Neprilysin is a zinc metallopeptidase with catalytic similarity to ACE and with a wide tissue distribution, although abundant at the proximal tubule brush border. Several pharmacologic neprilysin inhibitors have been investigated (e.g., candoxatril, thiorphan, and phosphoramidon). Although these agents, in general, lead to an increase in plasma levels of the NPs and, under some experimental conditions, induce natriuresis and diuresis with peripheral vasodilation, results of clinical trials in hypertension and heart failure have generally been disappointing.
Specifically, sustained antihypertensive effects have not been demonstrated, and some researchers have reported a paradoxical rise in blood pressure. This may be a consequence of the induction of both neprilysin and ACE expression with neprilysin inhibition and a consequent increase in angiotensin II levels. The biologic actions of the NPs are, however, restored in the presence of an inhibited RAS and this has led to the development of two classes of agent: (1) vasopeptidase inhibitors that inhibit both neprilysin and ACE and (2) combined angiotensin receptor blockade/neprilysin inhibition, the latter having gained regulatory authority approval for the treatment of heart failure.