title: In permanent atrial fibrillation, PDE3 reduces force responses to 5-HT, but PDE3 and PDE4 do not cause the blunting of atrial arrhythmias.
abstract: 5-HT increases force and L-type Ca(2) (+) current (ICa,L ) and causes arrhythmias through 5-HT4 receptors in human atrium. In permanent atrial fibrillation (peAF), atrial force responses to 5-HT are blunted, arrhythmias abolished but ICa,L responses only moderately attenuated. We investigated whether, in peAF, this could be due to an increased function of PDE3 and/or PDE4, using the inhibitors cilostamide (300 nM) and rolipram (1 μM) respectively.
  
  
  
  Contractile force, arrhythmic contractions and ICa,L were assessed in right atrial trabeculae and myocytes, obtained from patients with sinus rhythm (SR), paroxysmal atrial fibrillation (pAF) and peAF.
  
  
  
  Maximum force responses to 5-HT were reduced to 15% in peAF, but not in pAF. Cilostamide, but not rolipram, increased both the blunted force responses to 5-HT in peAF and the inotropic potency of 5-HT fourfold to sevenfold in trabeculae of patients with SR, pAF and peAF. Lusitropic responses to 5-HT were not decreased in peAF. Responses of ICa,L to 5-HT did not differ and were unaffected by cilostamide or rolipram in myocytes from patients with SR or peAF. Concurrent cilostamide and rolipram increased 5-HT's propensity to elicit arrhythmias in trabeculae from patients with SR, but not with peAF.
  
  
  
  PDE3, but not PDE4, reduced inotropic responses to 5-HT in peAF, independently of lusitropy and ICa,L , but PDE3 activity was the same as that in patients with SR and pAF. Atrial remodelling in peAF abolished the facilitation of 5-HT to induce arrhythmias by inhibition of PDE3 plus PDE4.
authors.affiliation: Department of Pharmacology, Dresden University of Technology, Dresden, Germany.|Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Internal Medicine II, Municipal Hospital Dresden-Friedrichstadt, Dresden, Germany.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Berk
authors.affiliation: Department of Pharmacology, Dresden University of Technology, Dresden, Germany.|Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Schwarz
authors.affiliation: Department of Pharmacology, Dresden University of Technology, Dresden, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.affiliation: Department of Heart Surgery, Dresden University of Technology, Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Knaut
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.|Department of Pharmacology, University of Murcia, Murcia, Spain.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Kaumann
mesh_terms: D000368:Aged; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D001281:Atrial Fibrillation / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*
chemical_list: D010726:Phosphodiesterase Inhibitors; D012701:Serotonin; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4