A novel, potent and selective inhibitor of the activity of inducible nitric oxide synthase (GW274150) reduces the organ injury in hemorrhagic shock.
An enhanced formation of nitric oxide (NO) by the inducible NO synthase (iNOS) may contribute to the pathophysiology of hemorrhagic shock. This study investigates the effect of a novel, potent and selective inhibitor of iNOS activity (GW274150) on the circulatory failure and the organ injury and dysfunction associated with hemorrhagic shock in the anesthetised rat. Hemorrhage (sufficient to lower mean arterial blood pressure to 45 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 the pancreatic injury. Pre-treatment of rats with GW274150 (5 mg/kg at 30 min prior to the onset of hemorrhage) attenuated the renal dysfunction as well as the liver and pancreatic injury caused by hemorrhage and resuscitation. Interestingly, GW274150 did not reduce the delayed fall in blood pressure associated with hemorrhagic shock. We propose that an enhanced formation of NO from iNOS contributes to the organ injury and dysfunction in hemorrhagic shock, and that highly selective inhibitors of iNOS activity, such as GW274150, may represent a novel therapeutic approach for the therapy of hemorrhagic shock.
McDonald
M C
MC
The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London EC1M6BQ, UK.
Izumi
M
M
Cuzzocrea
S
S
Thiemermann
C
C
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000378:metabolism; D008297:Male; D009102:Multiple Organ Failure / Q000473:pathology / Q000503:physiopathology; D009504:Neutrophils / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D012771:Shock, Hemorrhagic / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D013440:Sulfides / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D013440:Sulfides; C409004:GW 274150; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat