title: Captopril and lisinopril only inhibit matrix metalloproteinase-2 (MMP-2) activity at millimolar concentrations.
abstract: Matrix metalloproteinase-2 (MMP-2) shares structural similarities with the angiotensin-converting enzyme (ACE). ACE inhibitors have been described to inhibit MMP-2, but this inhibitory potential was not shown using a highly purified MMP-2. This study aimed to investigate the inhibitory potential of captopril and lisinopril regarding MMP-2 activity. The first objective was to test the potential of captopril to change the pH of the buffer solution. The second objective was to test the direct inhibitory effect of captopril and lisinopril on plasma MMP-2 and on recombinant human MMP-2 (rhMMP-2). The in vitro activity assays included gelatin zymography and a fluorimetric assay. Captopril solubilization significantly decreased the pH of the 50 mM Tris buffer solution at the following concentrations: 2 mM (p < 0.05), 4 mM and 8 mM (p < 0.01), while only the 8 mM lisinopril induced a drop in pH (p < 0.05). Thus, only 200 mM buffer solutions were used. Zymography results of plasma MMP-2 and rhMMP-2 showed that inhibition only happened at captopril concentrations ≥ 4 and 1 mM, respectively (p < 0.05), while only the higher concentration of lisinopril (8 mM) inhibited plasma MMP-2 (p < 0.05). In the fluorimetric assay, captopril led to significant inhibition of the rhMMP-2 activity at concentrations ≥2 mM (p < 0.01), whereas aminophenylmercuric acetate-activated rhMMP-2 was inhibited by 0.5 mM captopril (p < 0.01). The captopril and lisinopril concentrations found to inhibit MMP-2 are 3 orders of magnitude higher than those present in vivo after drug administration. We also discuss possible pitfalls for gelatinase inhibitory assays (besides the obvious pH problem already cited). In conclusion, this study's data show that captopril and lisinopril did not inhibit MMP-2 directly at the concentrations reached in vivo.
authors.forename: Luciana B
authors.initials: LB
authors.lastname: Kuntze
authors.forename: Raquel C
authors.initials: RC
authors.lastname: Antonio
authors.forename: Tatiane C
authors.initials: TC
authors.lastname: Izidoro-Toledo
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Meschiari
authors.forename: Jose E
authors.initials: JE
authors.lastname: Tanus-Santos
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Gerlach
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D002216:Captopril / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005470:Fluorometry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D017706:Lisinopril / Q000008:administration & dosage / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects*; D011994:Recombinant Proteins
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011994:Recombinant Proteins; D002216:Captopril; D017706:Lisinopril; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2