Omapatrilat Versus Lisinopril

Abstract

Abstract-Omapatrilat, a vasopeptidase inhibitor, simultaneously inhibits neutral endopeptidase and ACE. The efficacy and hormonal profile of omapatrilat and lisinopril were compared in salt-sensitive hypertensive patients. On enrollment, antihypertensive medications were withdrawn, and patients received a single-blind placebo. On day 15, salt-sensitivity determinations were made. Salt-sensitive hypertensive patients returned within 5 to 10 days for baseline evaluations of ambulatory diastolic blood pressure, ambulatory systolic blood pressure, and atrial natriuretic peptide. Salt-sensitive hypertensive patients were randomized to receive double-blind omapatrilat (nϭ28) or lisinopril (nϭ33) at initial doses of 10 mg for 1 week, increasing to 40 and 20 mg, respectively, for an additional 3 weeks. Ambulatory blood pressure and urinary atrial natriuretic peptide were assessed at study termination. Both omapatrilat and lisinopril significantly reduced mean 24-hour ambulatory diastolic and systolic blood pressures; however, omapatrilat produced significantly greater reductions in mean 24-hour ambulatory diastolic blood pressure (Pϭ0.008), ambulatory systolic blood pressure (Pϭ0.004), and ambulatory mean arterial pressure (Pϭ0.005) compared with values from lisinopril. Both drugs potently inhibited ACE over 24 hours. Omapatrilat significantly (PϽ0.001) increased urinary excretion of atrial natriuretic peptide over 0-to 24-hour (3.8-fold) and 12-to 24-hour (2-fold) intervals; lisinopril produced no change. Omapatrilat significantly (PϽ0.001) increased urinary excretion of cGMP over the 0-to 24-and 4-to 8-hour intervals compared with that from lisinopril. Neither drug had a diuretic, natriuretic, or kaliuretic effect. bradykinin, 2 and adrenomedullin 3 ) and inhibition of the production of the vasoconstrictor angiotensin II. The physiological effects of ANP and BNP include vasodilation and inhibition of the renin-angiotensin-aldosterone system. 4 -6 The metabolism of ANP and BNP involves 2 main pathways: an enzymatic degradation by NEP 24.11 7 and a receptor-mediated clearance process via the clearance receptor. 8 NEP 24.11 is widely distributed throughout the body and is particularly present at the level of the brush border membranes in the proximal tubule of the kidney. 9 Inhibition of NEP produces increases in plasma ANP concentrations and urine sodium and volume excretion and a decrease in blood pressure (BP) in deoxycorticosterone acetate-salt uninephrectomized rats. 10,11 NEP inhibitors, when given alone, have not been effective as long-term antihypertensive agents in humans, perhaps because of compensatory reflex renin-angiotensin-aldosterone system activation. 12,13 These limitations may be overcome by VPIs through their additional ability to inhibit ACE and to potentiate the kallikrein-kinin system, resulting in additional vasodilation. 14 Patients with salt-sensitive hypertension (SSH) do not respond as well to ACE inhibitor monotherapy as hypertensive patients who are not salt sensitive. 15 In response to a ...

Physiologic Consequences of Vasopeptidase Inhibition in Humans

“…It is consistent with previously published results on omapatrilat (10,46) and other vasopeptidase inhibitors (47). The effect of vasopeptidase inhibitors on urine sodium excretion probably depends on the clinical setting (3) or on the experimental model (48) used.…”

“…In both panels, the decrease in MAP after 40 or 80 mg of omapatrilat intake was not dose-dependent. These results are in accordance with the results obtained in the DOCA-salt model of hypertension (36) but also in sodium-sensitive hypertensive patients (10). They may have a major clinical consequence; the BP-lowering effect of omapatrilat in hypertensive patients is probably less dependent on sodium intake than that of ACE inhibitors.…”

“…In animal models, NEP inhibition may have additional beneficial effects on target organs damage beyond ACE inhibition (5)(6)(7)(8). Omapatrilat was shown to have a greater antihypertensive efficacy in hypertensive patients than ACE inhibitors, such as lisinopril (9,10) or enalapril (11). Vasopeptidase inhibition could have an advantage over selective ACE inhibition for the treatment of patients with congestive heart failure.…”

A randomized, double-blind, placebo-controlled, parallel-group study to assess the efficacy and safety of dual ACE/NEP inhibitor GW660511X in mild-to-moderate hypertensive patients

“…At the end of the placebo run-in period, patients were randomized to either GW665011X or placebo (1:1 ratio) treatment in a double-blind manner. Patients in the active treatment group received two consecutive 3-day dose titration periods of GW660511X 50 mg once daily (days 1-3) and then 100 mg once daily (days 4-6) followed by GW660511X 200 mg once daily for 14 days (days [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Patients in the placebo treatment group received the same dosing regimen with a matched placebo.…”

“…7,8 Clinical evidence thus far has shown that omapatrilat, sampatrilat and fasidotril are effective in the management of hypertension in different patient populations. [9][10][11][12][13][14] However, adverse events (AE) associated with omapatrilat, especially angioedema, raised a concern for the safety of vasopeptidase inhibitors. 15 GW660511X is a novel potent and selective dual inhibitor of ACE (IC 50 3.2 nM) and NEP (IC 50 1.8 nM) both in vitro and ex vivo.…”