardial 5-HT2A receptors.

In rats, 6 weeks after coronary ligation and with chronic heartfailure, 5-HT increases contractility and hastens relaxationaccompanied by a small cyclic AMP signal, almost exclusivelythrough 5-HT4 receptors (Qvigstad et al., 2005a). As in humanheart failure (Brattelid et al., 2004b) 5-HT4 mRNA is increased4-fold in chronic rat heart failure (Qvigstad et al., 2005a). Thefailing rat heart, 6 weeks after coronary ligation, thereforeappears to be an interesting model for ventricular 5-HT4

receptors of failing human heart. The appearance of functional5-HT4 receptors in the infarcted and failing rat heart (Qvigstad etal., 2005a) suggests transformation into a phenotype that differsfrom the phenotype of normal hearts, raising the possibility of anequivalent phenotype change in human failing and infarctedhearts. However, against this hypothesis are recent experimentsdemonstrating positive inotropic effects of 5-HT in ventriculartrabeculae from 2 non-failing human donor hearts, observed inthe absence of IBMX (E. Qvigstad et al., unpublished data).

Heart failure often starts with hypertrophy followed byfibrosis as demonstrated in mice with heart failure induced byoverexpression of β1-adrenoceptors (Engelhardt et al., 1999).Of relevance, cardiac hypertrophy by chronic isoprenalineperfusion in mice is prevented by the 5-HT2B-selective

antagonist SB206553 and absent in 5-HT2B receptor knock-out mice (Jaffré et al., 2004). Isoprenaline perfusion also causedan increase of plasma levels of the cytokines interleukin-1β andtumour necrosis factor-α and these effects were equallyprevented by SB206553 and absent in 5-HT2B knock-outmice. Remarkably, the blockade of the isoprenaline-inducedeffects, including the production of cytokines by fibroblasts,occurred in the absence of 5-HT, suggesting the existence ofcomplexes (heterodimers?) between 5-HT2B receptors and β1-adrenoceptors (Jaffré et al., 2004). These interesting findingsmust await verification in the human failing heart.

5-HT may also contribute indirectly to heart failure bystimulating aldosterone biosynthesis (Müller & Ziegler, 1968)and secretion. High plasma aldosterone levels are associatedwith left ventricular hypertrophy (Duprez et al., 1996), heartfailure and mortality (Swedberg et al., 1990) and treatment withaldosterone receptor antagonists reduces mortality (Pitts et al.,1999, 2003). Aldosterone secretion is enhanced in volunteers bythe 5-HT4 receptor partial agonists zacopride (Lefebvre et al.,1993), metoclopramide (Sommers et al., 1996) and cisapride(Lefebvre et al., 1993; Huang et al., 1997). Interestingly,Sommers et al. (1996) also reported a decrease of aldosteronesecretion with the 5-HT3/5-HT4 receptor antagonist tropisetron,consistent with tonic 5-HT-evoked aldosterone secretionthrough 5-HT4 receptors. 5-HT is localised and released fromperivascular mast cells in human adrenal slices and causescortisol secretion and an increase of cyclic AMP through 5-HT4

receptors (Lefebvre et al., 1992). Depletion of mast cell 5-HTwith compound 48/80 in perfused human adrenocorticalexplants causes marked release of 5-HT and secretion ofaldosterone (Lefebvre et al., 2001). The 5-HT precursor, 5-hydroxytryptophan (Shenker et al., 1985) and cisapride increaseplasma aldosterone levels in patients with idiopathic hyper-aldosteronism (Lefebvre et al., 2000) and in patients withadrenocortical aldosterone-producing adenomas (Lefebvre etal., 2002) without modifying renin, cortisol and potassiumlevels. 5-HT- and cisapride-induced aldosterone secretion,inhibited by the 5-HT4-selective antagonist GR113808, occursthrough 5-HT4 receptors located in adrenal glomerulosa cells(Lefebvre et al., 2002). Activation of adrenocortical 5-HT4

receptors increases both cyclic AMP and Ca2+ influx through T-type Ca2+ channels, thereby leading to corticosteroid andaldosterone secretion (Contesse et al., 1996). The major effectof increased adrenocortical cell Ca2+ is to increase steroido-genesis. Increased extracellular K+ enhances aldosteronesecretion by causing membrane depolarisation, thereby alsoactivating voltage-dependent T-type Ca2+ channels and elicitinga rapid rise in intracellular Ca2+, which in turn activatescalmodulin (CaM) kinases. CaM kinases then phosphorylatetranscription factors, including cAMP-response element (CRE)-binding protein (CREB; reviewed in Spät & Hunyady, 2004), apathway also plausibly activated through adrenocortical 5-HT4

receptors. The enhanced Ca2+ influx stimulates Ca2+-dependentadenylyl cyclase AC3, expressed in human glomerulosa cells(Côté et al., 2001), thereby increasing cyclic AMP levels,activating PKA, which in turn appears involved in the transferof aldosterone-precursor cholesterol from cytoplasm into the


inner mitochondrial membrane (Spät & Hunyady, 2004). Thediscussed evidence suggests that 5-HT conceivably is a factorthat, in addition to angiotensin II and high K+, enhancesaldosterone secretion in heart failure. Blockade of adrenocor-tical 5-HT4 receptors could therefore bring benefit in heartfailure.

