Sustained antihypertensive actions of a dual angiotensin-converting enzyme neutral endopeptidase inhibitor, sampatrilat, in black hypertensive subjects

Abstract

Our objective was to evaluate the safety and antihypertensive efficacy of sampatrilat, a novel dual inhibitor of both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), in subjects poorly responsive to ACE inhibitor monotherapy. The ability of sampatrilat (50 to 100 mg daily) (n ‫؍‬ ‫؍‬ 28) to lower blood pressure was compared with that of the ACE inhibitor lisinopril (10 to 20 mg daily) (n ‫؍‬ ‫؍‬ 30) using a double-blind, randomized, parallel group study design over a 56-day treatment period in black hypertensives. Changes in systolic (SBP) and diastolic (DBP) blood pressure were determined using repeated ambulatory blood pressure (ABP) monitoring. Both sampatrilat and lisinopril decreased plasma ACE concentrations after 28 and 56 days. The decrease in plasma ACE concentrations (U/L) was greater after lisinopril (؊ ؊9.33 ؎ ؎ 0.52) as compared with sampatrilat (؊ ؊6.31 ؎ ؎ 0.70) (P ‫؍‬ ‫؍‬ .0001) therapy. Lisinopril, but not sampatrilat, increased plasma renin activity. Lisinopril produced a transient decrease in mean 24-h ABP (mm Hg) at 28 days (SBP ‫؍‬ ‫؍‬ ؊ ؊9.0 ؎ ؎ 2.3, DBP ‫؍‬ ‫؍‬ ؊ ؊5.7 ؎ ؎ 1.3; P < < .01), which returned to pretreatment values by 56 days of therapy. Alternatively, sampatrilat produced a sustained decrease in mean ABP over the 56-day treatment period (day 28: SBP ‫؍‬ ‫؍‬ ؊ ؊7.3 ؎ ؎ 1.8, DBP ‫؍‬ ‫؍‬ ؊ ؊5.2 ؎ ؎ 1.2; P < < .01: day 56: SBP ‫؍‬ ‫؍‬ ؊ ؊7.8 ؎ ؎ 1.5; DBP ‫؍‬ ‫؍‬ ؊ ؊5.2 ؎ ؎ 0.95; P < < 0.01) with a greater treatment effect on DBP than that of lisinopril at day 56 (P ‫؍‬ ‫؍‬ .05). Treatment-emergent adverse events were noted to be similar between both treatment groups. We conclude that the antihypertensive actions of ACE/NEP inhibitor monotherapy in black subjects offers a novel therapeutic approach to patients otherwise resistant to the sustained antihypertensive actions of ACE inhibitor monotherapy. Am J Hypertens 1999; 12:563-571

Vasopeptidase Inhibitors

“…A study performed in 58 black hypertensive subjects, who are known to be poorly responsive to ACE monotherapy, confirmed these results. 37 …”

Omapatrilat Versus Lisinopril

“…The VPI sampatrilat produced a sustained antihypertensive activity in black hypertensive patients, a patient population with a high prevalence of salt sensitivity. 17 Omapatrilat has similar inhibition constants for both NEP and ACE and is effective in low-, normal-, and high-renin models of hypertension. 18 Clinical efficacy appears to be independent of age 19 and ethnicity and may be independent of renin and salt status.…”

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.…”