What is neprilysin?

What is Neprilysin?

Neprilysin is a zinc-dependent metalloprotease enzyme (also called neutral endopeptidase) that degrades multiple vasoactive peptides in the body, playing a critical role in cardiovascular regulation—its inhibition forms the basis of modern heart failure therapy with drugs like sacubitril/valsartan. 1

Biochemical Structure and Function

• Neprilysin is a cell surface metallo-endopeptidase that cleaves a wide variety of peptide substrates throughout multiple organ systems 2
• It functions as a zinc-dependent enzyme, requiring this metal cofactor for its catalytic activity 1
• The enzyme is expressed broadly across cardiovascular, renal, pulmonary, gastrointestinal, endocrine, and neurologic tissues 1, 3

Key Peptide Substrates

Vasodilatory Peptides (Degraded by Neprilysin)

• Natriuretic peptides (BNP, ANP, NT-proBNP): Critical for sodium excretion, vasodilation, and volume regulation 1, 4
• Bradykinin: Promotes vasodilation and has cardioprotective effects 1, 5
• Adrenomedullin: Vasodilatory peptide important in heart failure pathophysiology 1, 6
• Substance P: Involved in vasodilation and inflammatory responses 1, 5

Vasoconstrictor Peptides (Also Degraded by Neprilysin)

• Angiotensin I and II: Key components of the renin-angiotensin system 1, 4
• Endothelin-1: Potent vasoconstrictor peptide 5, 3

This dual action on both vasodilatory and vasoconstrictor peptides explains why neprilysin inhibition alone was initially unsuccessful—blocking the enzyme raises angiotensin II levels, which counteracts the beneficial effects 1

Clinical Significance in Heart Failure

• In heart failure, increased neprilysin activity enhances degradation of beneficial natriuretic peptides, worsening the disease state 2
• The enzyme inactivates peptides that have important roles in the pathogenesis and progression of heart failure 1
• Inhibiting neprilysin increases circulating levels of natriuretic peptides, leading to improved natriuresis, vasodilation, and reduced cardiac remodeling 1, 4

Therapeutic Application: The ARNI Concept

• Because angiotensin II is also a neprilysin substrate, neprilysin inhibitors must be combined with angiotensin receptor blockers (ARBs) to prevent harmful angiotensin II accumulation 1
• Neprilysin inhibitors cannot be combined with ACE inhibitors due to excessive bradykinin accumulation, causing unacceptably high rates of angioedema 1
• The combination drug sacubitril/valsartan (an ARNI) pairs neprilysin inhibition with ARB therapy, achieving superior outcomes in heart failure with reduced ejection fraction compared to enalapril alone 1, 6

Important Clinical Caveats

• A 36-hour washout period is mandatory when switching between ACE inhibitors and neprilysin inhibitors to minimize angioedema risk 1
• Patients with a history of angioedema should never receive neprilysin inhibitors 1
• The failed drug omapatrilat (combined ACE and neprilysin inhibitor) demonstrated a 3-fold increased angioedema risk, particularly in Black patients and smokers, leading to termination of its development 1

Effect on Biomarker Interpretation

• NT-proBNP is not metabolized by neprilysin, so it remains a reliable biomarker during ARNI therapy 1, 7
• BNP levels increase during neprilysin inhibition because the enzyme can no longer degrade it—BNP may rise by an average of 19%, with some patients experiencing doubling or tripling of levels 1, 7
• The American College of Cardiology recommends preferring NT-proBNP over BNP for clinical follow-up in ARNI-treated patients, especially during the first 8-10 weeks of treatment 7
• Despite the artificial elevation, BNP maintains prognostic value during ARNI treatment, and sustained longitudinal increases still predict adverse events 7