Natriuretic Peptides
The cardiac and vascular peptide family centered on atrial natriuretic peptide (ANP, de Bold 1981), B-type natriuretic peptide (BNP, Sudoh 1988), and C-type natriuretic peptide (CNP, Sudoh 1990) — the endogenous regulators of vascular tone, sodium balance, and fluid homeostasis. Plus nesiritide (recombinant BNP, FDA-approved 2001 for acute heart failure) and the related vascular peptide adrenomedullin.
Natriuretic peptides are a family of cardiovascular and vascular peptide hormones that regulate vascular tone, sodium balance, and fluid homeostasis through a shared family of guanylyl-cyclase-coupled receptors. The discovery story was led by Adolfo de Bold's seminal 1981 Life Sciences paper (PMID 7219045) reporting that intravenous injection of atrial myocardial extract in rats produced rapid and potent natriuresis — establishing the heart as an endocrine organ and identifying atrial natriuretic peptide (ANP) as the active factor. Tomoyuki Sudoh, Hisayuki Matsuo, and Kenji Kangawa at the National Cardiovascular Center in Osaka extended the family with the 1988 Nature paper on B-type natriuretic peptide (BNP, originally 'brain natriuretic peptide,' isolated from porcine brain but predominantly produced by ventricular cardiomyocytes; PMID 2964562) and the 1990 BBRC paper on C-type natriuretic peptide (CNP, with predominantly vascular and bone-growth-plate roles; PMID 2139780). The family signals through three transmembrane guanylyl-cyclase-A and guanylyl-cyclase-B receptors (NPR-A, NPR-B) plus the clearance receptor NPR-C, producing cGMP-mediated vasodilation, natriuresis, diuresis, and antifibrotic effects.
Clinically, the family has produced one approved therapeutic (nesiritide, recombinant BNP) and one major drug class targeting the natriuretic peptide system from a different angle (sacubitril/valsartan, the angiotensin receptor-neprilysin inhibitor combination that prolongs endogenous BNP and ANP lifetime by inhibiting the degrading enzyme neprilysin). The diagnostic value of plasma BNP and NT-proBNP measurement in heart failure has become a core element of cardiology practice — BNP is one of the most-used biomarkers in modern cardiology. Adrenomedullin sits adjacent to but separately from the natriuretic peptide family — a 52-residue vascular peptide with vasodilatory and other cardiovascular effects, often discussed alongside the natriuretic peptide system because of overlapping clinical territory.
This page is the family-level pillar covering the natriuretic peptide system as a whole. For individual peptide pages with full evidence ratings, dosing, and references, follow the links to each member below.
Peptides in Natriuretic Peptides
Adrenomedullin
Vasoactive peptide
An endogenous 52-amino-acid vasodilator peptide of the CGRP/calcitonin family, isolated in 1993 by Kitamura and colleagues from human pheochromocytoma tissue, signaling through the calcitonin-receptor-like receptor (CLR) coupled with RAMP2 or RAMP3 to regulate vascular tone, endothelial barrier integrity, and cardio-renal physiology — and the source of two clinically meaningful therapeutic angles: MR-proADM as a sepsis and cardiovascular biomarker, and the anti-AM monoclonal antibody enibarcimab (formerly adrecizumab) as an investigational sepsis therapeutic.
BNP
Natriuretic Peptide
An endogenous 32-amino-acid cardiac hormone secreted primarily by ventricular myocytes in response to wall stretch — the dominant natriuretic peptide in clinical practice and the basis of the BNP and NT-proBNP assays used worldwide for heart failure diagnosis, risk stratification, and management.
C-Type Natriuretic Peptide
Natriuretic Peptide
An endogenous 22-amino-acid peptide identified in 1990 by Sudoh, Minamino, Kangawa, and Matsuo as the third member of the natriuretic peptide family. Unlike ANP and BNP, CNP is predominantly endothelial and chondrocytic rather than cardiac, signals through NPR-B (not NPR-A), and is the master driver of endochondral long-bone growth — the biology that vosoritide (Voxzogo) was engineered to mimic for achondroplasia.
