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Effects of MDL 100,240, a Dual Inhibitor of Angiotensin-Converting Enzyme and Neutral Endopeptidase on the Vasopressor Response to Exogenous Angiotensin I and Angiotensin II Challenges in Healthy Volunteers

1998; Lippincott Williams & Wilkins; Volume: 31; Issue: 3 Linguagem: Inglês

10.1097/00005344-199803000-00012

1533-4023

Philippe Rousso, Thierry Buclin, Jürg Nussberger, Françoise Brunner‐Ferber, Hans R. Brunner, Jérôme Biollaz,

Hormonal Regulation and Hypertension

MDL 100,240, a dual inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), was administered intravenously to two panels of four healthy males in a four-period, dose-increasing (0, 1.56, 6.25, and 25 mg, and 0, 3.13, 12.5, and 50 mg, respectively) double-blind, placebo-controlled study. Plasma ACE activity and blood-pressure response to exogenous angiotensin I and angiotensin II i.v. challenges and safety and tolerance were assessed over a 24-h period. MDL 100,240 induced a rapid, dose-related, and sustained inhibition of ACE (>70% over 24 h at doses ≥12.5 mg). The time integral of ACE inhibition was related to the dose but with near-maximal values already attained at doses ≥12.5 mg. Systolic and diastolic blood-pressure responses to exogenous angiotensin I challenges were inhibited in a dose-dependent fashion, whereas the effects of angiotensin II remained unaffected. Mean supine blood pressure decreased transiently (3 h) at doses ≥3.125 mg and ≤24 h with the 25- and 50-mg doses, but not significantly. MDL 100,240 was well tolerated. In healthy subjects, MDL 100,240 exerts a dose-dependent and long-lasting ACE-blocking activity, also expressed by the inhibition of the pressor responses to exogenous angiotensin I challenges. The baroreceptor reflex, assessed by the response to exogenous angiotensin II challenge, remains unaltered.