Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 370, Issue 3, pp 157–166

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

  • Trond Brattelid
  • Eirik Qvigstad
  • James A. Lynham
  • Peter Molenaar
  • Halfdan Aass
  • Odd Geiran
  • Tor Skomedal
  • Jan-Bjørn Osnes
  • Finn Olav Levy
  • Alberto J. Kaumann
Original Article

DOI: 10.1007/s00210-004-0963-0

Cite this article as:
Brattelid, T., Qvigstad, E., Lynham, J.A. et al. Naunyn-Schmiedeberg's Arch Pharmacol (2004) 370: 157. doi:10.1007/s00210-004-0963-0

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) increases contractile force and elicits arrhythmias through 5-HT4 receptors in porcine and human atrium, but its ventricular effects are unknown. We now report functional 5-HT4 receptors in porcine and human ventricle. 5-HT4 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-HT4 receptor mRNA. Ventricular 5-HT4(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% (EC50=890 nM) and PKA activity by 20% of the effects of (−)-isoproterenol (200 μM) 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% (EC50=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 β-blocker-treated patients, pre-exposed to a relaxant solution with 0.5 mM Ca2+ and 1.2 mM Mg2+ followed by a switch to 2.5 mM Ca2+ and 1 mM Mg2+, 5-HT (1–100 μM, 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-HT4 receptor antagonists. We conclude that phosphodiesterase inhibition uncovers functional ventricular 5-HT4 receptors, coupled to a PKA pathway, through which 5-HT enhances contractility, hastens relaxation and can potentially cause arrhythmias.

Keywords

Serotonin5-Hydroxytryptamine5-HT4 receptorsArrhythmiasPorcine and human ventriclePKA and inotropic stimulation

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Trond Brattelid
    • 1
    • 2
    • 3
  • Eirik Qvigstad
    • 1
    • 2
  • James A. Lynham
    • 4
  • Peter Molenaar
    • 5
  • Halfdan Aass
    • 6
  • Odd Geiran
    • 7
  • Tor Skomedal
    • 1
    • 2
  • Jan-Bjørn Osnes
    • 1
    • 2
  • Finn Olav Levy
    • 1
    • 2
    • 3
  • Alberto J. Kaumann
    • 4
  1. 1.Department of PharmacologyUniversity of OsloOsloNorway
  2. 2.Center for Heart Failure ResearchUniversity of OsloOsloNorway
  3. 3.MSD Cardiovascular Research CenterRikshospitalet University HospitalOsloNorway
  4. 4.Department of PhysiologyUniversity of CambridgeCambridgeUK
  5. 5.Department of Medicine, The Prince Charles HospitalUniversity of QueenslandChermsideAustralia
  6. 6.Department of CardiologyRikshospitalet University HospitalOsloNorway
  7. 7.Department of Thoracic SurgeryRikshospitalet University HospitalOsloNorway