Vasopeptidase inhibition: effective blood pressure control for vascular protection

Angiotensin converting enzyme (ACE) inhibition is a well-established principle in the treatment of hypertension, and numerous large scale clinical studies have clearly demonstrated the beneficial effects of inhibiting the renin-angiotensin-aldosterone system (RAS) in hypertension. The clinical success of ACE inhibitors encouraged attempts to inhibit other key enzymes in the regulation of vascular tone, 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 augments vasodilatation and natriuresis through increased levels of atrial natriuretic peptide. By inhibiting the RAS and potentiating the natriuretic peptide system at the same time, combined NEP/ACE inhibitors, the so-called "vasopeptidase inhibitors," reduce vasoconstriction and enhance vasodilatation, and in turn decrease peripheral vascular resistance and blood pressure. Within the vessel wall this may lead to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and endothelin-1, and may increase local levels of bradykinin as well as natriuretic peptides. Based on these considerations, numerous preclinical studies with vasopeptidase inhibitors have been performed and reveal promising results in experimental hypertension. Correspondingly, large-scale clinical studies in patients with hypertension are on the way, to transfer the principle of vasopeptidase inhibition from bench to bedside.