<unk>  blocks the angiotensin II receptor type 1 (AT1). This receptor is found on both vascular smooth muscle cells, and on the zona glomerulosa cells of the adrenal gland which are responsible for aldosterone secretion. In the absence of AT1 blockade, angiotensin causes both direct vasoconstriction and adrenal aldosterone secretion, the aldosterone then acting on the distal tubular cells of the kidney to promote sodium reabsorption which expands extracellular fluid (ECF) volume. Blockade of (AT1) thus causes blood vessel dilation and reduction of ECF volume.<unk>  is a prodrug that is activated to<unk> at (LBQ657) by de-ethylation via esterases.<unk> at inhibits the enzyme neprilysin, a neutral endopeptidase that degrades vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Thus,<unk>  increases the levels of these peptides, causing blood vessel dilation and reduction of ECF volume via sodium excretion. Despite these actions, neprilysin inhibitors have been found to have limited efficacy in the treatment of hypertension and heart failure when taken on their own. This is attributed to a reduction in enzymatic breakdown of angiotensin II by the reduction of neprilysin activity, which results in an increase in systemic angiotensin II levels and the negation of the positive effects of this drug family in cardiovascular disease treatment. Combined treatment with a neprilysin inhibitor and an angiotensin converting enzyme (ACE) inhibitor has been shown to be effective in reducing angiotensin II levels, and demonstrated superiority in lowering blood pressure compared to ACE inhibition alone. However, due to an increase in bradykinins from the inhibition of both ACE and neprilysin, there was a threefold increase in relative risk of angioedema compared with ACE inhibition alone following this combination treatment. The combination of a neprilysin inhibitor with an angiotensin receptor blocker instead of the ACE inhibitor has been shown to have a comparable risk of angioedema, whilst also demonstrating superiority in treating moderate-severe heart failure to ACE inhibitor treatment. Neprilysin also has a role in clearing the protein amyloid beta from the cerebrospinal fluid, and its inhibition by<unk>  has shown increased levels of AB1-38 in healthy subjects (Entresto 194/206 for two weeks). Amyloid beta is considered to contribute to the development of Alzheimer's disease, and there exist concerns that<unk>  may promote the development of Alzheimer's disease.
Sacubitril/valsartan
Telmisartan/amlodipine
Lisinopril/amlodipine
Amlodipine/atorvastatin
Olmesartan/amlodipine
Amlodipine/valsartan
Enalapril/hydrochlorothiazide
Amlodipine/benazepril