5.2.2.3. Cardiac pain and 5-HT3 receptors? Intravenousadministration of 5-HT produces sensations of pain in humans(Hollander et al., 1957; Le Mesurier et al., 1959) and equivalentpseudoaffective responses in several animal models (reviewedby Meller & Gebhart, 1992). Cardiac sympathetic afferents,activated during cardiac ischaemia (Uchida & Murao, 1974),transmit nociceptive information from the heart to the CNS toelicit the perception of pain. Both exogenous 5-HT (Nishi et al.,1977; Fu & Longhurst, 2002) and platelet-derived 5-HT (Fu &Longhurst, 2002) stimulate afferent cardiac sympathetic Aδfibers and C-fibers during experimental cardiac ischaemia incats and these effects are prevented by tropisetron throughblockade of neuronal 5-HT3 receptors (Fu & Longhurst, 2002).A hypothetical contribution of 5-HT3 receptors in thetransmission of nociceptive stimuli from myocardial ischaemiain human heart needs to be investigated.

5.2.2.4. 5-HT4 receptor autoantibodies and congenital heartblock. Congenital heart block (CHB), detected before or atbirth in infants from mothers with systemic lupus erythematosus(SLE), is frequently associated with maternal autoantibodiesagainst ribonucleoproteins SSA/Ro and/or SSB/La. Antibodiesto the 52-kD SSA/Ro protein (Ro-52) causes atrioventricular(AV) block in the perfused human fetal heart and inhibits L-typeCa2+ currents ICa,L. The inhibition of ICa,L is due to shorter opentimes and longer closed times of the channels (Boutjdir et al.,1997). These changes in ICa,L are opposite to those caused by 5-HT through 5-HT4 receptors that increases ICa,L, lengthens opentimes and shortens closed times (Jahnel et al., 1993).

Using a synthetic peptide, G21V, corresponding to thesecond extracellular loop of the human 5-HT4 receptor,Eftekhari et al. (2000) were able to affinity-purify anti-G21V-autoantibodies which recognised both the 5-HT4 receptor andthe Ro52 protein, demonstrating the existence of cross-reactiveepitopes. They found that 17 of 26 SLE patients respondedpositively in a direct enzyme immunoassay with the G21Vpeptide. Eftekhari et al. (2000) also showed that the affinity-purified anti-G21V antibody partially antagonised the 5-HT-induced increases in ICa,L on human atrial myocytes. Subse-quently Eftekhari et al. (2001) immunised mice with G21V andseveral Ro52-derived peptides and the mice developed anti-peptide antibodies. Peptide-immune mice were mated and thepups monitored 2 days after birth. Mice immunised with 5-HT4-derived G21V produced stillborn pups with hearts of decreasedsize presenting hyperplasia. Living pups had sinus bradycardiaand increased QT interval but only 13% had AV block; thesemice also had skin rash. Interestingly, 5-HT4 receptors weredemonstrable in heart but not anymore 5 days after birth. Theauthors concluded that neonatal lupus is an autoimmune anti-5-HT4 receptor fetal disease. However, mice immunised with Ro-

52-derived peptides did not show AV block or skin rash, whichis puzzling.

Although the 5-HT4 autoantibody hypothesis is interesting, itdoes not explain why antibody against the Ro-52 protein causesAV block and inhibits ICa,L unless it is assumed that themyocytes from human fetal hearts of the work of Boutjdir et al.(1997) possessed 5-HT4 receptors that constitutively (i.e. in theabsence of 5-HT) opened ICa,L. Alternatively, unlike adultmurine hearts devoid of 5-HT4 receptor function, fetal heartsmay actually express functional 5-HT4 receptors activated with5-HT from the maternal blood.

A recent reassessment of 101 anti-SSA/Ro52-positivemothers yielded 74 CHB children, only 12 CHB were reactivewith the 5-HT4 peptide while 73 had circulating anti-SSA/Ro52autoantibodies (Kamel et al., 2005). Despite the lack ofgenerality of these findings, a putative physiological role of 5-HT4 receptors in the developing heart should be taken seriouslyand awaits further research.

