Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics

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.

Substance P Promotes Wound Healing in Diabetes by Modulating Inflammation and Macrophage Phenotype

“…NEP inhibitors have been proposed as possible treatments, but their use is hampered by the fact that they result in hydrolysis of a large number of peptides and are associated with serious adverse effects, such as angioedema. 41,42 However, local treatment with SP or SP analogs has the potential not only to promote diabetic foot ulceration healing but also to reverse the chronic proinflammatory state present in diabetic skin without major adverse effects expected.…”

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…NPRA and NPRB both exist as homodimers and the intracellular domain consists of a kinase homology domain, a dimerization domain, and a C‐terminal catalytic domain. Activation of NPRA and NPRB induce elevation of intracellular cyclic guanosine monophosphate (cGMP) and activation of its key effector molecule, protein kinase G (PKG), which is largely thought to exert the cardioprotective effects of NPs 8. NPRC, on the other hand, lacks the intracellular guanylate cyclase domain and has been shown to signal to inhibitory guanine nucleotide‐binding protein (inhibitory G protein) 9.…”

Evaluation of Pharmacokinetic and Pharmacodynamic Drug–Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild‐to‐Moderate Hypertension

“…Sacubitril/valsartan exerts its effects by inhibiting neprilysin and blocking the angiotensin II receptor 1 2, 3. Neprilysin inhibition results in increased cGMP, the second‐messenger involved in mediating natriuresis, diuresis, vasodilation, and multiple other beneficial effects of the neprilysin substrates ANP, B‐type natriuretic peptide (BNP), and C‐type natriuretic peptide (CNP) 3. Sildenafil is a widely prescribed medicine for the treatment of ED and pulmonary hypertension, and exerts its effects by increasing cGMP levels through inhibition of its degradation by PDE5 7, 14.…”

“…Sacubitril/valsartan is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with heart failure (NYHA Class II–IV) and reduced ejection fraction 1. Following oral administration, sacubitril/valsartan provides exposure to sacubitril, a prodrug which is further metabolized to the active neprilysin inhibitor sacubitrilat (LBQ657), and valsartan, an angiotensin receptor blocker (ARB) 2, 3. Neprilysin inhibition by sacubitrilat increases natriuretic peptide (NP) levels, thereby promoting natriuresis, diuresis, vasodilation, and inhibition of maladaptive fibrotic remodeling via their second‐messenger cyclic guanosine monophosphate (cGMP) 3, 4.…”

“…Following oral administration, sacubitril/valsartan provides exposure to sacubitril, a prodrug which is further metabolized to the active neprilysin inhibitor sacubitrilat (LBQ657), and valsartan, an angiotensin receptor blocker (ARB) 2, 3. Neprilysin inhibition by sacubitrilat increases natriuretic peptide (NP) levels, thereby promoting natriuresis, diuresis, vasodilation, and inhibition of maladaptive fibrotic remodeling via their second‐messenger cyclic guanosine monophosphate (cGMP) 3, 4. Along with neprilysin inhibition, simultaneous blockade of the renin‐angiotensin‐aldosterone system (RAAS) by valsartan inhibits the deleterious cardiovascular and renal effects of sustained activation of angiotensin II and its effectors 5, 6…”