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

Abstract

Previously, cardioexcitation by serotonin (5-hydroxytryptamine, 5-HT) was believed to be confined to atria in mammals including man, and mediated through 5-HT 4 receptors in pig and man, but 5-HT 2A receptors in rat. Recent studies, reviewed here, demonstrate that functional 5-HT 4 receptors can be revealed in porcine and human ventricular myocardium during phosphodiesterase inhibition, and that 5-HT 4 receptor mRNA is increased in human heart failure. In rats, functional 5-HT 4 and 5-HT 2A receptors appear in the cardiac ventricle during heart failure and mediate inotropic responses through different mechanisms. 5-HT 2A receptor signalling resembles that from α 1-adrenoceptors and causes inotropic effects through increased myosin light chain phosphorylation, resulting in Ca 2+ sensitisation. 5-HT 4 receptor signalling resembles that from β-adrenoceptors and causes inotropic effects through a pathway involving cAMP and PKA-mediated phosphorylation of proteins involved in Ca 2+ handling, resulting in enhanced contractility through increased Ca 2+ availability. Cyclic AMP generated through 5-HT 4 receptor stimulation seems more efficiently coupled to increased contractility than cAMP generated through β-adrenoceptor stimulation. Increasing contractility through cAMP is considered less energy efficient than Ca 2+ sensitisation and this may be one reason why β-adrenoceptor antagonism is beneficial in heart failure patients. Treatment of heart failure rats with the 5-HT 4 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.