Novel Natriuretic Peptides and the Cardiorenal Syndrome

Figure 1. Guanylyl cyclase (GC) pathways, activation of cGMP as their second messenger

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Nitric oxide (NO) activates soluble GC. ANP, BNP, and DNP stimulate GC-A, while CNP stimulates GC-B. NPs also bind to the non-GC linked NP clearance receptor (NPR-C). Cyclic GMP modulates cGMP-dependent protein kinase G (PKG), cGMP-regulated phosphodiesterases (PDEs), and cGMP-regulated cation channels. The cGMP signal is terminated by PDEs that hydrolyze cGMP to GMP. The NPs are degraded by peptidases such as neprilysin (also known as neutral endopeptidase 24.11), dipeptidyl peptidase IV (DPP4), and meprin A. Strategies to enhance cyclic GMP signaling therapeutically include 1) the use of NO-mimetics such as nitro vasodilators, 2) direct sGC stimulators, 3) exogenous native and designer NPs, 4) inhibiting NP degrading enzymes, 5) blocking NPR-C, 6) overexpressing GC-A or GC-B or both; and 7) inhibiting the activity of cGMP-hydrolyzing PDEs.

Figure 2CD-NP

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The structure of CD-NP combines the mature 22-amino acid structure of CNP and the 13-amino acid C-terminus of DNP representing a dual activator of GC-A and GC-B with receptor affinities (GC-B<GC-A) (24).

renal dysfunction in heart failure patients or the presence of cardiac functional impairment in renal failure patients invariably means a worsening prognosis in either setting (17). Clinical and experimental studies have concluded that there is not one unique mechanism for cardiorenal syndrome. Decreased renal perfusion in the heart failure setting has been a ssociated with renal hypoxia, increased sympathetic activity, elevated central venous pressure and increased intra-abdominal pressure, oxidative stress, endothelial dysfunction, as well as with activated renin-angiotensin-aldosterone system (RAAS) and vasopressin system (REF) (813).

Beyond elucidating the mechanisms of this syndrome, there is an unmet need for innovative therapeutics that aim both at the heart and the kidney to enhance both organ systems in the control of optimal cardiorenal function. Indeed, the goal of a cardiorenal therapeutic should be to 1) unload the heart including decreasing venous pressure while minimizing reductions in blood pressure, 2) directly target the nephron to preserve or enhance glomerular filtration rate (GFR) and reduce salt and water retention, and 3) suppress activated RAAS and arginine vasopressin (AVP) systems.

The cardiac natriuretic peptides are a family of hormones that include atrial natriuretic peptide (ANP), b-type or brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP). These peptides act via their second messenger cGMP. There are two receptors, GCA (guanylate cyclase A receptor, GC-A) that binds to ANP and BNP, and GCB (guanylate cyclase B receptor, GC-B) that binds to CNP. The peptides have multiple actions. They are natriuretic (via GA), renin and aldosterone inhibiting (via GA), venodilating (GB>A), antifibrotic (GB>A), anti-hypertrophic (GA>B), lusitropic (GA), anti-apoptotic (GA), and vascular regenerating (GA/B) (1416).

Among this family of peptides, the only approved for therapeutic use in the United States is BNP (nesiritide), specifically in the setting of acute decompensated heart failure (ADHF). BNP is a GC-A receptor agonist with potent arterial vasodilating properties. It enhances renal function in conditions such as cardiopulmonary bypass surgery, but in ADHF and because of excessive hypotension it may impair renal function. It is hoped that the resulting controversy will be clarified soon by completion of the ASCEND-HF trial in patients with ADHF, which will address the safety and efficacy of nesiritide in 7000 individuals randomized to BNP or standard care (17) .

The aim of improving natriuretic peptide therapy in terms of safety and efficacy led to the design of a novel chimeric natriuretic peptide that unloads the heart but does not cause excessive hypotension while enhancing renal function. This peptide, CD-NP, is currently being tested in phase II trials. CD-NP is a designer NP that integrates mature CNP with the C-terminus of DNP (1820). The rationale for the design of CD-NP is based on the vascular actions of CNP, produced by the endothelium and acting through GC-B, which possesses venodilatory properties causing less hypotension than ANP (19).

CNP also accelerates endothelial repair and is potently antifibrotic. It inhibits hypertrophy in cardiomyocytes but is not natriuretic nor does it suppress the RAAS (21). CNP lacks a C-terminus, making it very susceptible to degradation by neutral endopeptidase (NEP), the enzyme that degrades natriuretic peptides. DNP, on the other hand, is a natriuretic peptide that was originally found in a snake, the Dendroaspis angusticeps (Eastern Green Mamba) (22). This peptide binds to the GC-A receptor, the same receptor that ANP and BNP bind to, giving it natriuretic and diuretic properties. Importantly, the 15-amino acid C-terminus confers high resistance to degradation. CD-NP therefore is a designer chimeric natriuretic peptide, the first of its kind, that represents a dual GC-A and GC-B receptor agonist (18,19). Thus, CD-NP was engineered to exploit the characteristics of CNP so that CD-NP would be less hypotensive than BNP and possess renal-enhancing, cardiac preload-reducing, and RAAS-suppressing actions.

Preclinical studies in the laboratory showed that in plasma and urine, CD-NP compared to CNP had enhanced cGMP generation (18). In a different preclinical study, comparison to BNP showed that CD-NP had less hypotensive effects than BNP and that it possessed GFR-enhancing properties (18,19). Moreover, CD-NP reduced cardiac filling pressures and suppressed renin. In healthy insdividuals, CD-NP increased cGMP production in plasma as well as in urine compared to placebo. It also increased urinary sodium excretion without excessive hypotension, and it decreased aldosterone plasma levels. In preliminary studies in patients with heart failure, CD-NP improved GFR estimated from creatinine clearance, reduced cardiac filling pressures as demonstrated by a reduction in plasma, and suppressed aldosterone (19).

