NEP/ACE Inhibitors: Experimental and Clinical Aspects

Abstract

The human cardiova scular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone and structure as well as adhesion of blood cells by producing circulating and local vasoactive substances. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coron ary disease and heart failure. The clinical success of blocking the renin -angiotensin-aldosterone system by angiotensin-converting enzyme inhibitors has led to efforts to block other humoral systems as well. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with a similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and the vasoactive and natriuretic peptide adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of natriuretic and vasodilatory peptides including atrial or A-type natriuretic peptide (ANP), B-type natriuretic peptide (BNP) of myocardial cell origin, andC-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sod ium/water balance and in turn decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall this leads to a reduction in vasoconstrictor and proliferative mediators such as angiotensin 11 and endothelin-1 and increased local levels of bradykinin (and in turn nitric oxide) and natriuretic peptides. In hypertension, vasopeptidase inhibitors such as omapatrilat are more potent in lowering blood pressure than any other compound. In heart failure, the difference compared to ACE inhibitors is less. Nevertheless, combined inhibition of angiotensin-converting enzyme and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis or heart failure