Carvedilol induces greater control of β2- than β1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium

Molenaar, Peter, Christ, Torsten, Berk, Emanuel, Engel, Andreas, Gillette, Katherine T., Galindo-Tovar, Alejandro, Ravens, Ursula and Kaumann, Alberto J. (2014) Carvedilol induces greater control of β2- than β1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium. Naunyn-Schmiedeberg's Archives of Pharmacology, 387 7: 629-640. doi:10.1007/s00210-014-0974-4


Author Molenaar, Peter
Christ, Torsten
Berk, Emanuel
Engel, Andreas
Gillette, Katherine T.
Galindo-Tovar, Alejandro
Ravens, Ursula
Kaumann, Alberto J.
Title Carvedilol induces greater control of β2- than β1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium
Formatted title
Carvedilol induces greater control of β2- than β1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium
Journal name Naunyn-Schmiedeberg's Archives of Pharmacology   Check publisher's open access policy
ISSN 1432-1912
0028-1298
Publication date 2014-07
Year available 2014
Sub-type Article (original research)
DOI 10.1007/s00210-014-0974-4
Open Access Status
Volume 387
Issue 7
Start page 629
End page 640
Total pages 12
Place of publication Heidelberg Germany
Publisher Springer
Collection year 2015
Language eng
Formatted 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.
Keyword Human heart failure
β1-and β2-adrenoceptors
Phosphodiesterases 3 and 4
Noradrenaline and adrenaline
Inotropism and lusitropism
Carvedilol
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 1 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 2 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 29 Jul 2014, 02:05:19 EST by System User on behalf of School of Medicine