Natriuretic peptides (NPs) are a family of hormones that play a critical role in the regulation of blood pressure, fluid balance, and sodium homeostasis. They are produced in the heart and other tissues in response to changes in blood volume or pressure. The three major types of natriuretic peptides include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These peptides act via specific receptors to promote natriuresis (excretion of sodium), diuresis, and vasodilation, and they inhibit the renin-angiotensin-aldosterone system (RAAS).

Types of Natriuretic Peptides:

1. Atrial Natriuretic Peptide (ANP):

• Source: Secreted mainly by atrial myocytes in the heart in response to atrial stretch, which occurs when blood volume or pressure is elevated.
• Physiological Effects:
  • Natriuresis and Diuresis: ANP promotes the excretion of sodium and water by the kidneys, reducing blood volume.
  • Vasodilation: ANP causes relaxation of vascular smooth muscle, leading to a decrease in peripheral vascular resistance and blood pressure.
  • Inhibition of RAAS: It reduces renin and aldosterone secretion, further contributing to sodium and water excretion.
  • Decreased Sympathetic Activity: ANP inhibits sympathetic nervous system activity, leading to further vasodilation and reduced blood pressure.
• Receptor: ANP primarily acts through the NPR-A receptor (Natriuretic Peptide Receptor A), which has guanylate cyclase activity, leading to increased production of cyclic guanosine monophosphate (cGMP).

2. Brain Natriuretic Peptide (BNP):

   • Source: Despite the name, BNP is predominantly secreted by the ventricles of the heart, particularly in response to ventricular stretch and volume overload, such as in heart failure.
   • Physiological Effects:
     • BNP shares many of the same actions as ANP, including promoting natriuresis, diuresis, and vasodilation.
     • BNP has a longer half-life compared to ANP and is considered a more stable biomarker for diagnosing heart failure.
   • Receptor: Like ANP, BNP also acts through the NPR-A receptor, leading to increased cGMP levels.

3. C-type Natriuretic Peptide (CNP):

   • Source: CNP is produced by endothelial cells and has a more localized effect compared to ANP and BNP.
   • Physiological Effects:
     • CNP primarily acts as a vasodilator, but unlike ANP and BNP, it does not have significant natriuretic or diuretic effects.
     • It plays a role in regulating vascular tone and inhibiting smooth muscle proliferation.
   • Receptor: CNP acts via the NPR-B receptor (Natriuretic Peptide Receptor B), which also activates guanylate cyclase to increase cGMP levels.

Mechanism of Action:

Natriuretic peptides exert their effects by binding to specific receptors (NPR-A, NPR-B, and NPR-C) on the surface of target cells. The activation of these receptors stimulates guanylate cyclase, which converts GTP to cGMP. The increased intracellular cGMP leads to several downstream effects, including:

• Vasodilation: Relaxation of vascular smooth muscle cells.
• Natriuresis and Diuresis: Increased sodium and water excretion by the kidneys, primarily by increasing glomerular filtration rate (GFR) and inhibiting sodium reabsorption in the renal tubules.
• Inhibition of RAAS: Reduced renin release from the kidneys and aldosterone secretion from the adrenal glands, leading to decreased sodium retention.
• Anti-fibrotic and Anti-hypertrophic Effects: Natriuretic peptides inhibit the growth of cardiac fibroblasts and prevent pathological cardiac remodeling, particularly in conditions like heart failure.

Clinical Significance:

1. Heart Failure:

   • BNP and NT-proBNP (N-terminal pro-brain natriuretic peptide): These are commonly used biomarkers for diagnosing and managing heart failure. Elevated BNP or NT-proBNP levels correlate with increased ventricular pressure and volume overload, making them valuable tools in assessing the severity of heart failure.
   • BNP levels are used for:
     • Diagnosis: Elevated levels in the blood indicate heart failure or ventricular dysfunction.
     • Prognosis: Higher BNP levels are associated with worse outcomes in heart failure patients.
     • Monitoring: BNP levels are useful for tracking the effectiveness of heart failure therapies, as they decrease with successful treatment.

2. Hypertension:

   • ANP and BNP play a role in lowering blood pressure by promoting vasodilation and natriuresis. Although their endogenous effects are limited in chronic hypertension, they offer a protective role against high blood pressure.

