Vasopeptidase inhibitors: potential role in the treatment of heart failure.

Abstract

Current thinking views the progression of heart failure as the result of sustained activation of vasoconstrictor neurohormones. In this model, the sustained synthesis of vasoconstrictor neurohormones leads to disease progression through alterations in cardiomyocyte structure and function, which affects myocardial contractility, cardiac metabolism, and cellular growth. Ultimately, these events induce irreversible adverse ventricular remodeling through myocyte cell loss and progressive myocardial fibrosis. In the past decade, several landmark clinical trials tested the neurohormonal hypothesis, by targeting the activation of both the beta-adrenergic and the renin-angiotensin-aldosterone systems. Although the observed decrease in mortality using this strategy in heart failure populations was encouraging, morbidity and mortality levels remained elevated, and it has now been shown that several other humoral interactions are at play and potentially deserve antagonizing, or in the case of vasodilator neurohormones, deserve stimulation. It is known a family of vasodilator neurohormones - the natriuretic peptides - that have natriuretic, vasodilatory, and antiproliferative effects, endogenously inhibit the renin-angiotensin system. These peptides are degraded primarily by a neutral endopeptidase (NEP), an endothelial cell-surface zinc metallopeptidase, which shares a similar structure and catalytic site with the angiotensin converting enzyme (ACE). NEPs have broad substrate specificity, encompassing atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide, but also bradykinin and adrenomedullin. The recognition that ACE and NEP enzymes had related structures, led to the design and development of a class of molecules with a dual inhibitory effect on ACE and NEP, referred to as vasopeptidase inhibitors. Preliminary clinical trials in heart failure with vasopeptidase inhibitors have become available and show promising results. Thus, the combined inhibition of ACE and NEP, by attenuating excessive vasoconstriction and enhancing vasodilator substances, holds promise as a valuable option in heart failure treatment for the near future.