Angiotensin Receptor Neprilysin Inhibitor LCZ696 Attenuates Cardiac Remodeling and Dysfunction After Myocardial Infarction by Reducing Cardiac Fibrosis and Hypertrophy

Abstract

Background-Angiotensin

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events

“…This raises a concern of hypotension as a potential adverse effect with not just LCZ696, but possibly also with other NP‐enhancing drugs. Simultaneous blockade of angiotensin receptors and neprilysin by LCZ696 has also shown efficacy in an experimental model attenuating cardiac remodeling and dysfunction in rats post‐MI 118. The FDA has approved this drug, valsartan/sacubitril, as a treatment for HF in July 2015.…”

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

“…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…”

“…Thus, a CYP‐mediated pharmacokinetic drug–drug interaction between sacubitril/valsartan and sildenafil is not expected. However, both sacubitril/valsartan and sildenafil increase levels of the second‐messenger cGMP, which lowers blood pressure (BP) through its effects on basal vascular tone, indicating a potential for a pharmacodynamic interaction between sacubitril/valsartan and sildenafil with respect to the magnitude of BP reduction ( Supplemental Figure S1 ) 4, 7. Therefore, the present study was conducted to investigate the potential for pharmacokinetic and pharmacodynamic drug–drug interactions between sacubitril/valsartan and sildenafil.…”

LCZ696 An Innovation For Heart Failure: A Comment

“…Several peptides (ie, natriuretic peptides, bradykinin, and adrenomedullin) can attenuate vasoconstriction and sodium retention, and retard cardiac and vascular hypertrophy and remodeling, and thus act to ameliorate many of the pathophysiological abnormalities of heart failure [5,[11][12][13]. Biologically active NPs are degraded by the enzyme neutral endopeptidase or neprilysin; consequently, neprilysin inhibition represents an important pharmacological approach to augment the salutary actions of NPs [14][15][16].…”

“…Simultaneous blockade of RAAS and neprilysin through dual-acting ACE and NEPi (vasopeptidase inhibitors) has been evaluated a decade ago, but further development was halted because of increased rates of angioedema, presumably caused by accumulation of bradykinin in at-risk patients [16][17][18].…”