Natriuretic peptides increase beta1-adrenoceptor signalling in failing hearts through phosphodiesterase 3 inhibition

Cardiovasc Res. 2010 Mar 1;85(4):763-72. doi: 10.1093/cvr/cvp364. Epub 2009 Nov 9.


Aims: 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 and results: 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 (PLB) and troponin I was measured by western blotting. Stimulation of NPR-B enhanced beta1-adrenoceptor (beta1-AR)-evoked contractile responses through cGMP-mediated inhibition of phosphodiesterase 3 (PDE3). CNP enhanced beta1-AR-mediated increase of cAMP levels to the same extent as the selective PDE3 inhibitor cilostamide and increased beta1-AR-stimulated protein kinase A activity, as demonstrated by increased PLB 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 beta(1)-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Cyclic AMP / metabolism
  • Cyclic GMP / metabolism
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Cyclic Nucleotide Phosphodiesterases, Type 3 / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
  • Heart Failure / metabolism*
  • Heart Failure / pathology
  • Male
  • Myocardial Contraction / physiology
  • Myocytes, Cardiac / metabolism
  • Natriuretic Peptide, Brain / metabolism
  • Natriuretic Peptide, Brain / pharmacology*
  • Natriuretic Peptide, C-Type / metabolism
  • Natriuretic Peptide, C-Type / pharmacology
  • Phosphodiesterase 3 Inhibitors
  • Phosphodiesterase Inhibitors / pharmacology
  • Quinolones / pharmacology
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*


  • Phosphodiesterase 3 Inhibitors
  • Phosphodiesterase Inhibitors
  • Quinolones
  • Receptors, Adrenergic, beta-1
  • Natriuretic Peptide, Brain
  • Natriuretic Peptide, C-Type
  • cilostamide
  • Cyclic AMP
  • Cyclic GMP-Dependent Protein Kinases
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Cyclic GMP