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.
© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic alpha-Agonists / chemistry
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Adrenergic alpha-Agonists / pharmacology
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Adrenergic beta-1 Receptor Antagonists / adverse effects*
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Adrenergic beta-1 Receptor Antagonists / pharmacology
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Adrenergic beta-1 Receptor Antagonists / therapeutic use
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Adrenergic beta-2 Receptor Antagonists / pharmacology
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Adrenergic beta-Agonists / chemistry
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Adrenergic beta-Agonists / pharmacology
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Anti-Arrhythmia Agents / adverse effects
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Anti-Arrhythmia Agents / therapeutic use
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Cardiotonic Agents / pharmacology
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Cardiotonic Agents / therapeutic use
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Cyclic Nucleotide Phosphodiesterases, Type 3 / chemistry
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Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
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Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
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Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
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Drug Resistance / drug effects
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Epinephrine / agonists
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Epinephrine / pharmacology
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Heart Failure / drug therapy*
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Heart Failure / metabolism
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Heart Failure / physiopathology
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Heart Failure / surgery
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Heart Transplantation
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Heart Ventricles / drug effects*
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Heart Ventricles / metabolism
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Heart Ventricles / physiopathology
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Humans
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In Vitro Techniques
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Metoprolol / adverse effects*
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Metoprolol / therapeutic use
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Middle Aged
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Myocardial Contraction / drug effects
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Norepinephrine / agonists
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Norepinephrine / pharmacology
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Phosphodiesterase 3 Inhibitors / pharmacology
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Phosphodiesterase 4 Inhibitors / pharmacology
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Receptors, Adrenergic, beta-1 / chemistry
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Receptors, Adrenergic, beta-1 / metabolism*
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Receptors, Adrenergic, beta-2 / chemistry
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Receptors, Adrenergic, beta-2 / metabolism*
Substances
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ADRB1 protein, human
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ADRB2 protein, human
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Adrenergic alpha-Agonists
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Adrenergic beta-1 Receptor Antagonists
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Adrenergic beta-2 Receptor Antagonists
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Adrenergic beta-Agonists
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Anti-Arrhythmia Agents
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Cardiotonic Agents
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Phosphodiesterase 3 Inhibitors
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Phosphodiesterase 4 Inhibitors
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Receptors, Adrenergic, beta-1
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Receptors, Adrenergic, beta-2
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Cyclic Nucleotide Phosphodiesterases, Type 3
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Cyclic Nucleotide Phosphodiesterases, Type 4
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PDE3A protein, human
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PDE4A protein, human
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Metoprolol
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Norepinephrine
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Epinephrine