5.2.2.5. Valvular heart disease. 5-HT and serotonergicmedications can induce valvular heart disease (VHD). Carci-noid tumours cause usually right-side VHD by endogenouslyreleased 5-HT in 2/3 of the patients (Kulke & Mayer, 1999).Left-side VHD occurs in less than 10% of patients (Robiolio etal., 1995). 5-HT released from the enterochromaffin cells of thegut is mostly captured by platelets in the portal circulation. Non-platelet bound 5-HT is metabolised by monoamine oxidases inthe liver and lung to 5-hydroxyindole acetic acid (5-HIAA),thereby usually sparing the cardiac left-side valves fromexposure to high 5-HT levels. Patients with carcinoid syndromehave high levels of plasma 5-HT and platelet-bound 5-HT, aswell as urinary 5-HIAA (Robiolio et al., 1995), but alsoincreased levels of tachykinins and bradykinin (Lundin et al.,1988). In VHD tricuspid valve function is consistently affectedbut pulmonary valve function is also often perturbed (Møller etal., 2003). Valve lesions consist of carcinoid plaques containingsubendocardial deposits of fibroblasts and smooth muscle cellsin a myxoid matrix (Ferrans & Roberts, 1976; Sakai et al.,2000), associated with triscuspid and pulmonary valvemalfunction (Møller et al., 2003). Similar lesions weremimicked in tricuspid and aortic valves, accompanied byvalve malfunction, in rats chronically (3 months) injected with5-HT, indicating an etiological role of 5-HT (Gustafsson et al.,2005). These findings point to a pathogenic role of 5-HT inVHD, although a contribution of tachykinins and bradykinincannot be ruled out.

Proliferative plaques of mitral valve and/or thickening ofboth tricuspid and aortic valves have also been observed inpatients taking anorectic drugs (fenfluramine plus phentermine;Connolly et al., 1997). It was subsequently shown that treatmentwith fenfluramine or dexfenfluramine for four months or longercaused aortic and mitral regurgitation in 35 cases per 10,000(Jick et al., 1998). Fenfluramine and its (+)-enantiomerdexfenfluramine are metabolised to (±)-norfenfluramine and(+)-fenfluramine (Caccia et al., 1985). Fenfluramine and itsmetabolites release 5-HT and it has been discussed that VHDmay be produced through increased 5-HT plasma levels


(Fishman, 1999). However, this hypothesis has been rejectedbecause treatment with fenfluramine–phentermine actuallydecreases both plasma and platelet 5-HT but phentermine hasno significant effect (Rothman et al., 2000a). Instead, Rothmanet al. (2000b) provided evidence from systematic screening of11 5-HT receptor subtypes that fenfluramine and its metabolites(±)-norfenfluramine, (+)-norfenfluramine and (−)-norfenflura-mine, but not phentermine, had selectively high affinity for5-HT2B receptors and similar observations were made inde-pendently by Fitzgerald et al. (2000), consistent with a role of 5-HT2B receptors in VHD. 5-HT2B receptors may also be involvedin the VHD produced by methysergide and its metabolitemethylergonovine as well as ergotamine, dihydroergotamine(Creutzig, 1992) and the ergot-derivative dopamine agonistpergolide used in Parkinson's disease (Horvath et al., 2004)because these compounds also exhibited high affinity for 5-HT2B receptors (Rothman et al., 2000b). Fenfluramine,norfenfluramine and dihydroergotamine but also the ecstasydrug MDMA and its metabolite 3,4-methylenedioxyampheta-mine (MDA) exhibit mitogenic activity by stimulating [3H]thymidine incorporation on human valvular interstitial cells.These effects are antagonised by the 5-HT2B/5-HT2C-selectiveantagonist SB206553 (Setola et al., 2003). Since 5-HT2B

receptors, but hardly 5-HT2C receptors, are expressed in humanvalves (Fitzgerald et al., 2000), the experiments of Setola et al.(2003) are consistent with mediation of the mitogenic effects offenfluramine and MDMA through 5-HT2B receptors.

5.3. Vascular disease

5-HT receptors have been implicated in several vasculardiseases, including hypertension and preeclampsia, coronaryspasm, pulmonary hypertension, Raynauds phenomenon,migraine and portal hypertension. Although the intravenousadministration of the 5-HT2A receptor-selective antagonistketanserin lowered blood pressure in hypertensive patients(Vanhoutte et al., 1988), this may have occurred throughblockade of α1-adrenoceptors (Fozard, 1982) and/or suppres-sion of the amplification of noradrenaline responses by 5-HT(Van Nueten & Janssens, 1986; Van Nueten et al., 1988).

Vascular endothelium is damaged in preeclampsia (Zeeman& Dekker, 1992). The reduction of the protective endothelialfunction may facilitate platelet aggregation with 5-HT releaseand interaction with smooth muscle 5-HT receptors. Althoughketanserin treatment occasionally reduces blood pressure inhypertensive pregnant women with preeclampsia, there is ascarcity of appropriately designed studies (reviewed by Steyn &Odendaal, 2000). The plausible participation of 5-HT and 5-HTreceptors in hypertension requires fresh research.

