The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment.

M Volpe,M Carnovali,V Mastromarino

doi:10.1042/cs20150469

Abstract

After its discovery in the early 1980s, the natriuretic peptide (NP) system has been extensively characterized and its potential influence in the development and progression of heart failure (HF) has been investigated. HF is a syndrome characterized by the activation of different neurohormonal systems, predominantly the renin-angiotensin (Ang)-aldosterone system (RAAS) and the sympathetic nervous system (SNS), but also the NP system. Pharmacological interventions have been developed to counteract the neuroendocrine dysregulation, through the down modulation of RAAS with ACE (Ang-converting enzyme) inhibitors, ARBs (Ang receptor blockers) and mineralcorticoid antagonists and of SNS with β-blockers. In the last years, growing attention has been paid to the NP system. In the present review, we have summarized the current knowledge on the NP system, focusing on its role in HF and we provide an overview of the pharmacological attempts to modulate NP in HF: from the negative results of the study with neprilysin (NEP) inhibitors, alone or associated with an ACE inhibitor and vasopeptidase inhibitors, to the most recently and extremely encouraging results obtained with the new pharmacological class of Ang receptor and NEP inhibitor, currently defined ARNI (Ang receptor NEP inhibitor). Indeed, this new class of drugs to manage HF, supported by the recent results and a vast clinical development programme, may prompt a conceptual shift in the treatment of HF, moving from the inhibition of RAAS and SNS to a more integrated target to rebalance neurohormonal dysregulation in HF.

Highlights

Chronic heart failure (HF) is a syndrome with a complex pathophysiology in which the neuroendocrine activation plays a significant role
The therapeutic approach has been based on pharmacological interventions to down-modulate renin–angiotensin (Ang)–aldosterone system (RAAS), through Ang-converting enzyme (ACE) inhibitors [7,8,9,10,11,12] or Ang receptor blockers (ARBs) [13,14,15,16], aldosterone [17,18,19,20] and through mineralocorticoid receptor antagonists (MRA) and sympathetic nervous system (SNS) by β-blockers [21,22,23,24,25,26]
Angiotensin receptor neprilysin inhibition and ARB combination with LCZ696 compound Quite recently, a novel pharmacological approach based on the combination of Ang receptor NEP inhibitor (ARNI) has been developed with the rational to generate a novel tool to target natriuretic peptide (NP) enhancement and RAAS blockade without increasing side effects, overcoming the drawbacks and failures encountered with the strategies described above (Figure 3D)

Summary

Introduction

Chronic heart failure (HF) is a syndrome with a complex pathophysiology in which the neuroendocrine activation plays a significant role. Studies in an experimental model of HF have demonstrated that inhibition of the NP by either specific antibodies to their receptors or the NPR-A antagonist HS-142-1 causes further impairment in renal function, as expressed by increased renal vascular resistance and decreased GFR, RBF, urine flow, sodium excretion and activation of the RAAS [158].

Results

Conclusion