3. Renal Disorders:

   • Natriuretic peptides influence kidney function by increasing the GFR and reducing sodium reabsorption. In patients with chronic kidney disease, the kidney’s ability to respond to natriuretic peptides may be impaired, contributing to volume overload and hypertension.

4. Therapeutic Use:

   • Nesiritide: Recombinant human BNP (nesiritide) has been used for the treatment of acute decompensated heart failure. It mimics the effects of BNP by promoting vasodilation, natriuresis, and diuresis, though its routine use has declined due to mixed efficacy results.

Pathophysiology in Heart Failure:

In heart failure, the ventricles are stretched due to increased pressure and volume. This leads to an increased secretion of BNP as a compensatory mechanism to reduce the load on the heart by promoting natriuresis, diuresis, and vasodilation. However, chronic heart failure often leads to a state of resistance to the effects of natriuretic peptides, where despite elevated levels, the body’s response to these hormones diminishes.

Natriuretic Peptide Clearance:

Natriuretic peptides are cleared from circulation via two mechanisms:

1. Binding to NPR-C receptors: These receptors act as clearance receptors, binding to natriuretic peptides and internalizing them for degradation.
2. Enzymatic degradation by neprilysin: Neprilysin is a neutral endopeptidase that degrades natriuretic peptides. Inhibiting neprilysin (e.g., with drugs like sacubitril in combination with valsartan) increases natriuretic peptide levels and enhances their beneficial effects in conditions like heart failure.

Summary Table

Natriuretic Peptide	Source	Main Effects	Receptors	Clinical Use
ANP	Atrial myocytes	Natriuresis, vasodilation, RAAS inhibition	NPR-A	Not commonly measured clinically
BNP	Ventricular myocytes	Natriuresis, vasodilation, RAAS inhibition	NPR-A	Biomarker for heart failure diagnosis/prognosis
CNP	Endothelial cells	Vasodilation, inhibition of smooth muscle proliferation	NPR-B	Research and experimental therapeutics

BNP vs. NT-proBNP

B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are both biomarkers used to evaluate heart failure. These peptides are released in response to ventricular wall stress, typically due to increased pressure or volume overload. Both are derived from the same precursor molecule, but they differ in structure, half-life, and clinical utility.

Structure and Formation:

1. BNP:

   • BNP is an active 32-amino acid hormone produced in the ventricles of the heart.
   • It is released when the heart muscles are stretched, particularly under conditions such as heart failure or increased ventricular pressure.
   • BNP has vasodilatory, natriuretic, and diuretic effects, promoting sodium and water excretion and lowering blood pressure.

2. NT-proBNP:

   • NT-proBNP is an inactive fragment consisting of 76 amino acids, produced from the cleavage of proBNP (the precursor molecule of BNP).
   • Unlike BNP, NT-proBNP has no biological activity but serves as a reliable marker of heart failure because its levels correlate closely with those of BNP.

Both BNP and NT-proBNP are secreted in equimolar amounts when the precursor proBNP is cleaved. However, they differ significantly in terms of half-life and clearance.

Half-Life and Stability:

1. BNP:
   • BNP has a relatively short half-life of approximately 20 minutes.
   • It is rapidly cleared from the circulation through binding to natriuretic peptide receptors and enzymatic degradation, primarily by neprilysin.
2. NT-proBNP:
   • NT-proBNP has a longer half-life of approximately 60-120 minutes.
   • It is cleared from the blood primarily by the kidneys, making it more stable and more likely to accumulate in renal dysfunction.

Clinical Utility:

Both BNP and NT-proBNP are used for diagnosing and managing heart failure, but some differences make one preferable over the other in certain clinical contexts.

1. BNP:

   • Active Hormone: Since BNP is biologically active, it is directly involved in reducing blood pressure, increasing sodium excretion, and promoting diuresis.
   • Short Half-Life: The short half-life of BNP allows it to reflect real-time changes in heart failure status. BNP levels respond more rapidly to changes in ventricular pressure and volume overload, which can be useful for acute heart failure assessment.
   • Influence of Factors: BNP levels can be affected by body mass index (BMI), age, and renal function. Obese individuals tend to have lower BNP levels, while older adults or patients with impaired renal function tend to have higher levels.