5.3.1. Coronary spasm: differentrole of 5-HT1B and 5-HT2A receptors

Both 5-HT1B and 5-HT2A receptors can contribute tocoronary spasm, but often in different etiologies. Both 5-HTand sumatriptan can cause phasic contractions of isolatedhuman coronary artery, mimicking spasm, especially whenextracellular Ca2+ is higher than 2 mM (Cocks et al., 1993;

Kaumann et al., 1994). 5-HT can be used to induce coronaryspasm at spastic sites of patients with variant angina (Kanazawaet al., 1997). Coronary artery spasm is facilitated by theexistence of atheromatous plaques but can also occur in theabsence of atheroma (Prinzmetal's variant angina). 5-HT levelsin the coronary sinus increase in patients with coronary lesionsand severe angina (Rubanyi et al., 1987; Van den Berg et al.,1989) and 5-HT is associated with coronary artery disease,particularly in younger patients (Vikenes et al., 1999). Duringacute myocardial infarction thrombotic occlusion occurs withplatelet aggregation at ruptured plaques and release of 5-HT,thromboxane A2 (TXA2) and adenine nucleotides, which in turnfacilitate further platelet release (Zucker & Nachmias, 1985).Both 5-HT and sumatriptan and the TXA2 agonist U46619 actsynergistically to contract human coronary artery (Chester et al.,1993; Cocks et al., 1993; MaassenVanDenBrink et al., 1996).The effects of 5-HT are potentiated by U46619 in the presenceof ketanserin and potentiation is prevented by methiothepin,conceivably through blockade of 5-HT1B receptors (Chester etal., 1993). The marked increase of sumatriptan-inducedcontractions of human coronary artery by U46619 (Cocks etal., 1993) as well as reported reduction of the intracoronarydiameter with sumatriptan (MacIntyre et al., 1992) is alsoconsistent with mediation through 5-HT1B receptors. Isolatedcases of clinical coronary spasms caused by sumatriptan,mediated through 5-HT1B receptors, have been discussedelsewhere (Cocks et al., 1993; Kaumann et al., 1994 and inSection 5.3.4).

Intra-coronary infusions of 5-HT cause coronary arteryconstriction in patients with coronary atherosclerosis (Golino etal., 1991; McFadden et al., 1991). Golino et al. (1991) found inpatients with and without arteriosclerotic evidence thatketanserin completely blocked the decrease in large coronaryarterial diameter to intracoronary infusions of 5-HT. Earlyreports failed to find an effect of ketanserin in Prinzmetal'svariant angina, diagnosed with infusions of ergonovine (thatacts partially through 5-HT1B receptors) (DeCaterina et al.,1984; Freedman et al., 1984). Furthermore, McFadden et al.(1991) also failed to block spasms caused by intracoronaryinfusions of 5-HT in patients with Prinzmetal's angina. Afemale patient suffering from variant angina due to spasms ofthe right coronary artery for 20 years, exhibited postmortem invitro supersensitivity to 5-HT and sumatriptan, compared tocoronary arteries from patients without Prinzmetal's angina(Kaumann et al., 1994) and presumably occurring at 5-HT1B

receptors (Ishida et al., 1998). Taken together, the evidence withPrinzmetal's angina suggests that a 5-HT1B receptor-selectiveblocker could be beneficial to prevent at least some cases ofvariant angina.

5-HT levels are increased also in the coronary sinus duringvasoconstriction induced by coronary angioplasty; vasocon-striction was attenuated by ketanserin in 8 patients (Golino etal., 1994), consistent with 5-HT2A receptor activation. Thecontribution of 5-HT1B and 5-HT2A receptor to coronary spasmmay depend on specific locations within the same coronaryartery. For example, in a circumflex artery from a patient withischaemic heart disease, presenting a thrombotic occlusion, the


prestenotic segment but not the poststenotic segment presentedatheromatous plaques. 5-HT had the same contractile potencyon the prestenotic and poststenotic segments. However, 100 nMketanserin blocked most of the effect on the poststenoticsegment, consistent with mediation through 5-HT2A receptors,but hardly the effects of 5-HT on the prestenotic segment,probably mediated through 5-HT1B receptors (Kaumann &Brown, 1990).

5.3.2. Pulmonary hypertension:role of 5-HT1B and 5-HT2B receptors

Pulmonary hypertension has been associated with elevatedplasma 5-HT levels, a platelet defect that exhibits reduced 5-HTcapture, decreased 5-HT uptake and increased 5-HT releasefrom platelets of patients with chronic ingestion of the appetitesuppressant dexfenfluramine, as well as mutations of the 5-HTT(reviewed by Farber & Loscalzo, 2004). 5-HT contributes topulmonary hypertension by acting on extracellular andintracellular sites of vascular cells.

