Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure.

Abstract

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
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 370 Issue 3 Pg. 157-66 (Sep 2004) ISSN: 0028-1298 [Print] Germany
• PMID: 15365689 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Free Radical Scavengers
• Phosphodiesterase Inhibitors
• RNA, Messenger
• Serotonin 5-HT4 Receptor Antagonists
• Receptors, Serotonin, 5-HT4
• Serotonin
• Cyclic AMP-Dependent Protein Kinases
• Isoproterenol
• 1-Methyl-3-isobutylxanthine

Topics

• 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 (genetics)
• Serotonin (pharmacology, physiology)
• Serotonin 5-HT4 Receptor Antagonists
• Swine
• Ventricular Function