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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Peter Molenaar - , Queensland University of Technology (Autor:in)
  • Torsten Christ - (Autor:in)
  • Rizwan I Hussain - (Autor:in)
  • Andreas Engel - , Institut für Pharmakologie und Toxikologie (Autor:in)
  • Emanuel Berk - (Autor:in)
  • Katherine T Gillette - (Autor:in)
  • Lu Chen - (Autor:in)
  • Alejandro Galindo-Tovar - (Autor:in)
  • Kurt A Krobert - (Autor:in)
  • Ursula Ravens - (Autor:in)
  • Finn Olav Levy - (Autor:in)
  • Alberto J Kaumann - (Autor:in)

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.

Details

OriginalspracheEnglisch
Seiten (von - bis)528-538
Seitenumfang11
FachzeitschriftBritish journal of pharmacology
Jahrgang169
Ausgabenummer3
PublikationsstatusVeröffentlicht - Juni 2013
Peer-Review-StatusJa

Externe IDs

Scopus 84877821347
PubMed 23489141
PubMedCentral PMC3682702
ORCID /0000-0003-3021-1338/work/142251874

Schlagworte

Schlagwörter

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