Copyright © 2004, European Society of Cardiology
Appearance of a ventricular 5-HT4 receptor-mediated inotropic response to serotonin in heart failure
aDepartment of Pharmacology, University of Oslo, 0316 Oslo, Norway
bCenter for Heart Failure Research, University of Oslo, 0407 Oslo, Norway
cMSD Cardiovascular Research Center, Rikshospitalet University Hospital, 0027 Oslo, Norway
dInstitute for Experimental Medical Research, University of Oslo, 0407 Oslo, Norway
eDepartment of Cardiology, Ullevaal University Hospital, 0407 Oslo, Norway
fDepartment of Physiology, University of Cambridge, Cambridge CB2 3EG, UK
* Corresponding author. Department of Pharmacology, University of Oslo, Sognsvannsvn. 20, Bldg. A2/A3, P.O. Box 1057 Blindern, 0316 Oslo, Norway. Tel.: +47 22840237/01; fax: +47 22840202. Email address: f.o.levy{at}medisin.uio.no
Background: Current pharmacological treatment of congestive heart failure (CHF) addresses changes in neurohumoral stimulation or cardiac responsiveness to such stimulation. Yet, undiscovered neurohumoral changes, adaptive or maladaptive, may occur in CHF and suggest novel pharmacological treatment. Serotonin [5-hydroxytryptamine (5-HT)] enhances contractility and causes arrhythmias through 5-HT4 receptors in human atrium and ventricle but not through rat ventricular 5-HT4 receptors.
Objective: We investigated whether CHF could induce ventricular responsiveness to serotonin.
Methods: Postinfarction CHF was induced in male Wistar rats by coronary artery ligation. Contractility was measured in left ventricular papillary muscles 6 weeks after infarction. Messenger RNA was quantified by RT-PCR and cAMP by RIA.
Results: Serotonin caused positive inotropic (–logEC50=7.5) and lusitropic effects in CHF but not Sham papillary muscles. The inotropic effect of 10 µM serotonin in CHF (31.3 ± 2.2%) was of similar size as the effect of 10 µM isoproterenol (34.0 ± 1.7%). The effects of serotonin were antagonised by GR113808 (0.5–5 nM), consistent with mediation through 5-HT4 receptors. This was further supported by positive inotropic effects of the 5-HT4-selective partial agonist RS67506. Carbachol blunted the serotonin responses and serotonin increased ventricular and cardiomyocyte cAMP, consistent with coupling to Gs and adenylyl cyclase. Quantitative RT-PCR revealed fourfold increased 5-HT4(b) mRNA expression in CHF vs. Sham ventricles.
Conclusion: Functional ventricular 5-HT4 receptors are induced by myocardial infarction and CHF of the rat heart. We propose that they are a model for ventricular 5-HT4 receptors of human failing heart and may play a pathophysiological role in heart failure.
KEYWORDS Serotonin (5-HT); Heart failure; 5-HT4 receptor; Ventricle; Contractile function
1 EQ and TB contributed equally to the present work.
Time for primary review 30 days
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