The control of vascular endothelial cell injury.
The mechanism by which MCI-186 showed a potent cytoprotective effect on the in vitro endothelial cell injury due to 15-HPETE was studied. Stimulation of human leukocytes with various chemical mediators such as TPA, f-Met-Leu-Phe, LTB4, etc. elicited the production of active oxygens, which could be detected by luminol-dependent chemiluminescence. Among the chemical mediators tested, TPA elicited the chemiluminescence the most, and f-Met-Leu-Phe and LTB4 came next. When the leukocytes were directly placed on a monolayer of cultured endothelial cells, followed by stimulating the leukocytes with TPA, severe endothelial cell injury was observed. The effect of TPA was dose dependent. There was good correlation between the active oxygen releasing activity and the cytotoxic activity. When the leukocytes were placed on a filter which was set apart from the monolayer of endothelial cell in a culture dish, and stimulated the leukocytes with TPA, no cytotoxicity was observed. These data strongly suggest that the substance responsible for the cytotoxicity must be a very labile and short-lived substance, presumably active oxygens. On the other hand, MCI-186 was found to have a complete quenching activity to the chemiluminescence due to active oxygens in the TPA-leukocyte system. Taken together, these factors indicate that the potent cytoprotective effect of MCI-186 may be due to its specific radical scavenging activity.
Murota
S
S
Section of Physiological Chemistry, Faculty of Dentistry, Tokyo Medical and Dental University, Japan.
Morita
I
I
Suda
N
N
D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D000077553:Edaravone; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D016166:Free Radical Scavengers; D007962:Leukocytes / Q000378:metabolism; D015289:Leukotrienes / Q000633:toxicity; D008054:Lipid Peroxides / Q000633:toxicity; D008163:Luminescent Measurements; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016166:Free Radical Scavengers; D015289:Leukotrienes; D008054:Lipid Peroxides; C025086:15-hydroperoxy-5,8,11,13-eicosatetraenoic acid; D013755:Tetradecanoylphorbol Acetate; D000077553:Edaravone; D000983:Antipyrine