Asian Cardiovasc Thorac Ann 1998;6:11-16
© 1998 Asia Publishing EXchange Pte Ltd
Serotonin: Ubiquitous Neuromodulator in the Failing Heart
Ashim Ghatak, MD,
Ajay Agarwal, MD1,
Pankaj Singh, MD1,
Kripa Shankar, PhD2,
Mahesh Chandra, MD1
Division of Clinical & Experimental Medicine Central Drug Research Institute, Lucknow, India
1 Department of Medicine,
2 Department of Pharmacology KG Medical College, Lucknow, India
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Ashim Ghatak, MD Division of Clinical & Experimental Medicine Central Drug Research Institute Chattar Manzil, Post Box No. 173 Lucknow 226001, India Tel:91 522 21 2411 Fax:91 522 22 3405 or 22 3938 Email: root{at}cscdri.ren.nic.in
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ABSTRACT
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Serotonin exhibits various cardiovascular effects and evidence of its role in various cardiovascular disorders is emerging. Serotonin levels in whole blood and the platelet serotonin uptake were significantly increased in patients with heart failure compared to control subjects. However, the intraplatelet serotonin content was not significantly different in the two groups. We conclude that serotonin is involved in the syndrome of heart failure both directly and indirectly through its action on cardiac contractility, heart rate, preload, and afterload.
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INTRODUCTION
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Serotonin (5-hydroxytryptamine; 5-HT) was discovered by Irvin Page1 in 1954 but its role in cardiovascular disease has remained elusive until recently. However, there are now numerous publications in the field of 5-HT research2,3 and alterations in serotonin metabolism have been reported in various cardiovascular disorders including hypertension, myocardial ischemia, Raynaud's phenomenon, and shock.4–9 The advent of serotonin antagonists with antihypertensive activity has provided clues to the involvement of serotonin in cardiovascular diseases.10 It appears that serotonin exerts effects on the cardiovascular system through multiple receptors (Table 1
).2,3,11 This review highlights the role of serotonin in various pathophysiological changes in heart failure.
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BIOSYNTHESIS AND METABOLISM OF SEROTONIN
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Serotonin is found both in plants and animals. The most important storage sites in mammals are the enterochromaffin cells in the gastrointestinal tract (90%), the brain, pineal gland, and platelets. Significant amounts of serotonin have also been detected in the heart, kidney, spleen, and thyroid. Serotonin is synthesized in all the tissues where it is found with the exception of platelets. The stored serotonin in platelet dense granules comes from the gastrointestinal tract. Serotonin is synthesized from L-tryptophan by an enzymatic reaction and only 2% (10 mg) of ingested tryptophan is utilized for the daily requirements of serotonin synthesis.12 The rate-limiting enzyme in serotonin synthesis is tryptophan hydroxylase. Diets poor in tryptophan cause lower tissue serotonin concentrations.13 The major pathway for the metabolism of serotonin is by oxidative deamination to 5-hydroxyindolacetaldehyde that undergoes oxidation to 5-hydroxyindolacetic acid. Minor metabolic pathways for serotonin metabolism include conjugation, N-acetylation, and O-methylation (Figure 1). Nearly all of the released serotonin is inactivated by the liver and pulmonary endothelial cells but a small portion is taken up and stored in the platelets. Estimates of free plasma concentrations of 5-HT range between 3 and 20 µg L–1.