Vosoritide
CNP Analog
A modified C-type natriuretic peptide analog developed by BioMarin Pharmaceutical, FDA-approved as Voxzogo for children with achondroplasia. The first targeted pharmacological treatment for the most common form of genetic short stature.
ANP
Natriuretic Peptide
An endogenous 28-amino-acid cardiac hormone secreted by atrial myocytes in response to wall stretch; drives natriuresis, vasodilation, and renin-aldosterone suppression. Approved in Japan as carperitide (recombinant human ANP) for acute decompensated heart failure since 1995, but never FDA-approved in the United States.
Nesiritide
Recombinant Natriuretic Peptide
An FDA-approved (August 2001) recombinant human B-type natriuretic peptide given as an IV bolus and infusion for short-term symptom relief in acute decompensated heart failure. After the 2005 Sackner-Bernstein safety controversy and the largely neutral 2011 ASCEND-HF trial, nesiritide use collapsed and the drug is now rarely used in contemporary practice despite remaining nominally on-market.
Other members of the class
NT-proBNP (N-terminal pro-B-type natriuretic peptide)
The cleavage byproduct of proBNP processing — measured in plasma alongside BNP as a heart failure biomarker. Longer half-life than active BNP, which makes it the preferred laboratory measurement in many clinical contexts.
Sacubitril/valsartan (Entresto)
Angiotensin receptor-neprilysin inhibitor combining sacubitril (which inhibits neprilysin and prolongs endogenous ANP/BNP lifetime) with valsartan (an angiotensin receptor blocker). FDA-approved 2015 for HFrEF based on PARADIGM-HF trial. Targets the natriuretic peptide system from a different angle than direct administration.
Vosoritide (Voxzogo, BioMarin)
CNP analog FDA-approved 2021 for achondroplasia in children — addresses FGFR3-mutation-driven dwarfism by activating the CNP/NPR-B/cGMP pathway in growth plates. Tracked separately at /peptides/vosoritide.
Urodilatin
A kidney-derived ANP-like peptide (ANP 95-126) characterized in the 1980s. Predominantly renal in distribution. Studied as ularitide in heart failure trials without producing approved clinical use.
Carperitide (Carperitide / hANP)
Recombinant human ANP, approved in Japan since 1995 for acute decompensated heart failure. Not FDA-approved in the U.S.
Shared mechanism
The natriuretic peptide family signals through transmembrane guanylyl-cyclase-coupled receptors that produce cGMP as the second messenger. NPR-A (natriuretic peptide receptor A) is the principal receptor for ANP and BNP, with downstream cGMP-mediated effects including vasodilation (via cGMP-dependent protein kinase activation in vascular smooth muscle), natriuresis (via inhibition of sodium reabsorption in renal collecting ducts and inner medullary collecting duct), diuresis (via renal hemodynamic changes), suppression of renin and aldosterone secretion, and antifibrotic and antihypertrophic effects in cardiomyocytes. NPR-B is the principal receptor for CNP, with predominantly vascular endothelial, bone growth plate, and central nervous system effects rather than the cardiac/renal/diuretic profile of NPR-A. NPR-C is a clearance receptor that internalizes and degrades natriuretic peptides without producing signaling — important for plasma half-life regulation. Neprilysin (membrane metalloendopeptidase, NEP) is the principal enzyme degrading natriuretic peptides through enzymatic cleavage; neprilysin inhibition (sacubitril) prolongs endogenous natriuretic peptide lifetime.
The physiological role of the family is regulating vascular tone, sodium and water balance, and fluid homeostasis in response to atrial and ventricular wall stretch (heart filling pressure). Increased preload (from intravascular volume excess or heart failure) stretches the atrial and ventricular cardiomyocytes, triggering ANP and BNP release. The released peptides act on vascular smooth muscle (vasodilation, lower blood pressure), kidney (sodium and water excretion), and the renin-angiotensin-aldosterone system (suppression). The integrated effect lowers preload and corrects volume excess. Loss of natriuretic-peptide signaling (impaired in heart failure and other cardiovascular pathology) contributes to volume retention, hypertension, and disease progression.
