Elsevier

Pharmacology & Therapeutics

Volume 111, Issue 3, September 2006, Pages 674-706
Pharmacology & Therapeutics

Associate editor: P. Molenaar
5-Hydroxytryptamine receptors in the human cardiovascular system

https://doi.org/10.1016/j.pharmthera.2005.12.004Get rights and content

Abstract

The human cardiovascular system is exposed to plasma 5-hydroxytryptamine (5-HT, serotonin), usually released from platelets. 5-HT can produce harmful acute and chronic effects. The acute cardiac effects of 5-HT consist of tachycardia (preceded on occasion by a brief reflex bradycardia), increased atrial contractility and production of atrial arrhythmias. Acute inotropic, lusitropic and arrhythmic effects of 5-HT on human 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 with proliferative disease and thickening of cardiac valves, mediated through 5-HT2B receptors. 5-HT2B receptors have an obligatory physiological role in murine cardiac embryology but whether this happens in humans requires research. Congenital heart block (CHB) is, on occasion, associated with 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 only through 5-HT1B receptors. Both 5-HT1B and 5-HT2A receptors can mediate coronary artery spasm but only 5-HT1B receptors appear involved in coronary spasm of patients treated with triptans or with Prinzmetal angina. 5-HT2A receptors constrict the portal venous system including oesophageal 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.

Introduction

Serotonin (5-hydroxytryptamine, 5-HT) exerts its multiplicity of physiological effects through an unsurpassed diversity of receptors (Hoyer et al., 1994, Hoyer et al., 2002). At least 14 different 5-HT receptors, each encoded by a separate gene, are known in man and their roles in the human cardiovascular system 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 are being unraveled, resulting in possible interindividual differences in their response to serotonin (Göthert et al., 1998, Sanders-Bush et al., 2003).

A multitude of effects of 5-HT have been demonstrated on the cardiovascular system. Some of these effects are mediated through actions of 5-HT in the central nervous system, whereas 5-HT also has multiple and diverse effects through direct interaction with 5-HT receptors in different parts of the cardiovascular system. In each of these, for example different blood vessels or different parts of the heart, the physiological effects of 5-HT depend on the 5-HT receptors involved, the intracellular signals evoked through these receptors, and their cellular localisation. The aim of this review is to present a comprehensive overview of the current knowledge about the diverse effects of 5-HT on the human cardiovascular system, with emphasis on the direct, peripheral effects, as opposed to effects through the central nervous system, and to describe how this knowledge translates into understanding and hypotheses regarding the involvement of 5-HT and 5-HT receptors in the pathogenesis and treatment of human cardiovascular disease. Particular emphasis will be put on the role of 5-HT in heart disease and blood vessel disorders. We will also survey possible effects of polymorphic 5-HT receptor variants and mutants for human cardiovascular function.

Section snippets

Molecular biology of 5-hydroxytryptamine receptors 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, signal transduction properties and pharmacological properties (Hoyer et al., 1994, Hoyer et al., 2002).

Cardiac 5-hydroxytryptamine receptors

Human cardiac 5-HT receptors are depicted in Fig. 2. Functional cardiostimulant 5-HT4 receptors have been described 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 receptors mediate arrhythmias (Kaumann, 1994, Kaumann & Sanders, 1994, Pau et al., 2003, Brattelid et al., 2004b). Activation of 5-HT3 receptors, presumably located at epicardial afferent sensory nerve endings of the vagus,

Vasoconstriction

5-HT receptor subtypes mediating vasoconstriction were identified with the help of subtype-selective antagonists and by comparison with the pharmacology of recombinant receptors. Messenger RNA for both 5-HT1B and 5-HT2A receptors has been detected in smooth muscle cells of human aorta and pulmonary artery (Ullmer et al., 1995). Useful antagonists as tools have been the 5-HT2A-selective ketanserin (Van Nueten et al., 1981), 5-HT1B-selective SB224289 (Roberts et al., 1997) and 5-HT1D-selective

Genetic mutations and polymorphisms in 5-hydroxytryptamine receptors possibly relevant to the human cardiovascular system

Several polymorphic variants of human serotonin receptor genes have been reported. Polymorphisms located in the untranslated regions (UTR) may give rise to altered levels of receptor expression, through altered levels of transcription (e.g. polymorphisms in the promoter region) or through altered mRNA stability (e.g. polymorphisms in the 3′-UTR). Polymorphisms (usually single nucleotide polymorphisms or SNPs) located in the open reading frame (coding region) may be silent, either by causing no

Acknowledgements

Work in the authors' laboratories are funded by grants from the British Heart Foundation (to AJK) and from The Research Council of Norway, The Norwegian Council on Cardiovascular Diseases, Anders Jahre's Foundation for the Promotion of Science, The Novo Nordisk Foundation, The Family 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 (University of Glasgow) for sharing unpublished

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