title: The cardiac ventricular 5-HT4 receptor is functional in late foetal development and is reactivated in heart failure.
abstract: A positive inotropic responsiveness to serotonin, mediated by 5-HT(4) and 5-HT(2A) receptors, appears in the ventricle of rats with post-infarction congestive heart failure (HF) and pressure overload-induced hypertrophy. A hallmark of HF is a transition towards a foetal genotype which correlates with loss of cardiac functions. Thus, we wanted to investigate whether the foetal and neonatal cardiac ventricle displays serotonin responsiveness. Wistar rat hearts were collected day 3 and 1 before expected birth (days -3 and -1), as well as day 1, 3, 5 and 113 (age matched with Sham and HF) after birth. Hearts from post-infarction HF and sham-operated animals (Sham) were also collected. Heart tissue was examined for mRNA expression of 5-HT(4), 5-HT(2A) and 5-HT(2B) serotonin receptors, 5-HT transporter, atrial natriuretic peptide (ANP) and myosin heavy chain (MHC)-α and MHC-β (real-time quantitative RT-PCR) as well as 5-HT-receptor-mediated increase in contractile function exvivo (electrical field stimulation of ventricular strips from foetal and neonatal rats and left ventricular papillary muscle from adult rats in organ bath). Both 5-HT(4) mRNA expression and functional responses were highest at day -3 and decreased gradually to day 5, with a further decrease to adult levels. In HF, receptor mRNA levels and functional responses reappeared, but to lower levels than in the foetal ventricle. The 5-HT(2A) and 5-HT(2B) receptor mRNA levels increased to a maximum immediately after birth, but of these, only the 5-HT(2A) receptor mediated a positive inotropic response. We suggest that the 5-HT(4) receptor is a representative of a foetal cardiac gene program, functional in late foetal development and reactivated in heart failure.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Trond
authors.initials: T
authors.lastname: Brattelid
authors.forename: Eirik
authors.initials: E
authors.lastname: Qvigstad
authors.forename: Lise R
authors.initials: LR
authors.lastname: Moltzau
authors.forename: Silje V S
authors.initials: SV
authors.lastname: Bekkevold
authors.forename: Dagny L
authors.initials: DL
authors.lastname: Sandnes
authors.forename: Jon Arne K
authors.initials: JA
authors.lastname: Birkeland
authors.forename: Tor
authors.initials: T
authors.lastname: Skomedal
authors.forename: Jan-Bjørn
authors.initials: JB
authors.lastname: Osnes
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
mesh_terms: D000818:Animals; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism*; D008297:Male; D009200:Myocardial Contraction / Q000235:genetics; D010641:Phenotype; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4 / Q000235:genetics* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D050486:Serotonin Plasma Membrane Transport Proteins; D044422:Receptors, Serotonin, 5-HT4