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SEROTONIN RECEPTORS
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The hearts of several mammalian species including humans contain serotonin. Serotonin can elicit either bradycardia or tachycardia and either coronary vasodilation or vasoconstriction, depending on factors such as the presence or absence of an intact autonomic nervous system or endothelium. It is now recognized that these effects are mediated in different species by different mechanisms employing several receptor types. The multiple serotonin receptor subtypes cloned to date are the largest of all the neurotransmitter receptor families.14 These receptor subtypes have many common features but are coupled to various transmembrane signalling mechanisms. Seven serotonin receptor families have been identified but the functions of only S1, S2, S3 and S4 have been elucidated. More recently, molecular biological techniques have confirmed this classification and the subtypes have been found to have relatively dissimilar protein structures. The receptors S5, S6, and S7 have been cloned, expressed in cultured cell lines, and pharmacologically and functionally characterized. The S1, S2, and S4 to S7 receptor families are G protein-coupled receptors with a well-defined structure comprising an extracellular N-terminal segment linked to an intracellular C-terminus by seven transmembrane-spanning segments.15 On the other hand, the S3 receptor is a ligand-gated ion channel that gates Na+ and K+ and has a predicted membrane structure similar to the nicotinic cholinergic receptor.14
Individually, all five members of the S1 receptor subfamily are negatively coupled to adenylyl cyclase. S1A, S1B, S1D, S1E, and S1F receptor subtypes have been identified. All receptors are seven transmembrane G protein-coupled receptors encoded by intronless genes of between 365 and 422 amino acids with an overall sequence homology of 40%. They are present in the raphe nuclei of the brain stem where they function as somatodendritic autoreceptors and their stimulation leads to tachycardia in cats given spinal anesthesia, which can be mimicked by 5-carboxamidotryptamine and is effectively blocked by mixed S1 receptor antagonists. The positive inotropic effects of S1 stimulation have also been demonstrated in isolated cat atria.14–16
The S2 receptor family consists of three subtypes: S2A; S2B; and S2C. All three are single protein molecules of 458 to 471 amino acids with an overall homology of 50% rising to between 70% and 80% in the seven transmembrane domains. All three are thought to be linked to the phosphoinositol hydrolysis signal transduction system via the alpha subunit of Gq guanosine triphosphate binding protein. S2 stimulation also causes tachycardia in rats and dogs that is blocked by its specific antagonists. The S3 receptor binding site is widely distributed both centrally and peripherally and has been detected in a number of neuronally derived cells. Unlike other S receptors, S3 receptor subunits form a pentameric cation channel that is selectively permeable to sodium, potassium, and calcium ions, causing depolarisation. S3 receptor stimulation in isolated rabbit hearts leads to tachycardia and an inotropic action mediated by noradrenaline release, which is blocked by its specific antagonists.14–16 S4 receptors are highly concentrated in areas of the brain associated with dopamine function such as the striatum, basal ganglia, and nucleus accumbens where these receptors may be located on gamma aminobuteric acid-ergic or cholinergic interneurons and in the substantia nigra. The receptor is functionally coupled via the G G-protein. Peripherally, the S4 receptors in the gut cause contractions and are also involved in secretory processes. S4 receptors in the heart induce tachycardia and positive inotropic effects when stimulated and may be important in cardiovascular pathology. Kaumann and Sanders17,18 have demonstrated that the putative S4 receptors in the human atrium cause positive inotropy that can be blocked by specific antagonists. The S5 receptor has not been fully characterized at the present time, however, two subtypes termed S5A and S5B have been iden-tified, having 88% overall sequence homology. They are negatively linked to adenylyl cyclase via the Gs G-protein and may act as terminal autoreceptors. The S6 receptors have also not been fully characterized. They consist of 438 amino acids with seven transmembrane domains and are positively coupled to adenylyl cyclase via the Gs G-protein. The rat and the human receptors have a sequence homology of 89%. In the absence of selective ligands for the receptor, functional studies have been carried out using an antisense approach that suggests these receptors play a role in yawning, stretching, and chewing. The S7 human receptor has a sequence of 445 amino acids with seven transmembrane domains, it is positively coupled to adenylyl cyclase preferentially via Gs G-protein and has a very high degree (95%) of interspecies homology. As with S6, there are no selective ligands for this receptor at present (Table 1
).2,3,14–16
