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

• Published in: Journal of cardiovascular pharmacology Vol. 31; no. 3; p. 408
• Main Authors: Rousso, P, Buclin, T, Nussberger, J, Brunner-Ferber, F, Brunner, H R, Biollaz, J
• Format: Journal Article
• Language: English
• Published: United States 01.03.1998
• Subjects: Adult; Angiotensin I - administration & dosage; Angiotensin II - administration & dosage; Angiotensin-Converting Enzyme Inhibitors - pharmacokinetics; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Antihypertensive Agents - pharmacokinetics; Antihypertensive Agents - pharmacology; Area Under Curve; Benzazepines - pharmacokinetics; Benzazepines - pharmacology; Blood Pressure - drug effects; Double-Blind Method; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Humans; Male; Neprilysin - antagonists & inhibitors; Placebos; Pyridines - pharmacokinetics; Pyridines - pharmacology; Reference Values
• ISSN: 0160-2446
• DOI: 10.1097/00005344-199803000-00012

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 > or =12.5 mg). The time integral of ACE inhibition was related to the dose but with near-maximal values already attained at doses > or =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 > or =3.125 mg and < or =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.