The PARADIGM-HF trial established sacubitril/valsartan (ARNI) as superior to enalapril in HFrEF. The primary mechanism by which sacubitril provides benefit BEYOND ACE inhibition is:

• A Neprilysin inhibition augmenting natriuretic peptide levels (ANP/BNP/CNP) promoting natriuresis and vasodilation ✓
• B Direct bradykinin accumulation causing additional vasodilatation
• C Angiotensin II receptor blockade at AT2 receptors promoting vasoconstriction
• D Direct inhibition of aldosterone synthesis in the adrenal cortex

Explanation

Sacubitril is a prodrug converted to LBQ657 (active neprilysin inhibitor). Neprilysin degrades natriuretic peptides (ANP, BNP, CNP), adrenomedullin, bradykinin, and angiotensin II. Neprilysin inhibition augments endogenous natriuretic peptide (especially ANP, CNP) levels, promoting diuresis, natriuresis, vasodilation, and cardiomyocyte anti-fibrotic/anti-hypertrophic effects. The valsartan component blocks AT1 receptor and also prevents excessive angiotensin II accumulation from neprilysin inhibition. Bradykinin augmentation is a partial contribution but NP augmentation is the primary mechanism.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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Written and medically reviewed by the StethoPrep medical team.