INTRODUCTION:

Hypertension and heart failure, the most important CVD entities, are associated with imbalance in neurohormonal systems activity such as the renin-angiotensin-aldosterone system (RAAS), the sympathetic nervous system and the endothelin system. Blockade of the RAAS constitutes the most successful pharmacotherapeutic concept in hypertension and heart failure to date. The RAAS-opposing natriuretic peptide system constitutes the body's own BP-lowering system, and mediates a multitude of beneficial actions within cardiovascular tissues.

Heart failure is a debilitating and life-threatening disease in which the heart is unable to pump enough blood around the body leading to symptoms such as breathlessness and fatigue, and significantly impacting quality of life. The renin-angiotensin-aldosterone system (RAAS) is an effective target in patients with heart failure with reduced ejection fraction (HF rEF ), where the heart muscle does not contract effectively [2].

Inhibition of neprilysin by sacubitril prevents natriuretic peptide degradation thereby exerting beneficial cardiovascular and renal effects in heart failure, while valsartan concomitantly targets the angiotensin receptor.

Neprilysin, also known as membrane metallo-endopeptidase (MME), neutral endopeptidase (NEP), cluster of differentiation 10 (CD10), and common acute lymphoblastic leukemia antigen (CALLA) is an enzymethat in humans is encoded by the MME gene. Neprilysin is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin.[1] The metallopeptidase neprilysin (NEP) hydrolyzes natriuretic peptides. Conceptually, NEP inhibition would increase salutary natriuretic peptide actions in cardiovascular diseases (CVD).

Neprilysin is also associated with other biochemical processes, and is particularly highly expressed in kidney and lung tissues. Inhibitors have been designed with the aim of developing analgesic and antihypertensive agents that act by preventing neprilysin's activity against signaling peptides such as enkephalins, substance P, endothelin, and atrial natriuretic factor.[3][4]

NEPRILYSIN INHIBITORS:

Sacubitril (AHU-377), a component of LCZ696

Omapatrilat

Candoxatril

Ecadotril

MECHANISM OF ACTION:

Natriuretic peptides are a group of hormones that have potent effects on sodium and fluid balance.Additionally,they act to inhibit RAAS reduces sympathetic drive and have both antihypertensive and anti-proliferative effects.[5]

The latter mechanism leads to a reduction in blood volume.[6] identified: Atrial NP (ANP) and Brain or B-type NP (BNP), released from the atria and left ventricle, respectively, in response to increased filling pressures and increased cardiac chamber\wall stress, act to promote natriuresis, diuresis, and vasodilation.[7]The third, C-type NP (CNP) is found in the central nervous system, kidneys, and vascular endothelial cells.[8][9] The inhibition of neprilysin in order to increase circulating levels of NPs been studied for its therapeutic effect on BP. Though neprilysin inhibition alone has little, if any, antihypertensive effect, concomitant inhibition of both neprilysin and RAAS has demonstrated to synergistically lower BP.[5]

SACUBITRIL:

AHU-377 (Sacubitril) is a prodrug which is activated in vivo by hydrolytic enzyme esterases to form an active compound LBQ657 that selectively and potently inhibits the enzyme. Neprilysin is a protease responsible for the degradation of atrial and brain natriuretic peptides. AHU-377 (Sacubitril) is an investigational antihypertensive drug being studied for use in combination with Valsartan. The combination drug, known as LCZ696, is in clinical trials for the treatment of heart failure.[10]LCZ696 (sacubitril valsartan) is a first-in-class angiotensin receptor neprilysin inhibitor that has been developed for use in heart failure. This compound is composed of 2 molecular moieties in a single crystalline complex—the angiotensin receptor blocker valsartan and a neprilysin inhibitor prodrug.Its ability to inhibit the renin-angiotensin-aldosterone axis and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.[11]

In LCZ6969 (sacubitril valsartan)Valsartan blocks the angiotensin II receptor type 1 (AT₁) and thereby causes vasodilation and increases excretion of sodium and water via the kidneys (by reducing aldosterone production). Sacubitril is a prodrug that is activated to LBQ657 by de-ethylation via esterases.[12] LBQ657 inhibits the enzyme neprilysin,[13]which is responsible for the degradation of atrial and brain natriuretic peptide, two blood pressure lowering peptides that work mainly by reducing blood volume.[14]