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PHYSIOLOGY OF SEROTONIN
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Serotonin has complex and sometimes opposite effects on blood vessels. The net effect depends on species, route of administration, experimental conditions under which the amine is released or administered, and the presence of a functional endothelium. Serotonin has both vasoconstrictive and vasodilatory effects. There are four main mechanisms by which it causes vasoconstriction: activation of S2 receptors on vascular smooth muscle either by excess serotonin or an enhanced response to normal levels of serotonin; activation of alpha adrenoreceptors on vascular smooth muscle; release of norepinephrine and angiotensin; amplification of the contractile response once it occurs and sets off the disease process.18,19 The vasodilatory effects of serotonin have been attributed to: endothelial-dependent inhibition of vascular smooth muscle activity; activation of prejunctional serotonergic receptors; release of an inhibitory transmitter from peptidergic neurons; stimulation of beta adrenoreceptors and synthesis of prostacyclin.20–22 The vasconstricting effects of serotonin are dominant and generally vasodilation is not observed. The mechanism has been implicated to be via the control of Na+ and water reabsorption. An elevation in synaptic concentrations of serotonin in the central nervous system significantly increases sodium excretion.23 Studies suggest that excess serotonin in the central nervous system produces natriuresis by decreased efferent renal sympathetic nerve activity. An elevation of central nervous 5-HT stimulates arginine vasopressin secretion that is known to have a natriuretic effect in addition to an antidiuretic action. Secretion of aldosterone and renin is also stimulated by serotonin.23–25
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CARDIAC EFFECTS OF SEROTONIN
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Serotonin has positive inotropic and chronotropic effects, probably by enhancing the release of norepinephrine from adrenergic nerve endings. Its positive chronotropic effect is mediated by receptors other than S1 and S2. Ketanserin, a serotonin antagonist has a negative chronotropic effect. The inotropic effect of serotonin is similar to that of norepinephrine. A minor part of this effect is due to release of endogenous catecholamines. Serotonin can raise cardiac contractility without increasing cyclic adenosine monophosphate.26 It clearly augments the contractile state of the ventricular myocardium, increasing both the rate of tension development and peak isometric tension and shifting the force-velocity relationship upward and to the right. It increases stroke volume, peak aortic flow rate, peak left ventricular dp/dt at constant left ventricular end-diastolic pressure, mean aortic pressure, and heart rate by augmentation of the ventricular function curve.27 The augmentation in the rate of tension development and peak isometric tension is not accompanied by changes in time to peak tension. Thus, the peak tension correlates with the duration of the active state that in turn reflects the velocity of shortening and rate of tension development. Serotonin increases with little alteration in the duration of the active state and exerts an inotropic effect.27,28
Ketanserin potently blocks S2A receptors, less potently blocks S2C receptors, and has no significant effect on S3, S4 receptors, or any members of the S1 receptor family. However, it is important to note that ketanserin has a high affinity for alpha-adrenergic receptors and histamine Hl receptors.29 Ketanserin lowers blood pressure in hypertensive patients, the reduction being comparable to diuretics or beta blockers. The drug appears to reduce the tone of both capacitance and resistance vessels and hence is of particular use in the management of heart failure. Ketanserin also inhibits serotonin-induced platelet aggregation. Side-effects are minor and insignificant, its bioavailability is about 50%, and its plasma half-life is between 12 and 25 hours with elimination primarily by hepatic metabolism. Ritanserin is a more selective S2A receptor antagonist that also potently antagonises S2C receptors. The physiological significance of S2C receptor blockade is presently unknown but this group of drugs holds great promise for the future.30
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SEROTONIN IN HEART FAILURE
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Heart failure (HF) is one of the most common manifestations of cardiovascular disease and it is particularly prevalent in the Western world. In spite of improved understanding of its pathophysiology and the development of new therapeutic approaches, the mortality rate of HF remains comparable to that of the most malignant neoplasms. HF is a pathophysiologic state in which an abnormality of cardiac function is responsible for the failure of heart to pump blood at a rate commensurate with the requirement of tissue metabolism or it can do so only from an abnormally elevated filling pressure.
