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- Title
Appearance of a ventricular 5-HT<sub>4</sub> receptor-mediated inotropic response to serotonin in heart failure
- Authors
Qvigstad, Eirik; Brattelid, Trond; Sjaastad, Ivar; Andressen, Kjetil Wessel; Krobert, Kurt A.; Birkeland, Jon Arne; Sejersted, Ole M.; Kaumann, Alberto J.; Skomedal, Tor; Osnes, Jan-Bjørn; Levy, Finn Olav
- Abstract
Abstract: 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.
- Publication
Cardiovascular Research, 2005, Vol 65, Issue 4, p869
- ISSN
0008-6363
- Publication type
Academic Journal
- DOI
10.1016/j.cardiores.2004.11.017