COMBINED INHIBITION OF NEUTRAL ENDOPEPTIDASE AND ANGIOTENSIN-CONVERTING ENZYME BY SAMPATRILAT IN ESSENTIAL-HYPERTENSION

Background The antihypertensive response to angiotensin-converting enz yme (ACE) inhibitors may be attenuated by a compensatory decrease in a trial natriuretic factor production. If so, inhibition of atrial natri uretic factor breakdown by neutral endopeptidase (NEP) may enhance the antihypertensive effects of ACE inhibition. We compared effects of th e combined ACE-NEP inhibitor sampatrilat, lisinopril, and placebo on b lood pressure, plasma ACE, and renin activity and urinary cyclic guano sine monophosphate (cGMP) of patients with hypertension.Methods ann Re sults: After a 4-week placebo run-in period, 124 patients with a mean blood pressure of 162/102 mm Hg were randomized in a double-blind para llel-group design to 1 of 5 treatments, given once daily for 10 days: 50 mg, 100 mg, or 200 mg sampatrilat; 20 mg lisinopril; or placebo. Th e first dose of sampatrilat did not lower clinic or ambulatory blood p ressure. Lisinopril had an immediate antihypertensive effect that diff ered significantly from all doses of sampatrilat. After 10 days of tre atment, sampatrilat lowered clinic and ambulatory blood pressure signi ficantly at all doses, with a trend toward a dose response for systoli c ambulatory blood pressure. Sampatrilat inhibited plasma ACE in a dos e-dependent fashion but significantly less so than lisinopril on days 1 and 10 of treatment. Lisinopril but not sampatrilat significantly in creased plasma renin activity, whereas sampatrilat but not lisinopril significantly increased urinary cGMP excretion. Conclusion: The increa sing efficacy of sampatrilat compared with lisinopril over 10 days cou ld not be attributed to an increase in plasma ACE inhibition, suggesti ng that the NEP inhibitor activity of sampatrilat may have contributed to its antihypertensive action. NEP inhibition may enhance the antihy pertensive effect of ACE inhibition.