Journal
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
Volume 114, Issue 3, Pages 233-239Publisher
WILEY-BLACKWELL
DOI: 10.1111/bcpt.12151
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Funding
- Conselho Nacional de Desenvolvimento Cientofico e Tecnologico (CNPq-Brazil)
- FAPESP (The State of Sao Paulo Research Foundation)
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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 50mM Tris buffer solution at the following concentrations: 2mM (p<0.05), 4 mM and 8mM (p<0.01), while only the 8mM lisinopril induced a drop in pH (p<0.05). Thus, only 200mM buffer solutions were used. Zymography results of plasma MMP-2 and rhMMP-2 showed that inhibition only happened at captopril concentrations 4 and 1mM, respectively (p<0.05), while only the higher concentration of lisinopril (8mM) inhibited plasma MMP-2 (p<0.05). In the fluorimetric assay, captopril led to significant inhibition of the rhMMP-2 activity at concentrations 2mM (p<0.01), whereas aminophenylmercuric acetate-activated rhMMP-2 was inhibited by 0.5mM 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.
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