Mechanism of action of angiotensin receptor-neprilysin inhibitor​

Neprilysin, a neutral endopeptidase, degrades vasoactive neurohormones including natriuretic peptides, bradykinin, and adrenomedullin. Neprilysin also degrades angiotensin II. When a pure neprilysin inhibitor is administered, it prevents the degradation of these peptides, leading to an increase in the neurohormones that exert favorable effects (eg, natriuretic peptides) but also an increase in angiotensin II, which exerts detrimental effects. The up arrows depict the increase in angiotensin II levels resulting from neprilysin inhibition. In order to mitigate the effects of elevated angiotensin II levels, a strategy has emerged to combine a neprilysin inhibitor with an angiotensin receptor blocker. This class of agents is called ARNI, an abbreviation for angiotensin receptor-neprilysin inhibitor. In this manner, the deleterious effect of increased angiotensin II levels is prevented by preventing angiotensin II from interacting with its type 1 receptor, while the favorable effects of neprlysin inhibition can accrue. Because both neprilysin inhibitors and ACE inhibitors increase bradykinin, and bradykinin leads to angioedema, administration of a neprilysin inhibitor within 36 hours of administration of an ACE inhibitor is contraindicated, as this combination can result in an unacceptably high incidence of angioedema.