Clinical effects across the class span: vasodilation and natriuresis (relevant to acute decompensated heart failure — the basis of nesiritide's approved indication); plasma BNP and NT-proBNP measurement as the cardiology biomarker of choice for heart failure (BNP rises in proportion to ventricular wall stress); CNP-targeting for achondroplasia bone growth (vosoritide); and the broader natriuretic-peptide-system approach via neprilysin inhibition (sacubitril/valsartan) which has become standard-of-care for HFrEF (heart failure with reduced ejection fraction).
History & discovery
The natriuretic peptide story begins with Adolfo de Bold's group at the University of Ottawa in the late 1970s. de Bold had observed that atrial cardiomyocytes contained dense secretory granules of unknown function — anatomically resembling the secretory granules of established endocrine cells, but not fitting any then-known cardiac function. The seminal 1981 Life Sciences paper (de Bold AJ et al., 'A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats,' PMID 7219045) reported that injected atrial extract produced rapid and substantial natriuresis — establishing the heart as an endocrine organ, defining atrial natriuretic factor (later renamed atrial natriuretic peptide, ANP) as the active principle, and changing the conceptual framework for cardiovascular regulation. Subsequent work characterized ANP as a 28-residue peptide cleaved from a 126-residue prepro-ANP precursor, predominantly produced by atrial cardiomyocytes in response to atrial wall stretch, with effects on vascular tone, renal sodium handling, and fluid balance through the natriuretic-peptide-receptor-A (NPR-A) cGMP signaling pathway.
B-type natriuretic peptide (BNP) emerged from the work of Tomoyuki Sudoh, Hisayuki Matsuo, and Kenji Kangawa at the National Cardiovascular Center in Osaka — the same group that would go on to discover ghrelin, neuromedin U, and other landmark peptides. The 1988 Nature paper (Sudoh T et al., 'A new natriuretic peptide in porcine brain,' PMID 2964562) reported isolation of a 32-residue peptide initially named for its brain origin but subsequently recognized as predominantly produced by ventricular cardiomyocytes in response to ventricular wall stretch and overload. BNP shares the natriuretic-peptide structural fold (a 17-amino-acid disulfide-bonded ring with N- and C-terminal tails) and binds the same NPR-A receptor as ANP, but is more strongly induced in heart failure — the basis for plasma BNP and NT-proBNP measurement as the principal cardiac biomarker for heart failure diagnosis, severity grading, and prognosis. Plasma NT-proBNP measurement is now a routine cardiology investigation.
C-type natriuretic peptide (CNP) was reported by the same Osaka group in 1990 (Sudoh T et al., BBRC 1990, PMID 2139780). CNP differs from ANP and BNP in tissue distribution — predominantly vascular endothelium, bone growth plate cartilage, and central nervous system rather than cardiac — and binds the natriuretic-peptide-receptor-B (NPR-B) rather than NPR-A. The clinical relevance of CNP is most prominent in skeletal biology — CNP signaling at bone growth plates regulates endochondral ossification, and CNP analogs (vosoritide, BioMarin, FDA-approved 2021 as Voxzogo) have been developed for achondroplasia (FGFR3-mutation-driven dwarfism). The family was further extended by D-type natriuretic peptide (DNP), urodilatin (a kidney-derived ANP-like peptide), and other related peptides with more restricted clinical roles.
The therapeutic translation has produced one principal natriuretic-peptide drug — nesiritide (Natrecor, Scios/Johnson & Johnson, FDA-approved 2001), the recombinant form of human BNP, used for acute decompensated heart failure as an intravenous vasodilator. Nesiritide had a complicated clinical history including the ASCEND-HF trial that did not demonstrate mortality benefit and led to declining clinical use, but it remains FDA-approved and commercially available. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (Entresto, FDA-approved 2015 based on PARADIGM-HF) targets the natriuretic peptide system from a different angle — neprilysin is the principal enzyme degrading ANP and BNP, so neprilysin inhibition prolongs the endogenous natriuretic-peptide signal while the angiotensin-receptor-blocker component addresses the renin-angiotensin axis. Entresto has become a transformative heart failure therapy. Vosoritide (CNP analog, BioMarin) FDA-approved 2021 as Voxzogo for achondroplasia represents the CNP-targeting branch.