ECADOTRIL:

Ecadotril is aneutral endopeptidase inhibitor. Acute administration of ecadotril (10 and 30 mg/kg, orally) produced a dose-dependent decrease in systolic blood pressure with a maximal effect of −23 mm Hg between 2 and 4 h after oral administration. The NEP activity in plasma was significantly inhibited and the plasma levels of atrial (ANP) and brain (BNP) natriuretic peptides and their second messenger, cyclic GMP, were distinctly raised after oral administration[15]. Long term inhibition of neutral endopeptidase by ecadotril led to a significant decrease in left ventricular end-diastolic pressure and a significant reduction in cardiac hypertrophy.Secondary effects were increased levels of plasma atrial natriuretic peptide and excretion of cyclic adenosine monophosphate. Venticular hypertrophy and lung weight also tend to reduce with ecadopril treatment. ecadotril (sinorphan), was stopped because of an apparent excess of death resulting from pancytopenia.[16]

CANDOXITRIL:

It s an orally acting prodrug of candoxatrilat, a potent neutral endopeptidase (NEP) inhibitor ,used in the treatment of chronic heart failure condition.The systemic bioavailability of candoxatrilat was about 25% following each of oral treatment with candoxatril. Inhibition of NEP with candoxatrilat increases plasma atrial natriuretic peptide (ANP) by more than 155% during the development of pulmonary hypertension. NEP inhibition reduced mean pulmonary arterial pressure when compared with controls. The development of right ventricular hypertrophy was also reduced. Further, pulmonary vascular remodelling was reduced by NEP inhibition [17]. When pulmonary vascular tone was increased by hypoxia, candoxatrilat prolonged the vasodilator response to ANP but had no effect on the response to BNP [18] A single oral dose of candoxatril, blood pressure and heart rate remained unchanged [19]

OMAPATRILAT:

Omapatrilat (INN) is a novel antihypertensive agent that inhibits both neutral endopeptidase (NEP) and angiotensin converting enzyme. Omapatrilat is a dual inhibitor of both ACE and NEP, which has been evaluated for the treatment of hypertension and heart failure. In patients with hypertension, omapatrilat produces greater decreases in both systolic and diastolic blood pressure than does ACE inhibition alone [20] NEP inhibition results in elevated natriuretic peptide levels, promoting natriuresis, diuresis, vasodilation, and reductions in preload and ventricular remodeling. By inhibiting the renin-angiotensin-aldosterone system and potentiating the vasodilatory peptides, omapatrilat reduces vasoconstriction and enhances vasodilation, thereby decreasing vascular tone and lowering BP. omapatrilat was associated with greater reductions in blood pressure (BP) than enalapril, but the main side effect being the angioedema. The risk of angioedema was higher in black patients than in nonblacks, and in smokers than in nonsmokers.[21]

ADVERSE EFFECTS:

Common adverse effects include cough, hyperkalemia [22] ,renal dysfunction, and hypotension .[23]

CONCLUSION:

Heart failure is caused by a weakening of heart’s ability to pump blood. Perhaps the most discouraging statistics is that only 25% are alive at ten years.The consistent use of ACE inhibitors which dilate the blood vessels and allow the heart to function more effectively along with the beta-blockerswhich decrease the workload of the heart, has cut the risk of dying from heart failure in half[24].The investigational drug, called an angiotensin-receptor neprilysin inhibitor, or ARNI, combines sacubitril, a neprilysin inhibitor, with angiotensin receptor blocker (ARB), and it improved outcome in patients who were currently receiving the best possible therapy.

ACKNOWLEDGMENT:

The author s grateful to the authors/editors of all those articles, journals and books from where the data for this article has been reviewed and discussed.

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Received on 16.06.2015 Modified on 12.08.2017

Research J. Pharm. and Tech 2018; 11(5):2111-2113.

DOI: 10.5958/0974-360X.2018.00391.8