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

• Published in: British journal of pharmacology Vol. 169; no. 3; pp. 528 - 538
• Main Authors: Molenaar, Peter, Christ, Torsten, Hussain, Rizwan I, Engel, Andreas, Berk, Emanuel, Gillette, Katherine T, Chen, Lu, Galindo‐Tovar, Alejandro, Krobert, Kurt A, Ravens, Ursula, Levy, Finn Olav, Kaumann, Alberto J
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2013
• Subjects: 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; human heart failure; Humans; In Vitro Techniques; inotropism and lusitropism; metoprolol; Metoprolol - adverse effects; Metoprolol - therapeutic use; Middle Aged; Myocardial Contraction - drug effects; noradrenaline and adrenaline; Norepinephrine - agonists; Norepinephrine - pharmacology; Phosphodiesterase 3 Inhibitors - pharmacology; Phosphodiesterase 4 Inhibitors - pharmacology; phosphodiesterases 3 and 4; Receptors, Adrenergic, beta-1 - chemistry; Receptors, Adrenergic, beta-1 - metabolism; Receptors, Adrenergic, beta-2 - chemistry; Receptors, Adrenergic, beta-2 - metabolism; Research Paper with; β1 and β2 adrenoceptors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.12167

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. Linked Article This article is commented on by Eschenhagen, pp 524–527 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12168