Adrenomedullin sits adjacent to the natriuretic peptide system — discovered in 1993 by Kazuo Kitamura and colleagues as a 52-residue peptide from human pheochromocytoma tissue, with vasodilatory and other cardiovascular effects through CALCRL-RAMP receptor complexes. Adrenomedullin is often discussed alongside the natriuretic peptides because of overlapping clinical territory in heart failure and shock, and because plasma proAdrenomedullin (MR-proADM) has emerged as a complementary cardiovascular biomarker.
State of evidence
Evidence in this family is asymmetric. The diagnostic side (BNP and NT-proBNP measurement for heart failure) has extensive multi-decade validation and is part of standard cardiology practice — one of the most-used cardiac biomarkers in modern medicine. The therapeutic side has produced one direct natriuretic peptide drug (nesiritide) with mixed long-term clinical translation, plus the broader sacubitril/valsartan approach via neprilysin inhibition that has become transformative for HFrEF. Vosoritide (CNP analog) for achondroplasia is FDA-approved with Phase 3 evidence. Adrenomedullin diagnostic measurement has emerging clinical roles.
The principal known concerns: nesiritide's clinical track record is mixed — early enthusiasm based on hemodynamic effects and the ASCEND-HF trial that did not demonstrate mortality benefit; renal function concerns that emerged in some smaller analyses; and declining clinical use in favor of standard-of-care vasodilators (nitroglycerin, nitroprusside) for acute decompensated heart failure. The class is fundamentally defined by the diagnostic role of BNP and NT-proBNP measurement plus the broader system-level intervention via sacubitril/valsartan, rather than by direct natriuretic peptide drug administration.
How members compare
Within the family, the principal axes are receptor target (NPR-A for ANP/BNP/nesiritide vs NPR-B for CNP/vosoritide) and clinical application (acute heart failure for nesiritide vs achondroplasia for vosoritide vs diagnostic biomarker for plasma BNP/NT-proBNP measurement vs system-level intervention via sacubitril/valsartan for chronic HFrEF).
Outside the natriuretic peptide family, the closest comparators in heart failure are: standard vasodilators (nitroglycerin, nitroprusside, hydralazine) for acute decompensation; loop diuretics (furosemide, bumetanide, torsemide) for volume management; SGLT2 inhibitors (dapagliflozin, empagliflozin) which have emerged as transformative for HFrEF and HFpEF; ACE inhibitors and ARBs for the renin-angiotensin axis; beta-blockers for sympathetic axis; mineralocorticoid receptor antagonists (spironolactone, eplerenone, finerenone). The natriuretic peptide system is one piece of the integrated pharmacological approach to heart failure, with sacubitril/valsartan now positioned as standard quadruple therapy for HFrEF alongside SGLT2i, beta-blocker, and MRA.
Frequently asked questions
Why is BNP measured in heart failure?
BNP and NT-proBNP measurement is the principal cardiac biomarker for heart failure diagnosis, severity, and prognosis. Ventricular cardiomyocytes secrete BNP in proportion to ventricular wall stress (preload and afterload), so elevated plasma BNP reflects elevated cardiac filling pressures — the hallmark of heart failure. NT-proBNP is the cleavage byproduct of proBNP processing with a longer plasma half-life than active BNP, making it the preferred laboratory measurement in many contexts. Plasma BNP/NT-proBNP cut-points (typically <100 pg/mL for BNP or <300 pg/mL for NT-proBNP suggesting heart failure is unlikely; higher values supporting the diagnosis) are part of standard heart failure diagnostic algorithms in emergency departments and outpatient cardiology. Levels also correlate with prognosis and treatment response.
What is nesiritide and is it still used?
