Sacubitril/valsartan: beyond natriuretic peptides

Abstract

Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded as biomarkers in heart failure (HF). However, they are also possible therapeutic agents due to potentially beneficial physiological effects.The angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin-angiotensin-aldosterone system First we discuss how NPS physiology differs between healthy individuals and those with HF by looking at mechanisms like the overwhelming effects of RAAS on the NPS, natriuretic peptide receptor desensitisation and absolute natriuretic deficiency. Secondly, this review explores other hormones that are augmented by sacubitril/valsartan such as, bradykinin, substance-P and adrenomedullin that may contribute to the efficacy of sacubitril/valsartan in HF. We also discuss concerns that sacubitril/valsartan may interfere with amyloid β homeostasis with potential implications on Alzheimer's disease and macular degeneration. Finally, we explore the concept of 'auto-inhibition' which is a recently described observation that humans have innate NEP inhibitory capability when natriuretic peptide levels rise above a threshold. There is speculation that auto-inhibition may provide a surge of natriuretic and other vasoactive peptides to rapidly reverse decompensation. We contend that by pre-emptively inhibiting NEP, sacubitril/valsartan is inducing this surge earlier during decompensation, resulting in the better outcomes observed.

Novel heart failure biomarkers: why do we fail to exploit their potential?

“…MR-proADM was also predictive for cardiovascular events in the general population [143]. Adrenomedullin is a substrate of neprilysin and hence its levels may be affected by treatment with neprilysin inhibitors; it has been suggested that the positive effects of neprilysin inhibition by sacubitril may be due in part to the inhibition of adrenomedullin and other bioactive peptides [144]. Despite many studies, there is no evidence yet that MR-proADM or bio-ADM can be used in a biomarker-guided therapeutic strategy.…”

In-silico simulated prototype-patients using TPMS technology to study a potential adverse effect of sacubitril and valsartan

“…In pharmacological terms, it is an angiotensin receptor-neprilysin inhibitor. Consequently, it triggers the natriuretic peptide system by inhibiting neprilysin (NEP) and inhibits renin-angiotensin-aldosterone system by blocking the type-1 angiotensin II receptor (AT1R) [15]. In a previous work, TPMS was already applied to unveil the MoA of sacubitril/ valsartan synergy, revealing its effect against two molecular processes [9]: the left ventricular extracellular matrix remodeling, mediated by proteins like gap junction alpha-1 protein or matrix metalloproteinase-9; and the cardiomyocyte apoptosis, through modulation of glycogen synthase kinase-3 beta.…”

Dual Angiotensin Receptor and Neprilysin Inhibitor Ameliorates Portal Hypertension in Portal Hypertensive Rats

“…The superiority of LCZ-696 compared to valsartan comes from its potent vasodilatory effects. LCZ696 can not only augment NPs but also influence other vasoactive agents [20]. Our data showed that LCZ696, but not valsartan, significantly downregulated the hepatic ET-1 protein expression.…”