Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure.
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.
Brattelid
Trond
T
Department of Pharmacology, University of Oslo, P.O. Box 1057 Blindern, 0316 Oslo, Norway.
Qvigstad
Eirik
E
Lynham
James A
JA
Molenaar
Peter
P
Aass
Halfdan
H
Geiran
Odd
O
Skomedal
Tor
T
Osnes
Jan-Bjørn
JB
Levy
Finn Olav
FO
Kaumann
Alberto J
AJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006352:Heart Ventricles / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007545:Isoproterenol / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics* / Q000302:isolation & purification; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D058832:Serotonin 5-HT4 Receptor Antagonists; D013552:Swine; D016276:Ventricular Function
D002316:Cardiotonic Agents; D016166:Free Radical Scavengers; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D058832:Serotonin 5-HT4 Receptor Antagonists; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine