title: 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 alpha(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 beta-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 beta-adrenoceptor stimulation. Increasing contractility through cAMP is considered less energy efficient than Ca(2+) 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-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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Oslo, P.O. Box 1057 Blindern, N-0316 Oslo, Norway. f.o.levy@medisin.uio.no
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
authors.forename: Eirik
authors.initials: E
authors.lastname: Qvigstad
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Krobert
authors.forename: Tor
authors.initials: T
authors.lastname: Skomedal
authors.forename: Jan-Bjørn
authors.initials: JB
authors.lastname: Osnes
mesh_terms: D000818:Animals; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013552:Swine
chemical_list: D011985:Receptors, Serotonin; D018490:Serotonin Agents; D012701:Serotonin