PDE3, but not PDE4, reduces beta 1- and beta 2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

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 and Kaumann, Alberto J. (2013) PDE3, but not PDE4, reduces beta 1- and beta 2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients. British Journal of Pharmacology, 169 3: 528-538. doi:10.1111/bph.12167


Author 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.
Title PDE3, but not PDE4, reduces beta 1- and beta 2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients
Formatted title
PDE3, but not PDE4, reduces β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
1476-5381
Publication date 2013-06-01
Sub-type Article (original research)
DOI 10.1111/bph.12167
Volume 169
Issue 3
Start page 528
End page 538
Total pages 11
Collection year 2014
Language eng
Formatted 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.
Keyword Human heart failure
1 and 2 Adrenoceptors
Phosphodiesterases 3 and 4
Noradrenaline and adrenaline
Inotropism and lusitropism
Metoprolol
Cyclic-nucleotide phosphodiesterases
Congestive-heart-failure
Human atrial myocardium
Human cardiac-muscle
Cardiomyocyte apoptosis
Rat-heart
Receptors
Camp
beta(1)-Adrenoceptors
Arrhythmias
β1-Adrenoceptors
β1 and β2 Adrenoceptors
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
 
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