LCZ696

LCZ696, a combination of prodrug sacubitril and valsartan at equal molar ratios, is an oral active angiotensin II receptor-neprilysin inhibitor ^[1]. After ingestion, LCZ696 undergoes rapid dissociation into valsartan and sacubitril, which cause neprilysin inhibition and AT1 receptor blockade, resulting increases in ANP, plasma and urinary cGMP, renin concentration and activity ^[2]. LCZ696 has been widely used to improve heart and kidney functions and to induce memory and cognitive dysfunction in animals ^[3].

In vitro, LCZ696 treatment (20µM) for 24 hours significantly reduced the production of reactive oxygen species (ROS) and the level of malondialdehyde (MDA) in human umbilical vein endothelial cells (HUVECs), thereby alleviating the oxidative stress induced by Lipopolysaccharide (LPS) ^[4]. Treatment with 10µM LCZ696 for 24 hours reduced apoptosis-related events and increased the survival rate of podocytes cultured in high glucose conditions^[5]. Treatment with 1µM LCZ696 for 3 hours significantly reduced the expression of ANP, βMHC, and TIMP2 in cardiomyocytes, inhibited the increase in cardiomyocyte size caused by angiotensin II, and promoted the protein expression of ACE2^[6].

In vivo, LCZ696 treatment via oral administration at a dose of 68mg/kg/day for 4 weeks significantly reduced cardiac remodeling and dysfunction in rats after myocardial infarction^[7]. For 8 consecutive weeks, an oral dose of 60mg/kg of LCZ696 was administered daily, significantly improving the biochemical, morphological, and molecular biological indicators of renal injury in mice with cardiorenal syndrome^[8].

References:
[1] Minguet J, Sutton G, Ferrero C, et al. LCZ696: a new paradigm for the treatment of heart failure?[J]. Expert Opinion on Pharmacotherapy, 2015, 16(3): 435-446.
[2] Menendez J T. The mechanism of action of LCZ696[J]. Cardiac failure review, 2016, 2(1): 40.
[3] Poorgolizadeh E, Moghadam F H, Dormiani K, et al. Do neprilysin inhibitors walk the line? Heart ameliorative but brain threatening![J]. European journal of pharmacology, 2021, 894: 173851.
[4] Gao A, Wang Y, Gao X, et al. LCZ696 ameliorates lipopolysaccharide-induced endothelial injury[J]. Aging (Albany NY), 2021, 13(7): 9582.
[5] Zhang H, Yu M, Zhang Y, et al. LCZ696 improves oxidative stress injury in human podocytes induced by increased glucose levels via Nrf2/HO-1 signaling pathway[J]. European Journal of Medical Research, 2025, 30(1): 598.
[6] Wang Y, Guo Z, Gao Y, et al. Angiotensin II receptor blocker LCZ696 attenuates cardiac remodeling through the inhibition of the ERK signaling pathway in mice with pregnancy-associated cardiomyopathy[J]. Cell & Bioscience, 2019, 9(1): 86.
[7] von Lueder T G, Wang B H, Kompa A R, et al. Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy[J]. Circulation: Heart Failure, 2015, 8(1): 71-78.
[8] Li Y, Kang L, Rong K, et al. Renal protective effects and mechanisms of the angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome[J]. Life Sciences, 2021, 280: 119692.