The poor prognosis of HF may be related to incomplete understanding of its pathophysiology or irreversible changes occurring in the intrinsic ability of the myocardium to contract. Various compensatory mechanisms that are activated in this disorder ensure perfusion pressure to vital organs and maintain stroke volume and cardiac output. Only treatment with angiotensin converting enzyme inhibitors or the combination of hydralazine and isosorbide dinitrate is known to improve survival in these patients.31 Serotonin may be involved in HF by virtue of its cardiovascular effects and the stimulation of sympathetic activity. Sole and colleagues32 first showed in harvested myopathic hearts that the storage and rate of synthesis of cardiac serotonin is decreased with the development of heart failure. They also suggested that serotonin may provide inotropic support in the failing heart. Cardiac serotonin also decreases following salt loading.26 An alteration in the metabolism of tryptophan, the amino acid that is the critical factor in the synthesis of serotonin, may contribute to the pathogenesis of endocardial and myocardial damage and the development of heart failure. Tryptophan deficiency causes cardiomyopathy in experimental animals and the extent of tryptophan deficiency correlates with the degree of myocardial damage.33 The histologic profile of myocardial damage in rats with tryptophan deficiency closely resembles that in patients with African cardiomyopathy.33 Tryptophan supplementation prevents the progression of subclinical cardiomyopathy. It is well-known that carcinoid syndrome in which excess levels of 5-HT occur, is associated with endocardial and myocardial damage that predisposes to the development of HF. Thus, it appears that reduced cardiac serotonin or increased circulating serotonin produces cardiac failure by both myocardial and endocardial damage.26–29
We have recently studied the serotonin status in HF patients.34 The intraplatelet 5-HT, blood 5-HT levels, and platelet 5-HT uptake were measured in 18 patients with heart failure and 11 control subjects. The blood serotonin levels and platelet serotonin uptake were significantly increased in the patients with HF. The increased uptake of serotonin in platelets in HF may have been due to passive diffusion or a membrane defect. The congestive gastrointestinal tract in heart failure may also cause increased production of serotonin from the gastrointestinal enterochromaffin cells. The congestive liver in HF may cause mild liver dysfunction that in turn may result in decreased hepatic degradation of serotonin. Similarly, pulmonary congestion in HF may result in decreased degradation of serotonin in the lungs. All of these factors may have contributed to the increased levels of blood serotonin in HF found in our study. We also found low levels of serotonin in the platelets, which may be indicative of increased efflux of serotonin from platelets because of their activation. Thus, the net increase of serotonin in the blood of patients with HF is possibly the result of increased production, decreased degradation, and increased effiux of serotonin from platelets.
Increased serotonin levels in blood can influence cardiac function by producing direct myocardial and endocardial damage and by various other cardiac and vascular effects of serotonin. Serotonin may also contribute to various neurohormonal alterations found in heart failure. In addition, serotonin through its effects on the cardiovascular system and neurohormonal systems may contribute to additional compensatory mechanisms in patients with HF. Anti-serotonin drugs have been used in the treatment of heart failure. Demoulin and colleagues35 studied the role of ketanserin in patients with heart failure and demonstrated remarkably improved hemodynamics in these patients. These authors suggested that the beneficial effect of the serotonin antagonist was related to blockade of the vascular effect of serotonin released by aggregating platelets. Enhanced platelet aggregation in heart failure may be due to high plasma levels of catecholamines in these patients. Recently, modest improvements in hemodynamics have been seen with short-term administration of ketanserin.36 Thus, several lines of evidences indicate that 5-HT may be involved in the syndrome of heart failure by its action at various levels: cardiac contractility; heart rate; preload and afterload, both directly and indirectly. This evidence endorses the view that serotonin may be involved via various mechanisms in the etiopathogenesis of heart failure.
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ABSTRACT
INTRODUCTION
