Vasopeptidase Inhibitors: A New Class of Drugs

The human cardiovascular system is regulated by hemodynamic, neurohumoral and structural mechanisms. The endothelium and the neurohumoral system play a key role in modulating both vascular tone and structure by producing vasoactive substances as well as influencing the modulation of blood cell adhesion. Although the neurohormonal systems are essential in the vascular homeostasis, they become maladaptive in conditions such as hypertension, coronary disease and heart failure. The clinical success of blocking the renin-angiotensin system by angiotensin-converting enzyme (ACE) inhibitors and the sympathetic nervous system by β-blockers demonstrates the importance of neurohumoral blockades. The inadequate effect of ACE or neutral endopeptidase (NEP) inhibitor monotherapy seen in some patients treated for hypertension or congestive heart failure (CHF) and the promising effect seen after their combination led to the development of drugs that simultaneously inhibit both enzyme systems. NEP, like ACE, is an endothelial cell surface zinc metallopeptidase with a similar structure and catalytic site to ACE. NEP is the major enzymatic pathway for the degradation of natriuretic peptides. Natriuretic peptides can be viewed as endogenous inhibitors of the renin-angiotensin system. The dual metalloprotease inhibitors of ACE and NEP, called vasopeptidase inhibitors, represent a new class of drugs and an attractive therapeutic strategy for the treatment of cardiovascular diseases such as hypertension and CHF.