Skip Navigation



Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 9, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp364
This Article
Right arrow Full Text (PDF)
Right arrow Supplementary Data
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Qvigstad, E.
Right arrow Articles by Osnes, J.-B.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Qvigstad, E.
Right arrow Articles by Osnes, J.-B.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Natriuretic peptides increase beta-1-adrenoceptor signalling in failing hearts through phosphodiesterase 3 inhibition

Eirik Qvigstad1,2,*, Lise R. Moltzau1,2, Jan Magnus Aronsen2,3, Cam H.T. Nguyen1,2, Karina Hougen2,3, Ivar Sjaastad2,3, Finn Olav Levy1,2,*, Tor Skomedal1,2 and Jan-Bjørn Osnes1,2

1 Department of Pharmacology, University of Oslo, Oslo, Norway
2 Center for Heart Failure Research, University of Oslo, Oslo, Norway
3 Institute for Experimental Medical Research, University of Oslo, Oslo, Norway

* Corresponding authors: Department of Pharmacology, University of Oslo, P.O. Box 1057 Blindern, 0316 Oslo, Norway. Phone: +47-22840273/22840237, Fax: +47-22840202, E-mail: eirik.qvigstad{at}medisin.uio.no/f.o.levy{at}medisin.uio.no

Aim: Whereas natriuretic peptides increase cGMP levels with beneficial cardiovascular effects through protein kinase G, we found an unexpected cardio-excitatory effect of C-type natriuretic peptide (CNP) through natriuretic peptide receptor B (NPR-B) stimulation in failing cardiac muscle and explored the mechanism.

Methods: Heart failure was induced in male Wistar rats by coronary artery ligation. Contraction studies were performed in left ventricular muscle strips. Cyclic nucleotides were measured by radio- and enzyme immunoassay. Apoptosis was determined in isolated cardiomyocytes by Annexin-V/propidium iodide staining and phosphorylation of phospholamban and troponin I was measured by Western blotting.

Results: Stimulation of NPR-B enhanced β1-adrenoceptor (β1-AR)-evoked contractile responses through cGMP-mediated inhibition of phosphodiesterase 3 (PDE3). CNP enhanced β1-AR-mediated increase of cAMP levels to the same extent as the selective PDE3 inhibitor cilostamide and increased β1-AR-stimulated protein kinase A activity, as demonstrated by increased phospholamban and troponin I phosphorylation. CNP promoted cardiomyocyte apoptosis similar to inhibition of PDE3 by cilostamide, indicative of adverse effects of NPR-B signalling in failing hearts.

Conclusion: An NPR-B-cGMP-PDE3 inhibitory pathway enhances β1-AR-mediated responses and may in the long term be detrimental to the failing heart through mechanisms similar to those operating during treatment with PDE3 inhibitors or during chronic beta-adrenergic stimulation.

Time for primary review: 32 Days


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.