see also:

• congestive cardiac failure
• hypertension
• angiotensin II receptor blockers (ARBs)
• hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers

• angiotensin receptor–neprilysin inhibitors (ARNIs) are a new class of cardiovascular agents characterized by their dual action on the major regulators of the cardiovascular system, including the renin–angiotensin system (RAS) and the natriuretic peptide (NP) system:
  • inhibition of the angiotensin II type 1 receptor (AT1) via the included ARB
  • inhibition of the degrading enzyme neprilysin resulting in increased cardioprotective natriuretic peptides
• has been shown to be beneficial in patients with HF, particularly those with reduced ejection fraction (EF)
• clinical effects on HF with preserved EF (HFpEF) remain poorly established
• appear to be superior to preexisting RAS inhibitors in reducing blood pressure (BP) in hypertensive patients

• angiotensin II inhibition
  • see angiotensin II receptor blockers (ARBs)
• neprilysin
  • cleaves peptides at the amino side of hydrophobic residues
  • diverse targets include not only natriuretic peptides (NPs) but also glucagon, glucagon-like peptide-1 (GLP-1), bradykinin, substance P, neurotensin, oxytocin, enkephalins, angiotensin I, endothelin-1, adrenomedullin, amyloid β, and others
  • catalyzes the conversion of angiotensin I into angiotensin 1–7
• neprilysin inhibitors
  • the protective effect of neprilysin inhibitors on heart failure is primarily attributed to the inhibition of the degradation of NPs, which consist of atrial NP (ANP), brain NP (BNP), and C-type NP (CNP)
    • ANP and BNP, which are called cardiac NPs, are released from the atrial and ventricular walls, respectively, primarily triggered by wall stretching
    • the primary sources of CNP are the vascular endothelium and brain
    • there are three types of receptors for NPs:
      • NP receptor A (NPRA), NPRB, and NPRC, which have distinct roles in the signaling and metabolism of NPs.
      • NPRA, the receptors for ANP and BNP, and NPRB, the receptor for CNP, trigger biologically and physiologically potent cellular signaling, primarily through the generation of cyclic guanosine monophosphate (cGMP) and thus contribute to the regulation of systemic homeostasis and metabolism, including vasodilation, increased renal perfusion, natriuresis, antihypertrophic and antifibrotic actions, reduced water and salt intake, and lipolysis¹⁾

• sacubitril/valsartan