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Matrix metalloproteinase‐2 inhibition by temocapril and its important role in peritoneal transport
Author(s) -
Yamamoto Daisuke,
Takai Shinji,
Akimoto Tetsu,
Hirahara Ichiro,
Ito Chiharu,
Muto Shigeaki,
Kusano Eiji
Publication year - 2012
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2012.12003.x
Subject(s) - matrix metalloproteinase , peritoneal dialysis , pharmacology , chemistry , captopril , angiotensin converting enzyme , medicine , endocrinology , biochemistry , blood pressure
Summary Matrix metalloproteinase ( MMP )‐2 plays an important role in tissue remodelling during peritoneal injury caused by peritoneal dialysis ( PD ), but MMP ‐2 inhibitors have not yet been used clinically. Recently, it was reported that captopril, an angiotensin‐converting enzyme inhibitor ( ACEI ), can inhibit MMP ‐2. To investigate the potential usefulness of ACEI during PD , the molecular interaction between the MMP ‐2 active site and the active form of temocapril (temocaprilat) was investigated using molecular modelling. Furthermore, the effects of temocapril on MMP ‐2 activity in peritoneal effluents and the peritoneal solute transport rate of PD patients were determined. Temocaprilat bound to the MMP ‐2 active centre and recognized two hydrophobic substrate‐binding sites in the MMP ‐2 molecular model. Matrix metalloproteinase‐2 activity in peritoneal effluents was directly inhibited by temocaprilat ( IC 50 0.47 μmol/L). In one patient given temocapril, the peritoneal solute transport rate decreased gradually during PD . Temocapril may prove to be an important candidate for development as a novel therapeutic agent for MMP ‐2 inhibition to prevent peritoneal injury caused by PD .