Concomitant Angiotensin AT1 Receptor Antagonism and Neprilysin Inhibition Produces Omapatrilat-like Antihypertensive Effects Without Promoting Tracheal Plasma Extravasation in the Rat

Abstract

Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy but cause high incidence of angioedema. We examined whether dual inhibition of angiotensin AT1 receptor (ARB) and NEP (ARB-NEPI, valsartan-candoxatril) provides similar efficacy to omapatrilat without the risk of angioedema. Activity of test compounds at the targets was assayed using fluorescence-based enzyme assays (ACE, NEP, aminopeptidase P) or competition binding assays (AT1). Target engagement in vivo (ACE, AT1, and NEP) was quantified by measuring inhibition of angiotensin-pressor responses and potentiation of atrial natriuretic peptide-induced urinary cyclic guanosine monophosphate (cGMP) output in rats. Tracheal plasma extravasation (TPE) was used as a surrogate to assess propensity of compounds to promote upper airway angioedema. Antihypertensive efficacy in renin-dependent and -independent states was measured in spontaneously hypertensive rats and deoxycorticosterone acetate salt hypertensive rats, respectively. Administration of omapatrilat and coadministration of valsartan and candoxatril blocked angiotensin induced vasopressor responses and potentiated atrial natriuretic peptide-induced increase in urinary cGMP output. In spontaneously hypertensive rats, valsartan, omapatrilat, and valsartan-candoxatril combination all produced reduction in blood pressure to a similar extent, whereas candoxatril was ineffective. In deoxycorticosterone acetate rats, omapatrilat, candoxatril, and valsartan-candoxatril combination but not valsartan produced reduction in blood pressure. Antihypertensive doses of omapatrilat produced robust increases in TPE; by contrast, valsartan, candoxatril, or their combination did not increase TPE. Pretreatment with icatibant, a bradykinin B2 antagonist, abolished omapatrilat-induced TPE but not its antihypertensive effects. On the background of NEP inhibition, suppression of the renin-angiotensin system through ARB and ACE inhibition shows a similar antihypertensive efficacy but exerts differential effects on bradykinin metabolism and TPE indicative of reduced risk of angioedema. Thus, dual AT1 receptor blockade and NEP inhibition is potentially an attractive approach to retain the excellent antihypertensive effects of omapatrilat but with a superior safety profile.

Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure

“…17,18 LCZ696, which consists of the neprilysin inhibitor sacubitril (AHU377) and the ARB valsartan, was designed to minimize the risk of serious angioedema. 19,20 In small trials involving patients who had hypertension or heart failure with a preserved ejection fraction, LCZ696 had hemodynamic and neurohormonal effects that were greater than those of an ARB alone. 21,22 We examined whether the long-term effects of LCZ696 on morbidity and mortality were superior to those of ACE inhibition with enalapril in patients with chronic heart failure and a reduced ejection fraction.…”

Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure

“…15,16 Therefore, the preferred approach to parallel modulation of these neurohormonal systems is the combined use of a neprilysin inhibitor with an angiotensin receptor blocker. 17 The PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial compared the long-term effects of LCZ696-a complex of the neprilysin inhibitor sacubitril and the angiotensin receptor blocker valsartan-with enalapril in patients with heart failure with mild-to-moderate symptoms. 18 The trial demonstrated the superiority of LCZ696 over enalapril on both death from any cause, and on death from cardiovascular causes.…”

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

“…13,14 In a preclinical model, ARNi (using valsartan-candoxatril) provided similar antihypertensive efficacy as omapatrilat without inducing tracheal plasma extravasation (a surrogate of angioedema). 15 LCZ696 has been the first ARNi to be evaluated in patients with hypertension and HF. [16][17][18] LCZ696 combines a moiety of the ARB valsartan and the NEPi precursor, AHU377.…”