Nesiritide (Natrecor, Johnson & Johnson) is recombinant human BNP, FDA-approved 2001 for acute decompensated heart failure as an intravenous vasodilator. It produces vasodilation, natriuresis, and (theoretically) clinical improvement in acute heart failure presentations. The clinical track record has been mixed — initial enthusiasm based on hemodynamic effects, the ASCEND-HF trial (2011, ~7,000 patients) that did not demonstrate mortality benefit, and emerging renal-function concerns in some analyses. Clinical use has declined substantially since the early 2000s, with many institutions favoring standard intravenous vasodilators (nitroglycerin, nitroprusside) for acute decompensated heart failure. Nesiritide remains FDA-approved and commercially available but is not first-line in modern acute heart failure management.
How does sacubitril/valsartan (Entresto) relate to natriuretic peptides?
Sacubitril/valsartan (Entresto, FDA-approved 2015 based on PARADIGM-HF) targets the natriuretic peptide system from a different angle than direct natriuretic peptide administration. Sacubitril inhibits neprilysin — the principal enzyme degrading ANP and BNP — prolonging the endogenous natriuretic peptide signal in plasma. The valsartan component is an angiotensin receptor blocker addressing the renin-angiotensin axis. The combination produces both natriuretic peptide system enhancement (through neprilysin inhibition) and renin-angiotensin axis blockade — a dual mechanism that proved superior to enalapril alone in PARADIGM-HF for HFrEF mortality. Entresto has become a foundational HFrEF therapy alongside SGLT2 inhibitors, beta-blockers, and mineralocorticoid receptor antagonists.
What is CNP used for clinically?
CNP (C-type natriuretic peptide) signals primarily through NPR-B with predominantly vascular endothelial, bone growth plate, and central nervous system effects — distinct from the cardiac/renal/diuretic profile of ANP and BNP. The clinical translation of CNP has produced vosoritide (Voxzogo, BioMarin, FDA-approved 2021), a CNP analog used in children with achondroplasia (FGFR3-mutation-driven dwarfism) to enhance endochondral ossification and increase growth velocity. Vosoritide acts at NPR-B in growth plate chondrocytes, opposing the FGFR3-driven inhibition of bone growth. It is the principal disease-modifying therapy for achondroplasia. CNP itself is not used directly as a clinical agent.
Are natriuretic peptides used for hypertension treatment?
Direct natriuretic peptide drugs are not standard antihypertensive therapy. Nesiritide is reserved for acute decompensated heart failure rather than chronic hypertension. The natriuretic peptide system is targeted indirectly in chronic hypertension and HFrEF through sacubitril/valsartan (Entresto), which prolongs endogenous natriuretic peptide signaling via neprilysin inhibition while also blocking the angiotensin receptor. The standard antihypertensive drug classes — ACE inhibitors, ARBs, calcium channel blockers, thiazide diuretics, beta-blockers — work through other axes. The natriuretic peptide system is one of several integrated regulatory pathways in cardiovascular homeostasis, with the system-level neprilysin-inhibition approach (Entresto) being the dominant clinical translation rather than direct ANP/BNP administration.
References
- A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in ratsOriginal Research
de Bold AJ, Borenstein HB, Veress AT, and Sonnenberg H, Life Sciences 1981. The discovery paper establishing the heart as an endocrine organ — atrial myocardial extract injection produced rapid and substantial natriuresis in rats, identifying atrial natriuretic peptide (ANP) as the active factor. Foundational paper of the natriuretic peptide family.
- A new natriuretic peptide in porcine brainOriginal Research
Sudoh T, Kangawa K, Minamino N, and Matsuo H, Nature 1988. The discovery of B-type natriuretic peptide (BNP) — initially isolated from porcine brain (hence the name) but subsequently recognized as predominantly produced by ventricular cardiomyocytes. The basis for plasma BNP and NT-proBNP measurement as the modern cardiac biomarker for heart failure.
- C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brainOriginal Research
Sudoh T, Minamino N, Kangawa K, and Matsuo H, Biochemical and Biophysical Research Communications 1990. The discovery of C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family. CNP signals through NPR-B and has predominantly vascular endothelial and bone growth plate effects — the basis for vosoritide's achondroplasia indication.