PDE3, but not PDE4, reduces β₁ - and β₂-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

Br J Pharmacol. 2013 Jun;169(3):528-38. doi: 10.1111/bph.12167.

Abstract

Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Agonists / chemistry
  • Adrenergic alpha-Agonists / pharmacology
  • Adrenergic beta-1 Receptor Antagonists / adverse effects*
  • Adrenergic beta-1 Receptor Antagonists / pharmacology
  • Adrenergic beta-1 Receptor Antagonists / therapeutic use
  • Adrenergic beta-2 Receptor Antagonists / pharmacology
  • Adrenergic beta-Agonists / chemistry
  • Adrenergic beta-Agonists / pharmacology
  • Anti-Arrhythmia Agents / adverse effects
  • Anti-Arrhythmia Agents / therapeutic use
  • Cardiotonic Agents / pharmacology
  • Cardiotonic Agents / therapeutic use
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / chemistry
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
  • Drug Resistance / drug effects
  • Epinephrine / agonists
  • Epinephrine / pharmacology
  • Heart Failure / drug therapy*
  • Heart Failure / metabolism
  • Heart Failure / physiopathology
  • Heart Failure / surgery
  • Heart Transplantation
  • Heart Ventricles / drug effects*
  • Heart Ventricles / metabolism
  • Heart Ventricles / physiopathology
  • Humans
  • In Vitro Techniques
  • Metoprolol / adverse effects*
  • Metoprolol / therapeutic use
  • Middle Aged
  • Myocardial Contraction / drug effects
  • Norepinephrine / agonists
  • Norepinephrine / pharmacology
  • Phosphodiesterase 3 Inhibitors / pharmacology
  • Phosphodiesterase 4 Inhibitors / pharmacology
  • Receptors, Adrenergic, beta-1 / chemistry
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Receptors, Adrenergic, beta-2 / chemistry
  • Receptors, Adrenergic, beta-2 / metabolism*

Substances

  • ADRB1 protein, human
  • ADRB2 protein, human
  • Adrenergic alpha-Agonists
  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-2 Receptor Antagonists
  • Adrenergic beta-Agonists
  • Anti-Arrhythmia Agents
  • Cardiotonic Agents
  • Phosphodiesterase 3 Inhibitors
  • Phosphodiesterase 4 Inhibitors
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE3A protein, human
  • PDE4A protein, human
  • Metoprolol
  • Norepinephrine
  • Epinephrine