Document Detail


Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure.
MedLine Citation:
PMID:  15365689     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Serotonin (5-hydroxytryptamine, 5-HT) increases contractile force and elicits arrhythmias through 5-HT(4) receptors in porcine and human atrium, but its ventricular effects are unknown. We now report functional 5-HT(4) receptors in porcine and human ventricle. 5-HT(4) mRNA levels were determined in porcine and human ventricles and contractility studied in ventricular trabeculae. Cyclic AMP-dependent protein kinase (PKA) activity was measured in porcine ventricle. Porcine and human ventricles expressed 5-HT(4) receptor mRNA. Ventricular 5-HT(4(b)) mRNA was increased by four times in 20 failing human hearts compared with five donor hearts. 5-HT increased contractile force maximally by 16% (EC(50)=890 nM) and PKA activity by 20% of the effects of (-)-isoproterenol (200 microM) in ventricular trabeculae from new-born piglets in the presence of the phosphodiesterase-inhibitor 3-isobutyl-1-methylxanthine. In ventricular trabeculae from adult pigs (3-isobutyl-1-methylxanthine present) 5-HT increased force by 32% (EC(50)=60 nM) and PKA activity by 39% of (-)-isoproterenol. In right and left ventricular trabeculae from failing hearts, exposed to modified Krebs solution, 5-HT produced variable increases in contractile force in right ventricular trabeculae from 4 out of 6 hearts and in left ventricular trabeculae from 3 out of 3 hearts- range 1-39% of (-)-isoproterenol, average 8%. In 11 left ventricular trabeculae from the failing hearts of four beta-blocker-treated patients, pre-exposed to a relaxant solution with 0.5 mM Ca(2+) and 1.2 mM Mg(2+) followed by a switch to 2.5 mM Ca(2+) and 1 mM Mg(2+), 5-HT (1-100 microM, 3-isobutyl-1-methylxanthine present) consistently increased contractile force and hastened relaxation by 46% and 25% of (-)-isoproterenol respectively. 5-HT caused arrhythmias in three trabeculae from 3 out of 11 patients. In the absence of phosphodiesterase inhibitor, 5-HT increased force in two trabeculae, but not in another six trabeculae from 4 patients. All 5-HT responses were blocked by 5-HT(4) receptor antagonists. We conclude that phosphodiesterase inhibition uncovers functional ventricular 5-HT(4) receptors, coupled to a PKA pathway, through which 5-HT enhances contractility, hastens relaxation and can potentially cause arrhythmias.
Authors:
Trond Brattelid; Eirik Qvigstad; James A Lynham; Peter Molenaar; Halfdan Aass; Odd Geiran; Tor Skomedal; Jan-Bjørn Osnes; Finn Olav Levy; Alberto J Kaumann
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2004-09-07
Journal Detail:
Title:  Naunyn-Schmiedeberg's archives of pharmacology     Volume:  370     ISSN:  0028-1298     ISO Abbreviation:  Naunyn Schmiedebergs Arch. Pharmacol.     Publication Date:  2004 Sep 
Date Detail:
Created Date:  2004-09-20     Completed Date:  2005-02-01     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  0326264     Medline TA:  Naunyn Schmiedebergs Arch Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  157-66     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, University of Oslo, P.O. Box 1057 Blindern, 0316 Oslo, Norway.
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MeSH Terms
Descriptor/Qualifier:
1-Methyl-3-isobutylxanthine / pharmacology
Adolescent
Adult
Aged
Animals
Cardiotonic Agents / therapeutic use*
Cyclic AMP-Dependent Protein Kinases / drug effects,  metabolism*
Female
Free Radical Scavengers / pharmacology*
Heart Ventricles / drug effects*,  enzymology
Humans
Isoproterenol / therapeutic use*
Male
Middle Aged
Myocardial Contraction / drug effects*
Myocardial Ischemia / drug therapy,  enzymology*
Phosphodiesterase Inhibitors / pharmacology
RNA, Messenger / genetics*,  isolation & purification
Receptors, Serotonin, 5-HT4 / antagonists & inhibitors*,  genetics
Serotonin / pharmacology,  physiology*
Swine
Ventricular Function
Chemical
Reg. No./Substance:
0/Cardiotonic Agents; 0/Free Radical Scavengers; 0/Phosphodiesterase Inhibitors; 0/RNA, Messenger; 158165-40-3/Receptors, Serotonin, 5-HT4; 28822-58-4/1-Methyl-3-isobutylxanthine; 50-67-9/Serotonin; 7683-59-2/Isoproterenol; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases

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