Modulation of cGMP in heart failure: a new therapeutic paradigm

Abstract

Heart failure (HF) is a common disease that continues to be associated with high morbidity and mortality warranting novel therapeutic strategies. Cyclic guanosine monophosphate (cGMP) is the second messenger of several important signaling pathways based on distinct guanylate cyclases (GCs) in the cardiovascular system. Both the nitric oxide/soluble GC (NO/sGC) as well as the natriuretic peptide/GC-A (NP/GC-A) systems are disordered in HF, providing a rationale for their therapeutic augmentation. Soluble GC activation with conventional nitrovasodilators has been used for more than a century but is associated with cGMP-independent actions and the development of tolerance, actions which novel NO-independent sGC activators now in clinical development lack. Activation of GC-A by administration of naturally occurring or designer natriuretic peptides is an emerging field, as is the inhibition of enzymes that degrade endogenous NPs. Finally, inhibition of cGMP-degrading phosphodiesterases, particularly phosphodiesterase 5 provides an additional strategy to augment cGMP-signaling.

Figure 1

Simplified schematic of guanylate cyclase (GC) pathways. Cyclic GMP is the second messenger of several distinct signaling pathways. Nitric oxide is produced by endothelial cells and binds to soluble GC in the target cell. ANP and BNP, derived primarily from cardiomyocytes, stimulate GC-A (also called NP receptor A), while CNP, secreted by endothelial cells, stimulates GC-B (also called NP receptor B). Cyclic GMP modulates the activity of cGMP-dependent protein kinase G, cGMP-regulated PDEs, and cGMP-regulated cation channels. The cGMP signal is terminated by a variety of PDEs that hydrolyze cGMP to GMP, or by extrusion into the extracellular space. The NPs are degraded by a variety of peptidases. Cyclic GMP signaling can be augmented by (1) the use of NO-mimetics such as nitrovasodilators, (2) by direct sGC stimulators, (3) by administration of exogenous NPs, (4) by inhibiting NP degrading enzymes, and (5) by inhibiting the activity of cGMP-hydrolyzing PDEs. ANP, atrial natriuretic peptide, BNP, B-type natriuretic peptide, cGMP, cyclic guanosine monophosphate, GMP, guanosine monophosphate, GC, guanylate cyclase, DPP4, dipeptidyl peptidase IV, NEP, neutral endopeptidase, NO, nitric oxide, PDE, phosphodiesterase, PKG, protein kinase G, R_A, natriuretic peptide receptor A, sGC, soluble guanylate cyclase.

Figure 2

Effect of BAY 58–2667 administration on (A) mean arterial pressure (MAP), (B) systemic vascular resistance, (C) right atrial pressure (RAP), (D) pulmonary capillary wedge pressure (PCWP), (E) cardiac output (CO), and (F) renal blood flow (RBF). * indicates p<0.05 compared to baseline. Taken from Boerrigter et al. (2007).

Figure 3

Adjusted mean maximum decrease in glomerular filtration rate (GFR) from baseline through hospital discharge or by study day 14, whichever came first, using an analysis of covariance model. Lines above the bars indicate standard error of the mean (A). Kaplan-Meier survival curve to day 180 by treatment group in the ‘safety population’, which is a subset of the total study population added during the study to assess long-term safety (B). Taken from Mentzer et al. (2007); reprinted with permission from Elsevier.

Figure 3

Adjusted mean maximum decrease in glomerular filtration rate (GFR) from baseline through hospital discharge or by study day 14, whichever came first, using an analysis of covariance model. Lines above the bars indicate standard error of the mean (A). Kaplan-Meier survival curve to day 180 by treatment group in the ‘safety population’, which is a subset of the total study population added during the study to assess long-term safety (B). Taken from Mentzer et al. (2007); reprinted with permission from Elsevier.

Figure 4

CD-NP is a chimeric peptide consisting of the amino terminus and ring structure of C-type natriuretic peptide and the carboxy terminus of Dendroaspis natriuretic peptide.