title: The free-radical scavenger, edaravone, augments NO release from vascular cells and platelets after laser-induced, acute endothelial injury in vivo.
abstract: In vitro and in vivo experimental models have demonstrated that vascular endothelial function is significantly impaired as a result of oxidative stress, mediated by the generation of oxygen-derived free radicals in response to chronic or acute inflammation. In particular, super-oxide () at specific concentrations leads to the impairment of nitric oxide (NO) bioactivity, and it is known that NO plays a fundamental role in the maintenance of vascular homeostasis. The relationship between reactive oxygen species (ROS) and NO release in thrombosis-related endothelial damage in the peripheral microvasculature remains unclear, however. The purpose of the present study was to investigate the effect of the free-radical scavenger, edaravone, on NO synthesis and thrombotic potential in arterioles after exposure to laser irradiation. Highly sensitive electrochemical NO microsensors were positioned in femoral arterioles of mice, and the kinetics of NO release were recorded in response to standardized laser irradiation in vivo. In addition, images of NO release from damaged vascular cells were investigated in a similar rat model using the NO-sensitive dye 4,5-diaminofluorescein diacetate (DAF-2DA). Thrombogenesis was assessed in carotid arterioles by continuous video microscopy using image analysis software. Laser irradiation led to NO release from perturbed endothelial cells and from platelet-rich thrombi. Edaravone had no significant effect on NO release in non-laser treated, intact endothelium compared with placebo. In contrast, edaravone demonstrated a dose-dependent effect on NO release and thrombogenicity. At a concentration of 10.5 mg/kg per h, edaravone promoted a 5-fold increase in NO and a reduction in platelet-rich thrombus volume to 58% of the placebo values. Our data provide direct evidence to confirm that acute endothelial damage in peripheral microvessels initially induces NO release and that the free-radical scavenger, edaravone, augments NO synthesis leading to suppression of platelet thrombus formation.
authors.affiliation: Laboratory of Physiology, Faculty of Nutrition, and High Technology Research Center, Kobe Gakuin University, Kobe, Japan. tsutomu@nutr.kobegakuin.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
authors.forename: M
authors.initials: M
authors.lastname: Shoge
authors.forename: E
authors.initials: E
authors.lastname: Oda
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: J C
authors.initials: JC
authors.lastname: Giddings
authors.forename: S
authors.initials: S
authors.lastname: Kashiwagi
authors.forename: M
authors.initials: M
authors.lastname: Suematsu
authors.forename: J
authors.initials: J
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077553:Edaravone; D004563:Electrochemistry / Q000379:methods; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D019793:Fluorescein; D016166:Free Radical Scavengers / Q000494:pharmacology*; D007091:Image Processing, Computer-Assisted; D007202:Indicators and Reagents; D007834:Lasers; D008642:Mesenteric Veins / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000737:chemistry; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013927:Thrombosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D014652:Vascular Diseases / Q000503:physiopathology; D020246:Venous Thrombosis / Q000503:physiopathology
chemical_list: C414689:4,5-diaminofluorescein diacetate; D016166:Free Radical Scavengers; D007202:Indicators and Reagents; D009569:Nitric Oxide; D000077553:Edaravone; D000983:Antipyrine; D019793:Fluorescein