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

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.

• Authors: Peter Molenaar, Torsten Christ, Rizwan I Hussain, Andreas Engel, Emanuel Berk, Katherine T Gillette, Lu Chen, Alejandro Galindo-Tovar, Kurt A Krobert, Ursula Ravens, Finn Olav Levy, Alberto J Kaumann
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 169 Issue 3 Pg. 528-38 (Jun 2013) ISSN: 1476-5381 [Electronic] England
• PMID: 23489141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.

Chemical References

• 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

Topics

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