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-HT_2A 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-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 α₁-adrenoceptors and causes inotropic effects through increased myosin light chain phosphorylation, resulting in Ca²⁺ sensitisation. 5-HT₄ receptor signalling resembles that from β-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 β-adrenoceptor stimulation. Increasing contractility through cAMP is considered less energy efficient than Ca²⁺ 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-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.