Effects of serotonin in failing cardiac ventricle: Signalling mechanisms and potential therapeutic implications
Introduction
Serotonin is a cardioexcitatory neurotransmitter in the ventricle of some primitive organisms, e.g. aplysia (Sawada et al., 1984). However, in mammals, cardioexcitatory effects of serotonin have been considered to be restricted to the atria (Kaumann and Sanders, 1998). Possibly reflecting the ancient evolutionary origin of cardiac serotonin receptors and serotonin responses, the excitatory effects of serotonin are mediated by different receptors in different species, e.g. 5-HT2A in rat, 5-HT3 (through noradrenaline release) in rabbit, 5-HT3 and 5-HT4 in guinea pig and 5-HT7 in cat (see Kaumann and Sanders, 1998 for references). In pig and man, 5-HT4 receptors are present in atria, and a role for these receptors in atrial fibrillation has been suggested (Kaumann, 1994) and supported by experimental models (Rahme et al., 1999). The idea that porcine and human 5-HT4 receptors were restricted to atria gained support from several studies concluding that 5-HT4 receptor stimulation did not have effects on porcine (Lorrain et al., 1992, Saxena et al., 1992, Schoemaker et al., 1992) or human (Jahnel et al., 1992, Schoemaker et al., 1993) ventricle. However, several recent reports, reviewed below, have challenged the view that cardioexcitatory effects of serotonin are restricted to atria, particularly in heart failure, where ventricular inotropic responsiveness to serotonin becomes apparent, either through 5-HT4 receptors or through 5-HT2A receptors or through both, depending on species and stage of heart failure.
Heart failure can be considered a final end-point of cardiac disease, where the diseased heart is no longer able to meet the circulatory requirements of the body, due to myocardial infarction or other causes. This leads to several compensatory mechanisms, which are now generally considered to be of potential short-term benefit, but long-term disadvantage. Thus, modern pharmacological treatment of chronic heart failure is generally aimed at opposing these compensatory mechanisms. Examples of such treatment that have proven to reduce mortality in heart failure are β-adrenoceptor antagonism (Tendera and Ochala, 2001, Cleland, 2003), angiotensin converting enzyme (ACE) inhibition/angiotensin receptor antagonism (Poole-Wilson, 2003) and aldosterone receptor antagonism (Rajagopalan and Pitt, 2003). Whether serotonin receptor antagonism can be added to this list remains an open question and will be discussed below.
Of note, it is believed that some compensatory mechanisms are more deleterious than others. This is best illustrated by increased neurohormonal activation of the adrenergic system during heart failure, where β-adrenoceptors and α1-adrenoceptors utilise completely different signalling mechanisms to achieve increased contractility. Whereas β-adrenoceptors through increased cAMP levels cause increased contractility mainly through increased Ca2+ handling, α1-adrenoceptor stimulation has recently been shown to increase phosphorylation of regulatory myosin light chain (MLC-2), thought to increase contractility through Ca2+ sensitisation (Andersen et al., 2002). Whereas increasing contractility through β-adrenoceptor stimulation and thus increased Ca2+ handling is quite energy-consuming, it appears that increasing contractility through α1-adrenoceptor stimulation and thus increased Ca2+ sensitivity is more energy efficient (Hasenfuss et al., 1989). This may be a reason why β-adrenoceptor antagonism in heart failure is beneficial (Lohse et al., 2003), whereas α1-adrenoceptor antagonism is not (Osnes et al., 2000). Relating this to serotonin receptors, it is worth noting that 5-HT4 receptors and β-adrenoceptors both signal through Gs and increased cAMP formation, whereas 5-HT2A and α1-adrenoceptors are both classically considered as receptors which activate similar signalling pathways, by coupling to the G proteins Gq/11 and probably G12/13 (Fig. 1).