Extracellular effects of 5-HT appear mainly mediatedthrough 5-HT1B and 5-HT2B receptors, intracellular effects viacellular capture of 5-HT through the 5-HT uptake transporter 5-HTT. 5-HT1B receptors mediate acute pulmonary vasoconstric-tion by 5-HT released through local microthrombosis but havealso been proposed to act in synergy with Gq-coupled receptors(the 5-HT2 receptor family) by decreasing cyclic GMP(reviewed by MacLean et al., 2000). 5-HT and dexfenfluraminechronically facilitate smooth vascular cell proliferation andpulmonary vascular remodelling, mediated through 5-HT2B

receptors, in a model of chronic hypoxia in mice (Launay et al.,2002). Although direct evidence for an involvement of human5-HT2B receptors in pulmonary hypertension is unknown, amutation of the 5-HT2B gene was associated with pulmonaryhypertension in a patient undergoing a 9-month fenfluraminetreatment (Blanpain et al., 2003; see also Section 5.1.2.2),suggesting a possible role in man. This mutation (393X)appears to result in a gain of proliferative function mediatedthrough G13, despite loss of coupling to Gαq (Deraet et al.,2005). This implies a mechanism involving Rho family smallGTPases and is in line with the beneficial effects of Rho kinaseinhibition on sustained hypoxic pulmonary vasoconstriction inrats (Robertson et al., 2000).

An intracellular role of 5-HT as promoter of smooth musclehyperplasia from human pulmonary arteries is supported by theincreased expression and function of the 5-HTT and a greaterprevalence of the L-allelic variant in pulmonary hypertensivepatients compared to non-pulmonary hypertensive (Eddahibi etal., 2001, 2003). The same group demonstrated markedlyenhanced [3H]5-HT uptake and prevention by the uptakeblockers fluoxetine and citalopram in hyperplastic smoothmuscle cells from pulmonary hypertensive patients compared tocontrols (Marcos et al., 2004). Interestingly, the co-expressionof smooth muscle 5-HT1B, 5-HT2A and 5-HT2B receptors wasnot changed in pulmonary hypertension and blockade of thesereceptors did not affect the mitogenic activity of 5-HT,suggesting a minor role in pulmonary vascular remodelling(Marcos et al., 2004). Intracellular candidates as effectors for

the mitogenic effects of 5-HT are uncertain. An increase ofsuperoxide anion production and stimulation of tyrosinephosphorylation of GTPase-activating protein has been pro-posed (MacLean et al., 2000). Interestingly, 5-HT can betransamidated to small GTPases by transglutaminases duringactivation and aggregation of platelets, producing constitutivelyactive GTPases (Walther et al., 2003), but whether thismechanism is relevant to the intracellular effects in humanpulmonary artery smooth muscle needs to be investigated.

The future treatment of the 5-HT components of humanpulmonary hypertension is still uncertain. Blockade of the 5-HTtransporter 5-HTT or the 5-HT1B or 5-HT2B receptors arepossible approaches. Pulmonary vascular remodelling andincreased arterial contractions in response to 5-HT, inducedby chronic hypoxia, are decreased in 5-HT1B

�/� mice (Keeganet al., 2001). These findings, together with the demonstration offunctional 5-HT1B receptors in human pulmonary artery(MacLean et al., 2000), led to the suggestion of the use of aselective 5-HT1B receptor blocker in human pulmonaryhypertension (Keegan et al., 2001). Blockade of 5-HT2B

receptors in mice prevents pulmonary hypertension (Launayet al., 2002). On the other hand, blockade of endothelial 5-HT2B

receptors of porcine pulmonary arteries eliminates relaxationinduced by nitric oxide release (Glusa & Pertz, 2000). If thisbeneficial relaxation occurs in human pulmonary arteries,blockade of the 5-HT2B receptor-mediated synthesis of nitricoxide (Ullmer et al., 1996; Manivet et al., 2000) should becontraindicated in patients with pulmonary hypertension.Although 5-HT uptake blockers may initially enhance plasma5-HT levels, this is probably hardly of relevance because theseagents actually may protect against hypoxia-induced pulmonaryhypertension in mice (Marcos et al., 2003).

5.3.3. Raynaud's vasospasmRaynaud's phenomenon consists in transient episodic, cold-

induced, ischaemic vasoconstriction of digital arteries, pre-capillary arterioles and cutaneous arteriovenous shunts. Ray-naud reasoned that the ischaemia was the result of an excessiveactivity of sympathetic nerve endings of digital blood vesselsbut Lewis suggested an anomaly of the receptors responsible forvascular vasoconstriction (reviewed in Mourad & Priollet,1997). Raynaud's phenomenon is, on occasion, part of ageneralised vasospastic disorder of patients with Prinzmetalangina and migraine (Miller et al., 1981; O'Keefe et al., 1992),all disorders with a plausible involvement of 5-HT. A possiblerole of 5-HT during the reflex sympathetic response to coolingwas provided by the attenuation with the 5-HT2A-selectiveantagonist ketanserin of decreases in digital blood flow inducedby cooling from 25 °C to 20 °C (Coffman & Cohen, 1988).These results suggest a contribution of endogenous 5-HT tohand vascular constriction during cooling, which could alsohappen during Raynaud's ischaemic digital vasoconstriction,but the origin of 5-HT is unknown. Studies on platelet-boundand extra-platelet 5-HT are contradictory. Biondi et al. (1988)found increased platelet and plasma free 5-HT in Raynaudpatients compared to normal but Coffman and Cohen (1994)failed to find changes in plasma 5-HT during reflex stimulation


