Neutral Endopeptidase Inhibition and Natriuretic Peptide System
Neutral Endopeptidase Inhibition and Natriuretic Peptide System
Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin–angiotensin–aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension.
The burden of cardiovascular disease (CVD) continues to increase worldwide. The final common pathway in CVD is heart failure (HF), which often is mediated by progressive uncontrolled hypertension. Indeed, the important link between hypertension and HF is underscored by the recent report from the landmark ALLHAT Study that demonstrated that the development of HF in hypertensive patients was a powerful predictor for increased mortality A recent report further suggested the importance of the control of hypertension for the reduction in HF.
Today, there continues to be a high priority for the development of innovative therapeutic agents that better control blood pressure (BP) and also have a therapeutic potential in the setting of HF. Such agents should enhance current therapies for CVD and, importantly, prevent target-organ damage. Such therapeutics could be especially useful for high-risk populations such as the elderly, diabetics, African-Americans, and other populations in whom adequate BP control is of great importance. Currently, there is a widespread use of modulators of the renin–angiotensin–aldosterone system (RAAS) which may inhibit release of renin, antagonize angiotensin II (Ang II) at its receptor level, or block the actions of aldosterone. Such strategies underscore the deleterious properties of over-activated RAAS, which is a hallmark of CVD.
In this review, we will focus on an endogenous peptide system, the natriuretic peptide (NP) system, and on novel strategies aimed to enhance the biological activities of the NPs via inhibition of their degradation.
As will be discussed below, manipulation of this system so as to achieve target-organ protection, BP control, optimal volume homeostasis, and the inhibition or reversal of myocardial and renal remodeling represents a new therapeutic opportunity. Our focus will be upon inhibition of a key enzyme which degrades the NPs, specifically, neprilysin (neutral endopeptidase or EC 3.4.24.11 or NEP), and on the combination of NEP inhibition and RAAS antagonism by novel molecules.
Abstract and Introduction
Abstract
Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin–angiotensin–aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension.
Introduction
The burden of cardiovascular disease (CVD) continues to increase worldwide. The final common pathway in CVD is heart failure (HF), which often is mediated by progressive uncontrolled hypertension. Indeed, the important link between hypertension and HF is underscored by the recent report from the landmark ALLHAT Study that demonstrated that the development of HF in hypertensive patients was a powerful predictor for increased mortality A recent report further suggested the importance of the control of hypertension for the reduction in HF.
Today, there continues to be a high priority for the development of innovative therapeutic agents that better control blood pressure (BP) and also have a therapeutic potential in the setting of HF. Such agents should enhance current therapies for CVD and, importantly, prevent target-organ damage. Such therapeutics could be especially useful for high-risk populations such as the elderly, diabetics, African-Americans, and other populations in whom adequate BP control is of great importance. Currently, there is a widespread use of modulators of the renin–angiotensin–aldosterone system (RAAS) which may inhibit release of renin, antagonize angiotensin II (Ang II) at its receptor level, or block the actions of aldosterone. Such strategies underscore the deleterious properties of over-activated RAAS, which is a hallmark of CVD.
In this review, we will focus on an endogenous peptide system, the natriuretic peptide (NP) system, and on novel strategies aimed to enhance the biological activities of the NPs via inhibition of their degradation.
As will be discussed below, manipulation of this system so as to achieve target-organ protection, BP control, optimal volume homeostasis, and the inhibition or reversal of myocardial and renal remodeling represents a new therapeutic opportunity. Our focus will be upon inhibition of a key enzyme which degrades the NPs, specifically, neprilysin (neutral endopeptidase or EC 3.4.24.11 or NEP), and on the combination of NEP inhibition and RAAS antagonism by novel molecules.