Different Compartmentation of Responses to Brain Natriuretic Peptide and C-Type Natriuretic Peptide in Failing Rat Ventricle

We earlier found a negative inotropic (NIR) and positive lusitropic response (LR) to CNP in failing heart ventricle. In this study we investigate and compare the functional responses to the natriuretic peptides (NPs) BNP and CNP and relate them to cGMP regulation and effects on downstream targets. Experiments were conducted in left ventricular muscle strips and ventricular cardiomyocytes from Wistar rats with heart failure 6 weeks after myocardial infarction. As opposed to CNP, BNP did not cause a NIR or LR, despite increasing cGMP levels. The BNP-induced cGMP elevation was mainly and markedly regulated by PDE2, and only marginally increased by PDE3 or PDE5 inhibition. Combined PDE2, 3 and 5 inhibition failed to reveal any functional responses to BNP, despite an extensive cGMP elevation. BNP decreased, whereas CNP increased the amplitude of the Ca2+ transient. BNP did not increase phospholamban (PLB) or troponin I (TnI) phosphorylation, Ca2+ extrusion rate constant or SR Ca2+ load, whereas CNP did. Both BNP and CNP reduced the peak of the L-type Ca2+ current. Cyclic GMP elevations by BNP and CNP in cardiomyocytes were additive and the presence of BNP did not alter the NIR to CNP, or the CNP-induced PLB and TnI phosphorylation. However, a small increase in the LR to maximal CNP was observed in the presence of BNP. In conclusion, different responses to cGMP generated by BNP and CNP suggest different compartmentation of the cGMP signal and different roles of the two NPs in the failing heart.