associated with body cooling in normal or Raynaud patients,despite finding associated decreases in blood flow and increasesin vascular resistance. 5-HT seems to facilitate more plateletaggregation in Raynaud patients than in normal volunteers(Biondi &Marasini, 1989). However, platelet aggregation is notnecessary because a patient with Glanzmann's thromboasthe-nia, in which platelets cannot aggregate, exhibited typicalRaynaud's phenomenon (Bellucci et al., 1990). Initial reportssuggested some involvement of 5-HT2A receptors in Raynaud'sphenomenon because ketanserin relieved but did not preventcold-induced vasoconstriction in Raynaud's phenomenon(Seibold & Terregino, 1986). A hypothetical 5-HT-evokedvasocontriction can be amplified by cooling and blocked byketanserin as found in animal vascular models (Van Nueten &Janssens, 1986). Furthermore, in line with Raynaud's hypoth-esis, α-adrenoceptor blockers are effective in the treatment ofRaynaud's phenomenon (Wigley, 2002) and perhaps traces of5-HT could amplify through ketanserin-sensitive receptors thevasoconstrictor response to noradrenaline, as also observed inanimal models (Van Nueten et al., 1988). However, a meta-analysis of ketanserin results has challenged the usefulness ofketanserin (Pope et al., 2000). On the other hand, another 5-HT2A-selective antagonist, sarpogrelate appeared to reduce thefrequency and duration of Raynaud episodes (Kato et al., 2000).The 5-HT uptake inhibitor fluoxetine appears to reduce attackfrequency and severity of the Raynaud phenomenon, conceiv-ably related to a reduction of the 5-HT content in platelets(Coleiro et al., 2001). Emotional stress can also trigger Raynaudepisodes (Block & Sequeira, 2001) so that improvement of thefunction of CNS 5-HT receptors with fluoxetine could also beinvolved in the therapy of Raynaud's phenomenon. Unfortu-nately the nature of vascular 5-HT receptors, possibly involvedin the participation of Raynaud's digital vasoconstriction, iselusive and even paradoxical. A recent case of painfuldiscoloration of the fingers after exposure to cold in a youngwoman (21 years old) taking the 5-HT4 receptor partial agonisttegaserod was reported (Bertoli et al., 2003). Because 5-HT4

receptors are located in human endothelial cells (Ullmer et al.,1995), an agonist would presumably increase cell Ca2+ andrelease nitric oxide and cause vascular dilation, but notconstriction. However, it has recently been shown thattegaserod is a high affinity antagonist of 5-HT2B receptors(Beattie et al., 2004), and since these receptors are located onendothelial cells (Ullmer et al., 1995) they could hypotheticallybe involved in vasodilation through release of nitric oxide asseen in porcine pulmonary arteries (Glusa & Pertz, 2000). Sincethe origin of vascular 5-HT in Raynaud's phenomenon isobscure, one could speculate about the existence of a tonicdilation of human digital blood vessels through occupied oreven unoccupied endothelial 5-HT2B receptors. Clearly the roleof 5-HT and 5-HT receptor subtypes in Raynaud's phenomenonremains elusive and needs fresh research.

5.3.4. MigraineMigraine is a CNS disease with secondary cerebrovascular

changes, including vasodilation of meningeal arteries (Har-greaves & Shepheard, 1999) and extracranial arteries (Lance,

1992). Dilation of blood vessels causes pain and further nerveactivation of the trigeminal nerve (Goadsby et al., 2002).Intracarotid administration of 5-HT decreases the amplitude ofthe human temporal artery (Lance, 1992), presumably throughboth 5-HT1B and 5-HT2A receptors (Verheggen et al., 1996,1998, 2004), and sumatriptan constricts human meningealblood vessels (Henkew et al., 1996) through 5-HT1B receptors(Hamel et al., 1993). Sumatriptan also reverses the vasodilationof the middle cerebral artery during migraine (Friberg et al.,1991), presumably through constriction mediated via 5-HT1B

receptors (Hamel et al., 1993). Although cranial vasoconstric-tion is a plausible mechanism by which sumatriptan (Humphreyet al., 1990) and other triptans alleviate migraine pain,trigeminal neuronal inhibition appears also involved (Goadsbyet al., 2002).

5-HT administered intravenously into volunteers causeschest discomfort (Le Mesurier et al., 1959). Tightness of chest isobserved in 3–5% of patients treated with sumatriptan (Brownet al., 1991; Tansey et al., 1993), the triptan mostly used inmigraine. Tightness of chest could be due to a variety of causes,including coronary vasospasm, pulmonary vasoconstrictionand/or activation of sensory nerve endings (Hillis & MacIntyre,1993). On occasion, sumatriptan can produce anginal chest painand ischaemia (Willett et al., 1992), associated with ventricularfibrillation (Curtin et al., 1992) and transmural infarction(Ottervanger et al., 1993, 1997), possibly due to coronary arteryconstriction via 5-HT1B receptors. Due to these occasional sideeffects, the use of sumatriptan and other triptans is restricted incardiovascular disease. However, since these early reports therehas been a remarkably low incidence of serious cardiovascularevents in migraine patients treated with triptans, despite theability of all used triptans to cause some coronary arteryconstriction (Dodick et al., 2004).

