Vasopeptidase inhibitors: will they have a role in clinical practice?

The human cardiovascular system is regulated by haemodynamic, 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, and in the modulation of blood cell adhesion. Although the neurohormonal systems are essential in 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 nerve system by beta-blockers demonstrates the importance of neurohumoral blockade. The inadequate effect of angiotensin converting enzyme (ACE) or neutral endopeptidase (NEP) inhibitor monotherapy seen in some patients treated for hypertension or congestive heart failure, and the promising effect seen after their combination, led to the development of drugs that simultaneously inhibit both enzyme systems. Neutral endopeptidase, like ACE, is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site to ACE. NEP is the major enzymatic pathway for degradation of natriuretic peptides. The natriuretic peptide system can be viewed as the endogenous inhibitor of the renin angiotensin system. The dual metalloprotease inhibitors of ACE and NEP, called vasopeptidase inhibitors therefore represent a new and attractive therapeutic strategy for the treatment of cardiovascular disease. The ability to add incremental benefit over already proven therapy, with an acceptable side-effect profile however, is questionable in this new class of agents.