Andressen, Kjetil W

Aronsen, Jan M

Levy, Finn O

Meier, Silja

Moltzau, Lise R

Osnes, Jan-Bjørn

Qvigstad, Eirik

Sjaastad, Ivar

Skomedal, Tor

BMC Pharmacology and Toxicology

PubMed

Silja Meier

Kjetil Wessel Andressen

Jan Magnus Aronsen

Ivar Sjaastad

Tor Skomedal

Jan-Bjørn Osnes

Eirik Qvigstad

Finn Olav Levy

Lise Román Moltzau

Springer - Publisher Connector

MEETING ABSTRACT Open Access
Enhancement of cAMP-mediated inotropic
responses by CNP is regulated differently by
PDE2 in normal and failing hearts
Silja Meier1,2*, Kjetil Wessel Andressen1,2, Jan Magnus Aronsen2,3,4, Ivar Sjaastad2,3, Tor Skomedal1,2,
Jan-Bjørn Osnes1,2, Eirik Qvigstad1,2, Finn Olav Levy1,2, Lise Román Moltzau1,2
From 7th International Conference on cGMP Generators, Effectors and Therapeutic Implications
Trier, Germany. 19-21 June 2015
Background
Natriuretic peptide levels are increased in heart failure
(HF). Atrial (ANP) and brain (BNP) natriuretic peptide
mediate their effects preferentially through the natriuretic
peptide receptor (NPR)-A, and C-type natriuretic peptide
(CNP) through NPR-B. NPRs are membrane bound gua-
nylyl cyclases that increase cyclic GMP (cGMP) produc-
tion when activated. We have previously shown that
NPR-B stimulation by CNP enhances b1-adrenoceptor
(b1-AR)- and 5-HT4 serotonin receptor-mediated signal-
ing in failing hearts, probably through inhibition of phos-
phodiesterase (PDE) 3, a potential detrimental effect in
the failing heart. In this study we examine the role of
PDE2 in regulating the CNP-induced enhancement of
b1-AR and 5-HT4 signaling in non-failing (Sham) and
failing (HF) hearts, as PDE2 is a dual-selective PDE and
can potentially be stimulated by cGMP.
Methods
Chronic heart failure was induced in male Wistar rats
by 6-week coronary artery ligation. Contractility studies
were performed ex vivo in left ventricular muscle strips
in the presence of appropriate receptor agonist and
antagonists. cGMP measurements were performed on
isolated left ventricular cardiomyocytes and PDE activity
assays on left ventricular cardiomyocyte homogenates.
Results
CNP, by stimulating NPR-B, was able to enhance b1-AR-
and 5-HT4-mediated inotropic responses in Sham and HF
left ventricular strips. CNP elicited a similar increase of
cGMP in cardiomyocytes from Sham and HF. cGMP
reduced the cAMP-PDE activity of PDE3 and increased the
cAMP-PDE activity of PDE2 concentration-dependently in
cardiomyocyte homogenates in a similar way in Sham and
HF. In Sham inhibition of PDE2 by EHNA amplified the
CNP-induced enhancement of b1-AR- and 5-HT4-mediated
inotropic responses. In HF PDE2 inhibition did not influ-
ence the functional effects of CNP despite increasing the
cGMP response to the same marked extent as in Sham.
Conclusions
There is a preserved mechanism of CNP-induced
enhancement of b1-AR and 5-HT4 in Sham and HF.
cGMP levels and cGMP-mediated activation and inhibi-
tion of cAMP-PDE activity of PDE2 and PDE3, respec-
tively, are similar in Sham and HF. However, PDE2 seems
more involved in regulating the b1-AR and 5-HT4
enhancement in Sham compared to HF, which might
reflect differences between Sham and HF in PDE2 expres-
sion or compartmentation.
Authors’ details
1Department of Pharmacology, University of Oslo and Oslo University
Hospital, Oslo, Norway. 2K.G. Jebsen Cardiac Research Centre and Center for
Heart Failure Research, University of Oslo, Oslo, Norway. 3Institute for
Experimental Medical Research, University of Oslo and Oslo University
Hospital, Oslo, Norway. 4Bjørknes College, Oslo, Norway.
Published: 2 September 2015
doi:10.1186/2050-6511-16-S1-A66
Cite this article as: Meier et al.: Enhancement of cAMP-mediated
inotropic responses by CNP is regulated differently by PDE2 in normal
and failing hearts. BMC Pharmacology and Toxicology 2015 16(Suppl 1):
A66.
* Correspondence: silja.meier@medisin.uio.no
1Department of Pharmacology, University of Oslo and Oslo University
Hospital, Oslo, Norway
Full list of author information is available at the end of the article
Meier et al. BMC Pharmacology and Toxicology 2015, 16(Suppl 1):A66
http://www.biomedcentral.com/2050-6511/16/S1/A66
© 2015 Meier et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://
creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/
zero/1.0/) applies to the data made available in this article, unless otherwise stated.