5.3.5. Portal hypertension and 5-HT2A receptors revisitedPortal hypertension is a haemodynamic syndrome frequently

associated with cirrhosis of the liver. An often lethalcomplication is haemorrhage from gastroesophageal varices.The portal circulation is a low-pressure system (b10 mmHg)formed by venous drainage from the gastrointestinal tract,spleen, pancreas and gallbladder. Veins collecting from theseorgans form the splenic as well as superior and inferiormesenteric veins which merge to form the portal vein (Fig. 3).Portal hypertension is initiated by vascular obliteration causedby an increased resistance to portal flow in the shrunken,fibrotic liver. Mesenchymal stellate cells in the subendothelialspace of Disse undergo a transformation from a vitamin A richcell to a proliferating and fibrogenic cell type with reducedvitamin A content. The vascular obliteration results not onlyfrom obstruction to flow by extracellular matrix produced by thetransformed stellate cells, but also from sinusoidal contractioncaused by a change to a myoblast phenotype in cirrhosis(Friedman, 1993) (Fig. 3). Portal hypertension is establishedwhen portal venous pressure exceeds the pressure of the inferiorvena cava by at least 5 mmHg and portosystemic collateralvessels develop (Fig. 3) in order to equalise pressures betweenthese 2 venous systems. The clinically most important

Fig. 3. 5-HT2A receptors (red dots) in veins of the portal circulation (top panels) and stellate cells in the subendothelial space of the liver microcirculation in normalliver (left panels) and cirrhotic liver (right panels). The drawing was adapted from Friedman (1993).


collaterals are the oesophageal varices. Because pressure is afunction of both resistance and flow, increases in flow due tohyperdynamic circulation of cirrhosis and mesenteric arteriolarvasodilation also contribute to portal pressure elevation(Groszmann, 1994).

There is evidence from animal models showing the existenceof 5-HT receptors in the portal vascular system (Fig. 3) whosefunction is changed by experimental portal hypertension. 5-HTinduces contractions in isolated inferior and superior mesentericveins of the rat, antagonised by nanomolar concentrations ofketanserin, and therefore mediated through 5-HT2A receptors(Cummings et al., 1986). 5-HT also contracts portal veins ofmice (Silva et al., 1998) and rats (Jacob et al., 1991). In bothoesophageal and mesenteric superior veins of the rabbit,precontracted in 60 mM K+, 5-HT caused relaxations throughunknown 5-HT receptors (Jensen et al., 1987). 5-HT causescontractions and increases the expression of TGF-beta1,involved in matrix formation by stellate cells; the effects areantagonised by ketanserin and therefore mediated through 5-HT2A receptors, consistent with 5-HT2A mRNA expression (Liet al., 2003). The change to a myocyte phenotype in cirrhosissuggests that these cells may also participate in vascularconstriction through 5-HT2A receptors.

5-HT receptor function is altered in experimental portalhypertension. The sensitivity to 5-HT of rat mesenteric veins,but not the affinity of ketanserin for 5-HT2A receptors, isincreased in portal hypertension (Cummings et al., 1986). Thecontractile responses to 5-HT of the portal vein from miceinfested with Schistosoma mansoni were also increasedcompared to non-infested mice (Silva et al., 1998). Oesophagealcollateral veins lose the ability to relax with 5-HT in portal

hypertensive rabbits (Jensen et al., 1987). 5-HT contracts thecollateral vascular bed in a rat model of portal hypertension;these effects are antagonised by nanomolar concentration of 5-HT2A-selective antagonist ICI169369 (Mosca et al., 1992).These in vitro changes of 5-HT function in experimental portalhypertension were important because the 5-HT2A-selectiveketanserin also lowered portal pressure (Cummings et al.,1986).

Following the initial work of Cummings et al. (1986) withketanserin, the blockade of 5-HT2A receptors as a mechanism tolower portal pressure was confirmed with the 5-HT2A-selectiveantagonists ICI169369 (Kaumann et al., 1988), ritanserin(Mastai et al., 1990; Nevens et al., 1991; Fernandez et al.,1993) and the ketanserin analogue AT-112 (Lin et al., 1997) inrats and with ritanserin in conscious, unrestrained cirrhotic dogs(Mastai et al., 1989).

