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Cyclic GMP generated by natriuretic peptide receptor B enhances β1-adrenoceptor signaling in normal and failing hearts
BMC Pharmacology volume 11, Article number: P46 (2011)
Atrial (ANP), B-type (BNP) and C-type (CNP) natriuretic peptide levels are increased in heart failure. Natriuretic peptides mediate their effects through natriuretic peptide receptors (NPRs), ANP and BNP preferentially through NPR-A and CNP through NPR-B. NPRs are membrane bound guanylyl cyclases that increase cyclic GMP (cGMP) production when activated. Increased cGMP levels may have beneficial cardiovascular effects through protein kinase G. In contrast, we have previously shown that NPR-B stimulation by CNP enhances β1-adrenoceptor (β1-AR) mediated signaling in failing hearts through inhibition of phosphodiesterase 3 (PDE3) . This cardioexcitatory influence is longstanding and is thus probably detrimental in the failing heart. However, a comparison of the PDE3 inhibitory effect of NPR-B signaling in non-failing and failing hearts was not elucidated.
Heart failure was induced in male Wistar rats by coronary artery ligation. Contraction studies were performed ex vivo in left ventricular muscle strips in the presence of appropriate receptor antagonists.
Results and conclusion
We now demonstrate that CNP through NPR-B is able to potently inhibit PDE3 and thus increase cAMP signaling in non-failing as in failing hearts. This was evident from a marked ability of CNP to potentiate the inotropic and lusitropic responses to β1-AR stimulation in left ventricular strips. This conserved mechanism may enhance detrimental β1-AR effects during pathological remodeling, and may contribute to the development of the failing cardiac phenotype.
Qvigstad E, Moltzau LR, Aronsen JM, Nguyen CH, Hougen K, Sjaastad I, Levy FO, Skomedal T, Osnes JB: Natriuretic peptides increase β1-adrenoceptor signalling in failing hearts through phosphodiesterase 3 inhibition. Cardiovasc Res. 2010, 85: 763-772. 10.1093/cvr/cvp364.
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Meier, S., Aronsen, J.M., Sjaastad, I. et al. Cyclic GMP generated by natriuretic peptide receptor B enhances β1-adrenoceptor signaling in normal and failing hearts. BMC Pharmacol 11 (Suppl 1), P46 (2011). https://doi.org/10.1186/1471-2210-11-S1-P46
- Natriuretic Peptide
- Guanylyl Cyclase
- Muscle Strip
- Natriuretic Peptide Level
- Coronary Artery Ligation