Vasopeptidase inhibitors are an emerging class of drug
used for the treatment of cardiovascular disease
. They inhibit the enzymes angiotensin-converting enzyme
(ACE) and neutral endopeptidase
(NEP), both of which are proteases
involved in the regulation of blood pressure.
ACE is a membrane-bound zinc metallopeptidase present on all endothelial cells and many endothelial cells which acts as part of the renin-angiotensin system. In this system the kidney secretes the enzyme renin in response to a decrease in blood volume, blood pressure or sodium concentration in the blood. This enzyme cleaves the glycoprotein angiotensinogen (secreted into the circulation by the liver) to form the 10 residue long peptide angiotensin I which in turn has two residues removed by ACE to form angiotensin II, the primary active hormone of the system which induces an increase in blood pressure by vasoconstriction (narrowing of the blood vessels). Competitive inhibitors of ACE have been available since the 1980s as treatments for cardiovascular disease to help lower blood pressure by reducing levels of angiotensin II.
NEP is also a membrane-bound zinc dependent metallopeptidase located primarily in the kidneys which functions to degrade the natriuretic peptides. Natriuretic peptides behave as antagonists to the renin-angiotensin system causing vasodilation among other functions. Competetive inhibitors of NEP were initially used in an attempt to maintain high levels of natriuretic peptides and thus provide a means of lowering blood pressure. Unfortunately NEP inhibitors were unsuccessful in providing significant long-term effects due to compensation by the renin-angiotensin system. However, when combined with ACE inhibitors the beneficial effects of NEP inhibitors were apparent and treatments were more successful than either inhibitor on its own. Bearing in mind the structural similarities of the two enzymes' active sites compounds were designed to simaltaneously inhibit both ACE and NEP, termed vasopeptidase inhibitors. These drugs, which include omapatrilat fasidotril and candoatril, thus inhibit the renin-angiotensinogen system while enhancing the effects of natriuretic peptides.
ACE inhibitors, although well established as a treatment of hypertension (high blood pressure) have shown 50% of patients to require additional therapy while treatment with NEP inhibitors alone was unsuccessful as mentioned above. However, recent studies with vasopeptidase inhibitors have shown them to have a potent antihypertensive effect which is improved on those of ACE inhibitors while similar results have been observed in studies regarding heart failure. They are particularly effective in the reduction of systolic blood pressure which is now recognised as a greater threat to health than dystolic blood pressure and as such preclinical trials provide much promise for this emerging class of drug.
Bralet J, Schwartz J-C, Vasopeptidase inhibitors: an emerging class of cardiovascular drugs, Trends in Pharmacological Sciences 22: pp106-109, 2001.
Veelkens R, Schmieder R E, Neutral endopeptidase inhibition: the potential of a new therapeutic approach in cardiovascular disease evolves, Journal of Hypertension 20: pp599-603 2002.
Kubota et al., Essays in Biochemistry Volume 38: Proteases in Biology and Medicine, Chapter 10 - Inhibition of peptidases in the control of blood pressure Portland Press, 2002