The work of Cummings et al. (1986) also prompted theclinical use of 5-HT2A antagonists in human portal hyperten-sion. Intravenous ketanserin lowered portal pressure andreduced azygos flow, reflecting superior portosystemic collat-eral blood flow, in cirrhotic patients (Hadengue et al., 1987).Hadengue et al. (1989) showed that the beneficial effects ofketanserin and propranolol on splanchnic circulation wereadditive. Vorobioff et al. (1989) also observed that ketanserin,administered orally, reduced portal pressure in cirrhotics duringprolonged treatment, but reported that some patients underwenta reversible portosystemic encephalopathy. High ketanserinconcentrations not only block 5-HT2A receptors but also blockα1-adrenoceptors (Fozard, 1982) thereby lowering bloodpressure (Reimann & Frolich, 1983). However, Vorobioff etal. (1989) found no correlation between reductions in portal


pressure and mean arterial pressure in their study on cirrhoticpatients. Ritanserin, that blocks 5-HT2A receptors at nanomolarconcentrations but does not block α1-adrenoceptors, alsoreduces portal pressure in cirrhotic patients (Huet et al.,1987). In portal-hypertensive rats with long-term bile ductligation infusion of ritanserin reduces portal pressure withoutsystemic haemodynamic changes (Fernandez et al., 1993).

While ketanserin significantly lowers portal pressure inportal hypertensive rats, α1-adrenoceptor selective prazosinonly does so marginally, while both drugs caused a matchingdecrease in blood pressure; these results are consistent withketanserin acting mainly through 5-HT2A receptor blockade(Cummings et al., 1988). The reversible portosystemicencephalopathy observed with prolonged ketanserin treatmentin some cirrhotics by Vorobioff et al. (1989) could be related tothe hypotensive effects of ketanserin.

The reviewed experimental and clinical evidence is consis-tent with a role of 5-HT2A receptors in portal hypertension. 5-HT, formed in the enterochromaffin cells of the gut, is secretedinto the portal venous circulation and can cause vasoconstric-tion through 5-HT2A receptors located at (Fig. 3): (i) mesentericveins, (ii) oesophageal collaterals and (iii) hepatic stellate cells.In addition, it is also possible that 5-HT normally has a relaxanteffect on oesophageal veins and mesenteric veins, as observedin the rabbit, where the effect is abolished in oesophagealvarices and mesenteric veins from portal hypertensive rabbits(Jensen et al., 1987). The nature of the 5-HT receptors thatmediate relaxation is unknown, but it is possible that they actthrough release of nitric oxide from endothelial cells becausethere is a defect in both NO release and NO-mediated dilation ofthe portal vascular tree in portal hypertension (Groszmann &Abraldes, 2005). Endothelial 5-HT receptors that could causerelease of NO could be 5-HT2B (Ullmer et al., 1995) and thenature of the 5-HT receptors that possibly mediate relaxation ofthe portal venous system requires investigation. Directinformation about the 5-HT receptors mediating both contractileand possibly relaxant effects of 5-HT needs to be generated inveins of the human portal system to understand the mechanismof action of 5-HT2A blockers in human portal hypertension.

Based on the short transit time between gut and liver (∼20 s)(Kotelanski et al., 1972), it has been argued that little plateletuptake of 5-HT released from the gut occurs before the liver(Anderson et al., 1987). It is therefore likely that the extra-platelet 5-HT concentration is sufficiently high to activate 5-HTreceptors of the portal venous system. Portal pressure in patientswith cirrhosis can increase after a meal (McCormick et al.,1990) and the portal blood of fed dogs has more 5-HT than theblood from starved dogs (Black et al., 1959). Blood and plasmalevels of 5-HT are altered in patients with cirrhosis. Wholeblood 5-HT levels are lower (Beaudry et al., 1994), presumablybecause there is a storage (Laffi et al., 1992) and uptake (Ahteeet al., 1981) defect in platelets from cirrhotic patients. However,unconjugated 5-HT levels, which represent the active form of 5-HT, are increased in patients with cirrhosis (Beaudry et al.,1994).

The comprehensive evidence for a role of 5-HT in portalhypertension and the initial clinical benefit of treatment with

ketanserin have demonstrated a harmful participation of 5-HT2A

receptors in patients with cirrhosis. However, the treatment withketanserin has been currently put on hold due to the detrimentalside effects such as systemic hypotension and portosystemicencephalopathy (Vorobioff et al., 1989). There is scope fortreatment of portal hypertensive patients with another clinicallyeffective 5-HT2A receptor blocker devoid of these side effects.

Acknowledgements

Work in the authors' laboratories are funded by grantsfrom the British Heart Foundation (to AJK) and from TheResearch Council of Norway, The Norwegian Council onCardiovascular Diseases, Anders Jahre's Foundation for thePromotion of Science, The Novo Nordisk Foundation, TheFamily Blix Foundation and the University of Oslo (to FOL).AJK wishes to thank Dr. T. Christ (TU Dresden, Germany)for comments about arrhythmias and Dr. D. Pau (Universityof Glasgow) for sharing unpublished observations about atrialfibrillation. Parts of this review were written when AJK was avisiting scientist at the Department of Pharmacology,University of Murcia, Spain.

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