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-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.
Levy
Finn Olav
FO
Department of Pharmacology, Faculty of Medicine, University of Oslo, P.O. Box 1057 Blindern, N-0316 Oslo, Norway. f.o.levy@medisin.uio.no
Qvigstad
Eirik
E
Krobert
Kurt A
KA
Skomedal
Tor
T
Osnes
Jan-Bjørn
JB
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
D011985:Receptors, Serotonin; D018490:Serotonin Agents; D012701:Serotonin