Abstract
Background Natriuretic peptides increase in heart failure. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) activate the natriuretic peptide receptor (NPR)-A and C-type natriuretic peptide (CNP) the NPR-B, causing production of cyclic 3’,5’-guanosine monophosphate (cGMP). Our group has previously shown that CNP potentiates b1-adrenoceptor-mediated inotropic response by increasing cAMP levels. This is explained by a crosstalk between cGMP and cAMP, where cGMP produced by NPR-B inhibits phosphodiesterase (PDE) 3 from degrading cAMP. Increased b1-adrenoceptor signalling is harmful in heart failure which is the basis for use of b-blockers in heart failure therapy. Further, PDE3 inhibition has been associated with increased mortality in heart failure. Thus, an NPR-B antagonist could eliminate the unwanted effects due to PDE3 inhibition and increased b1-adrenoceptor signalling by CNP. There are no selective NPR-B antagonists available, and our aim is to identify and characterize novel non-peptide small molecular selective NPR-B antagonists for potential use in heart failure therapy.
Highlights
This is explained by a crosstalk between cGMP and cAMP, where cGMP produced by natriuretic peptide receptor (NPR)-B inhibits phosphodiesterase (PDE) 3 from degrading cAMP
Small molecular compounds were screened for activity and selectivity towards NPR-A and NPR-B, using a cGMP assay based on AlphaScreen technology
We can identify compounds that interfere with brain natriuretic peptide (BNP)- and C-type natriuretic peptide (CNP)-stimulated cGMP production through the NPR-A and NPR-B receptor, respectively
Summary
Identification and characterization of small molecular NPR-B receptor antagonists. From 7th International Conference on cGMP Generators, Effectors and Therapeutic Implications Trier, Germany. From 7th International Conference on cGMP Generators, Effectors and Therapeutic Implications Trier, Germany. 19-21 June 2015
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