Vasopeptidase inhibition for blood pressure control: emerging experience

Vasopeptidase inhibition is a novel treatment approach in cardiovascular disease such as hypertension and heart failure. Since the inhibition of the angiotensin-converting enzyme (ACE) turned out to represent a very successful principle in the treatment of hypertension in numerous large scale clinical studies, their results encouraged attempts to inhibit other key enzymes in the regulation of vascular tone as well--such as the neutral endopeptidase (NEP). Similar to ACE, NEP is an endothelial cell surface metalloproteinase, which is involved in the degradation of several regulatory peptides including the natriuretic peptides and thus augments vasodilatation and natriuresis through increased levels of atrial natriuretic peptide (ANP). By simultaneous inhibition of the RAS and potentiation of the natriuretic peptide system, combined NEP/ACE inhibitors--the so called vasopeptidase inhibitors--reduce vasoconstriction and enhance vasodilatation, therefore, decreasing peripheral vascular resistance and blood pressure. Based on these considerations, numerous preclinicial studies with vasopeptidase inhibitors were performed and revealed promising results in experimental hypertension. Correspondingly, large scale clinical studies in patients with hypertension are on the way. Their preliminary results indicate that combined inhibition of ACE and NEP by vasopeptidase inhibitors represents an effective strategy in the treatment of hypertension and other cardiovascular disease such as heart failure. However, clinical data also suggest that the incidence of angioedema may increase on vasopeptidase inhibition. Therefore, careful evaluation of the safety of this promising therapeutic principle in large scale clinical studies is mandatory before vasopeptidase inhibition may be considered a novel option in the treatment of cardiovascular disease.