A membrane-permeable radical scavenger reduces the organ injury in hemorrhagic shock.
Reactive oxygen species (ROS) contribute to the multiple organ failure (MOF) in hemorrhagic shock. Here we investigate the effects of a membrane-permeable radical scavenger (tempol) on the circulatory failure and the organ injury and dysfunction (kidney, liver, lung, intestine) associated with hemorrhagic shock in the anesthetized rat. Hemorrhage (sufficient to lower mean arterial blood pressure to 500 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure, renal and liver injury and dysfunction as well as lung and gut injury. In all organs, hemorrhage and resuscitation resulted in the nitrosylation of proteins (determined by immunohistochemistry for nitrotyrosine) suggesting the formation of peroxynitrite and/or reactive oxygen species. Treatment of rats upon resuscitation with the membrane-permeable radical scavenger tempol (30 mg/kg bolus injection followed by an infusion of 30 mg/kg/h i.v.) attenuated the delayed circulatory failure as well as the multiple organ injury and dysfunction associated with hemorrhagic shock. Thus, we propose that an enhanced formation of ROS and/or peroxynitrite importantly contributes to the MOF in hemorrhagic shock, and that membrane-permeable radical scavengers, such as tempol, may represent a novel therapeutic approach for the therapy of hemorrhagic shock.
Mota-Filipe
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The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, UK.
McDonald
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Cuzzocrea
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Thiemermann
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D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects*; D003497:Cyclic N-Oxides / Q000627:therapeutic use*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009102:Multiple Organ Failure / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000188:drug therapy*; D013113:Spin Labels; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D013113:Spin Labels; C002744:3-nitrotyrosine; D014443:Tyrosine; C001803:tempol