Effects of serotonin in failing cardiac ventricle: Signalling mechanisms and potential therapeutic implications

Previously, cardioexcitation by serotonin (5-hydroxytryptamine, 5-HT) was believed to be confined to atria in mammals including man, and mediated through 5-HT4 receptors in pig and man, but 5-HT2A receptors in rat. Recent studies, reviewed here, demonstrate that functional 5-HT4 receptors can be revealed in porcine and human ventricular myocardium during phosphodiesterase inhibition, and that 5-HT4 receptor mRNA is increased in human heart failure. In rats, functional 5-HT4 and 5-HT2A receptors appear in the cardiac ventricle during heart failure and mediate inotropic responses through different mechanisms. 5-HT2A receptor signalling resembles that from alpha(1)-adrenoceptors and causes inotropic effects through increased myosin light chain phosphorylation, resulting in Ca2+ sensitisation. 5-HT4 receptor signalling resembles that from beta-adrenoceptors and causes inotropic effects through a pathway involving cAMP and PKA-mediated phosphorylation of proteins involved in Ca2+ handling, resulting in enhanced contractility through increased Ca2+ availability. Cyclic AMP generated through 5-HT4 receptor stimulation seems more efficiently coupled to increased contractility than cAMP generated through beta-adrenoceptor stimulation. Increasing contractility through cAMP is considered less energy efficient than Ca2+ sensitisation and this may be one reason why beta-adrenoceptor antagonism is beneficial in heart failure patients. Treatment of heart failure rats with the 5-HT4 antagonist SB207266 (piboserod) resulted in potentially beneficial effects, although small. Further studies are needed to clarify if such treatment will be useful for patients with heart failure. (C) 2008 Elsevier Ltd. All rights reserved.