We have previously shown that the natriuretic peptide receptor B (NPR-B) agonist C-type natriuretic peptide (CNP) enhances cyclic adenosine 3´，5´-monophosphate (cAMP)-mediated signaling in failing hearts， through cyclic guanosine 3´，5´-monophosphate (cGMP)-mediated phosphodiesterase (PDE) 3 inhibition. As several signaling pathways are importantly changed in failing hearts， it could not be taken for granted that this crosstalk would be the same in non-failing hearts. Thus， we wanted to clarify to which extent this effect of CNP occurred also in non-failing hearts. Inotropic and lusitropic responses were measured in muscle strips and cGMP levels， localized cAMP levels， cAMP-PDE activity and mRN... More
We have previously shown that the natriuretic peptide receptor B (NPR-B) agonist C-type natriuretic peptide (CNP) enhances cyclic adenosine 3´，5´-monophosphate (cAMP)-mediated signaling in failing hearts， through cyclic guanosine 3´，5´-monophosphate (cGMP)-mediated phosphodiesterase (PDE) 3 inhibition. As several signaling pathways are importantly changed in failing hearts， it could not be taken for granted that this crosstalk would be the same in non-failing hearts. Thus， we wanted to clarify to which extent this effect of CNP occurred also in non-failing hearts. Inotropic and lusitropic responses were measured in muscle strips and cGMP levels， localized cAMP levels， cAMP-PDE activity and mRNA levels were analyzed in isolated cardiomyocytes from left ventricles of non-failing and failing rat hearts. CNP increased cGMP and enhanced β- and β-adrenoceptor-mediated inotropic and β-adrenoceptor-mediated lusitropic responses， in non-failing and failing hearts. The NPR-A agonist brain natriuretic peptide (BNP) increased cGMP， but did not affect inotropic or lusitropic responses， indicating different compartmentation of cGMP from the two natriuretic peptide receptors. cAMP-PDE activity of PDE3 was concentration-dependently inhibited by cGMP with the same potency and to the same extent in non-failing and failing cardiomyocytes. CNP enhanced β-adrenoceptor-induced cAMP increase in living cardiomyocytes in the absence， but not in the presence of a PDE3 inhibitor indicating involvement of PDE3. In summary， CNP sensitizes cAMP-mediated signaling in non-failing as in failing hearts， via NPR-B-mediated increase of cGMP that inhibits the cAMP-PDE activity of PDE3.
