Mixed-Type Inhibition of Pulmonary Angiotensin I-Converting Enzyme by Captopril, Enalaprilat and Ramiprilat

Abstract We have compared at the enzymological level pulmonary angiotensin I-converting enzymes (ACE) purified to electrophoretic homogeneity from four mammalians species: pig, rat, monkey and human. Using both substrates hippuryl-histidyl-Ieucine and furylacryloyi-phenylal-anyl-glycyi-glycine in st...

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Bibliographic Details
Published in:Journal of enzyme inhibition 1999, Vol.14 (6), p.447-456
Main Authors: Baudin, Bruno, Bénéteau-Burnat, BÉNÉDicte
Format: Article
Language:English
Subjects:
Angiotensin I-converting enzyme
Angiotensin-Converting Enzyme Inhibitors - pharmacology
Animals
Binding, Competitive
Captopril
Captopril - pharmacology
Enalapril
Enalaprilat - pharmacology
Enzyme inhibition
Humans
Kinetics
Lung - enzymology
Macaca fascicularis
Peptidyl-Dipeptidase A - metabolism
Ramipril
Ramipril - analogs & derivatives
Ramipril - pharmacology
Rats
Rats, Sprague-Dawley
Swine
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Summary:Abstract We have compared at the enzymological level pulmonary angiotensin I-converting enzymes (ACE) purified to electrophoretic homogeneity from four mammalians species: pig, rat, monkey and human. Using both substrates hippuryl-histidyl-Ieucine and furylacryloyi-phenylal-anyl-glycyi-glycine in steady-state conditions, all the ACES exhibited Michaelis kinetics with identical Michaelis constants, maximal velocities, optimal pH and optimal activating chloride-concentrations. The apparent inhibitory constant was higher for Captopril than for Enalaprilat and even more so for Ramiprilat irrespective of the origin of ACE and the substrate used. Although these inhibitors have been described as competitive inhibitors, Lineweaver-Burk plots were not in accordance with a simple competitive model; moreover, Dixon plots were rather characteristic of non-competitive inhibition. These data emphasize the hypothesis that ACE inhibitors act with mixed-type inhibition, which is consistent with their slow-tight binding to the ACE active center, also with binding of chloride on a critical lysine residue leading to a potential conformational change, and finally with the fact that ACE has two domains, each bearing one catalytic site. On the other hand, as identical kinetic parameters were obtained on the different ACE preparations, results from animal models should allow the extrapolation to humans, in particular for investigations on both renin-angiotensin and kallikrein-kinin systems, and on their inhibition.
ISSN:1475-6366
8755-5093
1475-6374
DOI:10.3109/14756369909030335