title: PDE3, but not PDE4, reduces β₁ - and β₂-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients.
abstract: OBJECTIVE
  PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 μM) or PDE4 inhibitor rolipram (1-10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium.
  
  
  METHODS
  Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β₁ adrenoceptors (β₂ adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β₂ adrenoceptors (β₁ adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from -logEC₅₀s.
  
  
  RESULTS
  Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients.
  
  
  CONCLUSIONS
  Metoprolol induces a control by PDE3 of ventricular effects mediated through both β₁ and β₂ adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β₂ adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.
authors.affiliation: Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Molenaar
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.forename: Rizwan I
authors.initials: RI
authors.lastname: Hussain
authors.forename: Andreas
authors.initials: A
authors.lastname: Engel
authors.forename: Emanuel
authors.initials: E
authors.lastname: Berk
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Gillette
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.forename: Alejandro
authors.initials: A
authors.lastname: Galindo-Tovar
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Krobert
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Kaumann
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000737:chemistry / Q000494:pharmacology; D058671:Adrenergic beta-1 Receptor Antagonists / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000737:chemistry / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000737:chemistry / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism; D004351:Drug Resistance / Q000187:drug effects; D004837:Epinephrine / Q000819:agonists / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008790:Metoprolol / Q000009:adverse effects* / Q000627:therapeutic use; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000819:agonists / Q000494:pharmacology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000737:chemistry / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism*
chemical_list: C547787:ADRB1 protein, human; C553443:ADRB2 protein, human; D000316:Adrenergic alpha-Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517287:PDE3A protein, human; C517355:PDE4A protein, human; D008790:Metoprolol; D009638:Norepinephrine; D004837:Epinephrine