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

Abstract

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 b -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.

Atrial natriuretic peptide and related peptides

“…The effects of NEP inhibitors induce increased urinary sodium and cGMP excretion (28) because renal tubular NEP is the major site of natriuretic peptide metabolism. Angiotensin-converting enzyme (ACE) combined with NEP inhibition is now under investigation as a potential method to treat cardiac failure and salt-sensitive hypertension (29). However, a high incidence of angioedema has been observed and rapidly increased bradykinin levels have induced potentially life-threatening side effects.…”

ProBNP‐derived peptides in cardiac disease

“…The metabolic half-life of BNP-32 has been reported to be 13 -20 min [40,41]. Interestingly, the enzymatic degradation by neutral endopeptidase has been targeted for therapeutic inhibition, which might be a clinical strategy to pursue in order to increase the endogenous concentration of ANP and BNP [42,43]. Importantly, an increase in plasma ANP and BNP concentrations not only improves the hemodynamics in heart failure patients but also seems to mediate direct effects on the myocardium [44 -46].…”

Hypertension: Pathophysiology and Treatment

“…However, further studies assessing the utility of the latter group is imperative considering the ambiguity of treatment efficacy and the potential side effects in specific patient subgroups [86][87][88][89]. Other potential targets such as endothelin receptor antagonists and vasopeptidase inhibitors have been studied but no role has yet been identified for these therapies [90].…”

“…Weight: maintenance of normal body weight as defined by BMI of 18.5-24.9 kg/m2 5-20 mmHg/10kg reduction in weight [90,91] Sodium consumption: reduction of dietary sodium to less than 100 mmol per day (2.4 g sodium or 6 g sodium chloride).…”