Carvedilol induces greater control of β2- than β 1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Peter Molenaar - , Princess Alexandra Hospital Brisbane, University of Queensland (Author)
  • Torsten Christ - , Dresden University of Technology, University Hospital Hamburg Eppendorf (Author)
  • Emanuel Berk - (Author)
  • Andreas Engel - , Institute of Pharmacology and Toxicology (Author)
  • Katherine T Gillette - (Author)
  • Alejandro Galindo-Tovar - (Author)
  • Ursula Ravens - (Author)
  • Alberto J Kaumann - (Author)

Abstract

The β-blockers carvedilol and metoprolol provide important therapeutic strategies for heart failure treatment. Therapy with metoprolol facilitates the control by phosphodiesterase PDE3, but not PDE4, of inotropic effects of catecholamines in human failing ventricle. However, it is not known whether carvedilol has the same effect. We investigated whether the PDE3-selective inhibitor cilostamide (0.3 μM) or PDE4-selective inhibitor rolipram (1 μM) modified the positive inotropic and lusitropic effects of catecholamines in ventricular myocardium of heart failure patients treated with carvedilol. Right ventricular trabeculae from explanted hearts of nine carvedilol-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 the PDE inhibitors. The inotropic potency, estimated from -logEC50s, was unchanged for (-)-noradrenaline but decreased 16-fold for (-)-adrenaline in carvedilol-treated compared to non-β-blocker-treated patients, consistent with the previously reported β2-adrenoceptor-selectivity of carvedilol. Cilostamide caused 2- to 3-fold and 10- to 35-fold potentiations of the inotropic and lusitropic effects of (-)-noradrenaline and (-)-adrenaline, respectively, in trabeculae from carvedilol-treated patients. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline. Treatment of heart failure patients with carvedilol induces PDE3 to selectively control the positive inotropic and lusitropic effects mediated through ventricular β2-adrenoceptors compared to β1-adrenoceptors. The β2-adrenoceptor-selectivity of carvedilol may provide protection against β2-adrenoceptor-mediated ventricular overstimulation in PDE3 inhibitor-treated patients. PDE4 does not control β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in carvedilol-treated patients.

Details

Original languageEnglish
Pages (from-to)629-640
Number of pages12
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume387
Issue number7
Publication statusPublished - Jul 2014
Peer-reviewedYes

External IDs

Scopus 84904130391
PubMed 24668024
ORCID /0000-0003-3021-1338/work/142251878

Keywords

Keywords

  • Adrenergic beta-Antagonists/pharmacology, Adult, Carbazoles/pharmacology, Carvedilol, Cyclic Nucleotide Phosphodiesterases, Type 3/physiology, Cyclic Nucleotide Phosphodiesterases, Type 4/physiology, Epinephrine/pharmacology, Female, Heart Failure/physiopathology, Heart Transplantation, Humans, Male, Middle Aged, Norepinephrine/pharmacology, Phosphodiesterase 3 Inhibitors/pharmacology, Phosphodiesterase 4 Inhibitors/pharmacology, Propanolamines/pharmacology, Quinolones/pharmacology, Receptors, Adrenergic, beta-1/physiology, Receptors, Adrenergic, beta-2/physiology, Rolipram/pharmacology