Sacubitril/valsartan (LCZ696) is superior to enalapril in heart failure with reduced ejection fraction. Sacubitril's beneficial hemodynamic effects arise from inhibition of which enzyme?

• A Angiotensin-converting enzyme (ACE), preventing angiotensin II formation
• B Neprilysin (neutral endopeptidase), preventing degradation of natriuretic peptides, bradykinin, and adrenomedullin ✓
• C Chymase, an alternative pathway for angiotensin II synthesis in cardiac tissue
• D Aldosterone synthase (CYP11B2), directly reducing aldosterone production

Explanation

Sacubitril is a prodrug converted to LBQ657, which inhibits neprilysin — a neutral endopeptidase that degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, substance P, and adrenomedullin. Neprilysin inhibition increases levels of these vasoactive peptides, producing natriuresis, vasodilation, and reduced cardiac fibrosis/remodelling. Combined with valsartan (ARB), the dual mechanism (ARNI) prevents the angioedema that occurs with combined ACE inhibition + neprilysin inhibition (due to bradykinin accumulation). Chymase inhibition and aldosterone synthase inhibition are not sacubitril's mechanisms.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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