Recently, a second designer natriuretic peptide based on a genomic approach has been reported (23,24). In this case, based upon alternative splicing of the BNP gene, a BNP-like peptide was discovered and has been called AS-BNP. Owing to intron retention, alternative splicing codes for a unique 34-amino acid C-terminus while preserving the remainder of native BNP. From AS-BNP, a novel shorter amino acid peptide was designed that results in a renal-selective action. In experimental heart failure, this designer peptide (AS-BNP.1) enhances GFR, increases sodium excretion, and suppresses renin. Importantly, it has no effect on blood pressure, which is preserved (23). It is hypothesized that this second designer peptide may activate a novel renal natriuretic peptide receptor. Clinical trials are expected to start soon.

The cardiorenal syndrome will continue to be a clinical challenge. We still need to understand its mechanisms and seek more effective and safe therapies. The native natriuretic peptides and their respective cGMP-linked receptors possess renal-enhancing actions but are limited by untoward effects on the kidney. Novel drug discovery and design taking key parts of native natriuretic peptides and creating designer drugs like CD-NP may optimize renal-favorable effects such as renal protection and limit adverse actions such as excessive hypotension but still unload the heart. Second, use of genomic research tools may provide opportunities to find novel natriuretic peptides resulting in the engineering of renal-specific peptides such as AS-BNP.1, which may prove efficacious in the cardiorenal syndrome. We all await exciting results of new and ongoing trials of these novel natriuretic peptides for cardiorenal disease.

Notes

[1] Fernando L. Martin, MD, and John C. Burnett, Jr., MD, are with the cardiorenal research laboratory, division of cardiovascular diseases and division of nephrology and hypertension, Mayo Clinic, Rochester, MN.

References

1.

Coresh J, Astor B, Sarnak MJ. Evidence for increased cardiovascular disease risk in patients with chronic kidney disease. 2004; 13:73–81.

2.

Culleton, BF, et al. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. 1999; 56:2214–2219.

3.

Dries DL, et al. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol 2000; 35:681–689.

4.

Garg, AX, et al. Moderate renal insufficiency and the risk of cardiovascular mortality: results from the NHANES I. Kidney Int 2002; 61:1486–1494.

5.

Go AS, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351:1296–1305.

6.

Henry RM, et al. Mild renal insufficiency is associated with increased cardiovascular mortality: The Hoorn Study. Kidney Int 2002; 62:1402–1407.

7.

van Dokkum RP, et al. Myocardial infarction enhances progressive renal damage in an experimental model for cardio-renal interaction. J Am Soc Nephrol 2004; 15:3103–3110.

8.

Doty JM, et al. Effect of increased renal venous pressure on renal function. 1999; 4:1000–1003.

9.

Malbrain ML, et al. Results from the International Conference of Experts on Intra-abdominal Hypertension and Abdominal Compartment Syndrome. I. Definitions. Intensive Care Med 2006; 32:1722–32.

10.

Damman K, et al. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53:582–8.

11.

Schlaich MP, et al. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med 2009; 361:932–4.

12.

St John Sutton M, et al. Cardiovascular death and left ventricular remodeling two years after myocardial infarction: baseline predictors and impact of long-term use of captopril: information from the Survival and Ventricular Enlargement (SAVE) trial. Circulation 1997; 96:3294–9.

13.

Vaziri ND, et al. Oxidative stress and dysregulation of superoxide dismutase and NADPH oxidase in renal insufficiency. Kidney Int 2003; 63:179–85.

14.

Martin FL, et al. B-type natriuretic peptide: beyond a diagnostic. Heart Fail Clin 2008; 4:449–54.

15.

Boerrigter G, Lapp H, Burnett JC. Modulation of cGMP in heart failure: a new therapeutic paradigm. Handb Exp Pharmacol 2009; 191:485–506.

16.

Cataliotti A, et al. Natriuretic peptides as regulators of myocardial structure and function: pathophysiologic and therapeutic implications. Heart Fail Clin 2006; 2:269–76.

17.

Mohammed SF, et al. Nesiritide in acute decompensated heart failure: current status and future perspectives. Rev Cardiovasc Med 2008; 9:151–8.

18.

Lisy O, et al. Design, synthesis, and actions of a novel chimeric natriuretic peptide: CD-NP. J Am Coll Cardiol 2008; 52:60–8.

19.

Lee CY, et al. Pharmacodynamics of a novel designer natriuretic peptide, CD-NP, in a first-in-human clinical trial in healthy subjects. J Clin Pharmacol 2009; 49:668–73.

20.

McKie PM, Sangaralingham SJ, Burnett JC Jr. CD-NP: An Innovative Designer Natriuretic Peptide Activator of Particulate Guanylyl Cyclase Receptors for Cardiorenal Disease. Curr Heart Fail Rep 2010.

21.

Rubattu S, et al. Natriuretic peptides: an update on bioactivity, potential therapeutic use, and implication in cardiovascular diseases. Am J Hypertens 2008; 21:733–41.

22.

Best PJ, et al. Dendroaspis natriuretic peptide relaxes isolated human arteries and veins. Cardiovasc Res 2002; 55:375–84.

23.

Pan S, et al. Biodesign of a renal-protective peptide based on alternative splicing of B-type natriuretic peptide. Proc Natl Acad Sci USA, 2009; 106:11282–7.

24.

Dickey DM, Burnett JC Jr., Potter LR. Novel bifunctional natriuretic peptides as potential therapeutics. J Biol Chem 2008; 283:35003–9.