Enhancement of cAMP-mediated inotropic responses by CNP is regulated differently by PDE2 in normal and failing hearts

NORA - Norwegian Open Research Archives

MEETING ABSTRACT Open AccessEnhancement of cAMP-mediated inotropicresponses by CNP is regulated differently byPDE2 in normal and failing heartsSilja Meier1,2*, Kjetil Wessel Andressen1,2, Jan Magnus Aronsen2,3,4, Ivar Sjaastad2,3, Tor Skomedal1,2,Jan-Bjørn Osnes1,2, Eirik Qvigstad1,2, Finn Olav Levy1,2, Lise Román Moltzau1,2From 7th International Conference on cGMP Generators, Effectors and Therapeutic ImplicationsTrier, Germany. 19-21 June 2015BackgroundNatriuretic peptide levels are increased in heart failure(HF). Atrial (ANP) and brain (BNP) natriuretic peptidemediate their effects preferentially through the natriureticpeptide receptor (NPR)-A, and C-type natriuretic peptide(CNP) through NPR-B. NPRs are membrane bound gua-nylyl cyclases that increase cyclic GMP (cGMP) produc-tion when activated. We have previously shown thatNPR-B stimulation by CNP enhances b1-adrenoceptor(b1-AR)- and 5-HT4 serotonin receptor-mediated signal-ing in failing hearts, probably through inhibition of phos-phodiesterase (PDE) 3, a potential detrimental effect inthe failing heart. In this study we examine the role ofPDE2 in regulating the CNP-induced enhancement ofb1-AR and 5-HT4 signaling in non-failing (Sham) andfailing (HF) hearts, as PDE2 is a dual-selective PDE andcan potentially be stimulated by cGMP.MethodsChronic heart failure was induced in male Wistar ratsby 6-week coronary artery ligation. Contractility studieswere performed ex vivo in left ventricular muscle stripsin the presence of appropriate receptor agonist andantagonists. cGMP measurements were performed onisolated left ventricular cardiomyocytes and PDE activityassays on left ventricular cardiomyocyte homogenates.ResultsCNP, by stimulating NPR-B, was able to enhance b1-AR-and 5-HT4-mediated inotropic responses in Sham and HFleft ventricular strips. CNP elicited a similar increase ofcGMP in cardiomyocytes from Sham and HF. cGMPreduced the cAMP-PDE activity of PDE3 and increased thecAMP-PDE activity of PDE2 concentration-dependently incardiomyocyte homogenates in a similar way in Sham andHF. In Sham inhibition of PDE2 by EHNA amplified theCNP-induced enhancement of b1-AR- and 5-HT4-mediatedinotropic responses. In HF PDE2 inhibition did not influ-ence the functional effects of CNP despite increasing thecGMP response to the same marked extent as in Sham.ConclusionsThere is a preserved mechanism of CNP-inducedenhancement of b1-AR and 5-HT4 in Sham and HF.cGMP levels and cGMP-mediated activation and inhibi-tion of cAMP-PDE activity of PDE2 and PDE3, respec-tively, are similar in Sham and HF. However, PDE2 seemsmore involved in regulating the b1-AR and 5-HT4enhancement in Sham compared to HF, which mightreflect differences between Sham and HF in PDE2 expres-sion or compartmentation.Authors’ details1Department of Pharmacology, University of Oslo and Oslo UniversityHospital, Oslo, Norway. 2K.G. Jebsen Cardiac Research Centre and Center forHeart Failure Research, University of Oslo, Oslo, Norway. 3Institute forExperimental Medical Research, University of Oslo and Oslo UniversityHospital, Oslo, Norway. 4Bjørknes College, Oslo, Norway.Published: 2 September 2015doi:10.1186/2050-6511-16-S1-A66Cite this article as: Meier et al.: Enhancement of cAMP-mediatedinotropic responses by CNP is regulated differently by PDE2 in normaland failing hearts. BMC Pharmacology and Toxicology 2015 16(Suppl 1):A66.* Correspondence: silja.meier@medisin.uio.no1Department of Pharmacology, University of Oslo and Oslo UniversityHospital, Oslo, NorwayFull list of author information is available at the end of the articleMeier et al. BMC Pharmacology and Toxicology 2015, 16(Suppl 1):A66http://www.biomedcentral.com/2050-6511/16/S1/A66© 2015 Meier et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided theoriginal work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Enhancement of cAMP-mediated inotropic responses by CNP is regulated differently by PDE2 in normal and failing hearts

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