Section snippets
5-HT4-mediated effects in porcine and failing human ventricle
The first demonstration of 5-HT4 mRNA expression in mammalian ventricle was published by Bach et al. (2001), who reported expression of 5-HT4(a) and 5-HT4(b) receptor mRNA in human left and right cardiac ventricle in post-mortem material from two persons with no reported history of heart failure. Previous reports had failed to detect 5-HT4(a) or 5-HT4(b) receptor mRNA in human ventricle (Blondel et al., 1997, Blondel et al., 1998) and had failed to detect cardiostimulant effects of 5-HT in
5-HT4-mediated effects in chronic failing rat ventricle
In rats, serotonin caused positive inotropic and lusitropic effects in papillary muscles from rats with chronic congestive heart failure (CHF) 6 weeks after a large myocardial infarction induced by coronary artery ligation, but not from sham-operated controls (Qvigstad et al., 2005a). The finding was surprising, since functional 5-HT4 receptors had previously not been detectable in rat heart, even in the atria, despite the presence of 5-HT4 receptor mRNA (Läer et al., 1998). The inotropic effect
5-HT2A-mediated effects in rat and human ventricle
It turned out that responsiveness to serotonin appeared early after myocardial infarction in the rat ventricle and was already apparent 1 day after infarction in rats with severe acute heart failure (Qvigstad et al., 2005c). It was observed that the potency of serotonin to stimulate an inotropic response was lower in acute (up to about 7 days) than chronic (6 weeks) heart failure. Since it is known that the affinity of serotonin for 5-HT2A receptors is rather low, this led Qvigstad et al. (2005c)
How does 5-HT2A receptor stimulation increase cardiac contractility?
Whereas the 5-HT4-mediated inotropic response (studied in the presence of ketanserin) developed rapidly and was fully developed in about 1 min after serotonin addition, the 5-HT2A-mediated inotropic response (studied in the presence of GR113808) developed more slowly and was not fully developed until more than 5 min after addition of serotonin (Qvigstad et al., 2005c). Further studies revealed that the 5-HT2A-mediated inotropic response was triphasic, consisting of an initial positive component,
Combined 5-HT2A- and 5-HT4-mediated inotropic responses in afterload-induced cardiac hypertrophy and failure
From the studies of rats with myocardial infarction and post-infarction heart failure outlined above, it could not be inferred that serotonin responsiveness would also become apparent in the ventricles of rats with heart failure from other causes. It was also unknown whether cardiac hypertrophy would be associated with ventricular serotonin responsiveness. This was addressed in a recent study (Brattelid et al., 2007), where rats were subjected to banding of the ascending aorta to increase
Functional 5-HT2A and 5-HT4 receptors are expressed in cardiomyocytes
Since stimulation of 5-HT2A and 5-HT4 receptors led to positive inotropic effects in papillary muscles and ventricular muscle strips, it could be inferred that these receptors must be localised on cardiomyocytes, as opposed to other cell types present in these preparations. Additional functional evidence that both these receptors are actually localised on the cardiomyocytes was obtained by Birkeland et al. (2007b), who documented electrophysiological and contractile responses to stimulating
Does 5-HT4 and 5-HT2A expression in heart failure reflect reactivation of a foetal gene programme?
One characteristic of the failing ventricle is a transition towards a foetal gene expression pattern (Chien et al., 1991). To explore the role of 5-HT4, 5-HT2A and 5-HT2B receptors in the foetal heart, Brattelid et al. (2006) collected ventricle from Wistar rats 3 days and 1 day before expected birth (days −3 and −1), as well as 1, 3, 5 and 113 days after birth, and measured expression of 5-HT4, 5-HT2A and 5-HT2B receptor mRNA by real-time quantitative RT–PCR as well as contractile function
How similar is 5-HT4 receptor stimulation and β-adrenoceptor stimulation in the failing ventricle?
Both 5-HT4 receptors and β-adrenoceptors are coupled to the G protein Gs. Thus, it is to be expected that stimulation of these receptors will have similar effects in the failing ventricle. Although more than one mechanism of action may be involved in the 5-HT4-mediated inotropic response, several lines of evidence indicate that the ventricular inotropic effect of serotonin is at least partly mediated through cAMP (Brattelid et al., 2004b, Qvigstad et al., 2005a, Qvigstad et al., 2005b). (1)
Is 5-HT4 receptor stimulation deleterious in CHF, and could blockade of these receptors represent a new treatment modality?
Since β-adrenoceptor-mediated signalling is deleterious in heart failure, and given that the mechanism of stimulating ventricular inotropic response is similar between 5-HT4 receptors and β-adrenoceptors, a natural question to ask is whether 5-HT4 receptor stimulation is also deleterious in CHF. So far, all clinical trials with cAMP-enhancing agents in chronic heart failure, including phosphodiesterase inhibitors, have adversely affected survival (Amsallem et al., 2005). Even apparently weak
Acknowledgements
Work in the authors’ laboratories is funded by grants 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.
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