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 acetateactivated 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.

Matrix Metalloproteinases in Myocardial Infarction and Heart Failure

“…113 For example, captopril and lisinopril inhibit MMP-2 activity at concentrations greater than 4 and 1 mmol/L, whereas MMP-9 was inhibited by 87 nmol/L of captopril. 114, 115 ACE inhibitors bind to S1 and S1′ subsite of MMP-9, which forms a deep hydrophobic pocket similar to the hydrophobic moieties in the ACE active site. 113 Lisinopril is stabilized to the MMP-9 active site by specific hydrogen bonds and hydrophobic interactions, and its hydrophobic group showed greater affinity with the S1 site in comparison to the S1′ site.…”

(Un)suitability of the use of pH buffers in biological, biochemical and environmental studies and their interaction with metal ions – a review

“…Inhibition of gelatinases by captopriland lisinopril 177 Tris Nitrogenase electron transfer mechanism 178 MOPS Modulation of connexin channel activity 92 MES, HEPES and TAPS Characterization of P-type ATPase in Thermus thermophilus 179 Tris Measurement of high-density lipoprotein-subclass cholesterol 35 BES Separation of nucleic acids and proteins by electrophoresis 9,96 Tris 91 and MES, HEPES and TAPS, when in the protonated form, inhibit the connexin channel activity in rat liver cells. 92 Animal cells seem to be more sensitive to the presence of the buffer, most likely due the absence of a cell wall.…”

Matrix Metalloproteinases are Involved in Cardiovascular Diseases

“…Most importantly, in the clinical setting, these drugs do not emerge at millimolar levels in the plasma or tissues. Using highly purified MMP-2 to conduct both zymograms and fluorimetric assays, Kuntze et al [147] have shown that the pH of the solution containing the drugs may drop, which is most likely the reason why a series of studies in the past found that captopril inhibited gelatinases. MMP-2 inhibition by captopril and lisinopril only takes place at millimolar levels.…”

“…MMP‐2 inhibition by captopril and lisinopril only takes place at millimolar levels. Thus, direct MMP inhibition by ACE inhibitors is probably only a minor concern for the in vivo situation .…”