2. NT-proBNP:

   • Longer Half-Life and Stability: Due to its longer half-life, NT-proBNP provides more stable and reliable readings, particularly in chronic heart failure patients. It is less affected by rapid hemodynamic changes compared to BNP.
   • Better for Renal Dysfunction: Since NT-proBNP is cleared primarily by the kidneys, its levels are higher in patients with renal impairment. This makes NT-proBNP a more reliable marker in chronic heart failure, although care must be taken in patients with advanced chronic kidney disease.
   • Less Affected by BMI: NT-proBNP is less influenced by obesity compared to BNP, making it more accurate in assessing heart failure in overweight or obese patients.

Diagnostic Thresholds:

1. BNP Diagnostic Thresholds for Heart Failure:

   • <100 pg/mL: Heart failure is unlikely.
   • 100-400 pg/mL: Consider heart failure, particularly if other clinical signs and symptoms are present.
   • >400 pg/mL: Heart failure is likely.

2. NT-proBNP Diagnostic Thresholds for Heart Failure:

   • <300 pg/mL: Heart failure is unlikely.
   • Age-specific cutoffs:
     • <50 years: >450 pg/mL suggests heart failure.
     • 50-75 years: >900 pg/mL suggests heart failure.
     • >75 years: >1800 pg/mL suggests heart failure.

NT-proBNP values are typically higher than BNP values due to the longer half-life and slower clearance of NT-proBNP.

Clinical Considerations:

1. Use in Acute vs. Chronic Heart Failure:

   • BNP is often favored in acute heart failure due to its shorter half-life and rapid response to treatment. It is sensitive to changes in heart failure status, making it useful for monitoring acute decompensation.
   • NT-proBNP is more commonly used in chronic heart failure due to its stability and the fact that it is less influenced by rapid hemodynamic changes. It also provides better diagnostic utility in older patients and those with renal dysfunction.

2. Impact of Renal Function:

   • BNP levels tend to be less affected by renal dysfunction, although very high levels of BNP may still occur in advanced kidney disease.
   • NT-proBNP is significantly influenced by renal function because it is cleared by the kidneys. As renal function declines, NT-proBNP levels increase, even in the absence of worsening heart failure. This requires careful interpretation in patients with chronic kidney disease.

3. Use in Obesity:

   • BNP levels are typically lower in obese patients, possibly due to increased clearance or reduced production. This can lead to underestimation of heart failure severity in obese individuals.
   • NT-proBNP is less affected by BMI and may provide a more accurate diagnosis of heart failure in obese patients.

BNP and NT-proBNP in Monitoring Heart Failure:

Both BNP and NT-proBNP are used not only for diagnosis but also for monitoring the progression of heart failure and response to therapy. As patients receive treatment, falling levels of BNP or NT-proBNP are associated with improved outcomes, whereas persistently elevated levels may indicate poor prognosis or worsening heart failure.

Summary Table: BNP vs. NT-proBNP

Characteristic	BNP	NT-proBNP
Structure	Active 32-amino acid hormone	Inactive 76-amino acid fragment
Biological Activity	Biologically active	Biologically inactive
Half-Life	~20 minutes	~60-120 minutes
Clearance	Cleared by natriuretic peptide receptors, neprilysin	Cleared primarily by kidneys
Diagnostic Use	Acute heart failure	Chronic heart failure, renal dysfunction
Influence of Renal Function	Less influenced by renal dysfunction	Significantly influenced by renal dysfunction
Influence of BMI	Affected by obesity (lower levels in obese patients)	Less affected by obesity
Diagnostic Threshold	<100 pg/mL (unlikely heart failure), >400 pg/mL (likely heart failure)	<300 pg/mL (unlikely heart failure), >450-1800 pg/mL (age-specific thresholds)
Use in Clinical Practice	More commonly used in acute settings	More stable for chronic monitoring

Conclusion:

BNP and NT-proBNP are both valuable biomarkers for diagnosing and managing heart failure, each with distinct advantages depending on the clinical context. BNP is more useful in acute heart failure due to its shorter half-life and rapid response to changes, while NT-proBNP is preferred for chronic heart failure assessment because of its stability and reliability. Both markers provide critical insights into disease severity and prognosis, helping guide therapeutic decisions and improving patient outcomes.