Vasopeptidase inhibition: a new concept in blood pressure management.
Vasopeptidase inhibition is a new concept in cardiovascular therapy. It involves simultaneous inhibition with a single molecule of two key enzymes involved in the regulation of cardiovascular function, neutral endopeptidase (EC 24.11; NEP) and angiotensin-converting enzyme (ACE). Simultaneous inhibition of NEP and ACE increases natriuretic and vasodilatory peptides (including atrial natriuretic peptide [ANP], brain natriuretic peptide [BNP] of myocardial cell origin, and C-type natriuretic peptide [CNP] of endothelial cell origin) and increases the half-life of other vasodilator peptides including bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide system, vasopeptidase inhibitors (VPIs) reduce vasoconstriction and enhance vasodilation, thereby decreasing vascular tone and lowering blood pressure. Omapatrilat, a heterocyclic dipeptide mimetic, is a novel vasopeptidase inhibitor and a single molecule that simultaneously inhibits NEP and ACE with similar inhibition constants. Unlike ACE inhibitors, omapatrilat demonstrates antihypertensive efficacy in low-, normal-, and high-renin animal models. Unlike NEP inhibitors, omapatrilat provides a potent and sustained antihypertensive effect in spontaneously hypertensive rats (SHR), a model of human essential hypertension. In animal models of heart failure, omapatrilat is more effective than ACE inhibition in improving cardiac performance and ventricular remodeling and prolonging survival. Omapatrilat effectively reduces blood pressure, provides target-organ protection, and reduces morbidity and mortality from cardiovascular events in animal models. Omapatrilat is the first VPI to enter advanced USA clinical trials. Omapatrilat appears to be a safe, well-tolerated and effective antihypertensive in humans. Vasopeptidase inhibition is a novel and efficacious strategy for treating cardiovascular disorders, including hypertension and heart failure, that may offer advantages over currently available therapies.
Burnett
J C
JC
Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA. Burnett.john@mayo.edu
D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D008969:Molecular Sequence Data; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000187:drug effects; D020098:Natriuretic Peptide, C-Type / Q000097:blood / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects*; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use*; D013841:Thiazepines / Q000737:chemistry / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D011725:Pyridines; D013841:Thiazepines; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; C106266:omapatrilat; D009320:Atrial Natriuretic Factor; D007703:Peptidyl-Dipeptidase A; D015260:Neprilysin