title: Inhibition of Glutathione S-Transferase by Ethacrynic Acid Augments Ischemia-Reperfusion Damage and Apoptosis and Attenuates the Positive Effect of Ischemic Postconditioning in a Bilateral Acute Hindlimb Ischemia Rat Model.
abstract: OBJECTIVE
  We studied the effects of the inhibition of the endogene antioxidant glutathione-S-transferase (GST) by ethacrynic acid (EA) on ischemia-reperfusion (IR) injury and postconditioning (PC) in the lower extremities. We aimed to examine the oxidative stress parameters (OSP), inflammatory response and activation of proapoptotic signaling proteins (PSP) after revascularization surgery.
  
  
  METHODS
  Sixty Wistar rats were divided into 6 groups: control, IR, PC, EA-control, IR and administration of EA (IR/EA) and PC and administration of EA (PC/EA). The IR, PC, IR/EA and PC/EA groups underwent 60 min of infrarenal aortic cross-clamping. After that, PC was performed in the PC and PC/EA groups. In 3 of the groups, the animals were treated with EA (EA-control, IR/EA and PC/EA groups) as well. The ischemia was followed by 120 min of reperfusion. Blood samples and biopsy specimens were collected from the quadriceps muscle. Plasma malondialdehyde, reduced glutathione, thiol/sulfhydryl group levels, TNF-α and IL-6 concentrations and superoxide-dismutase enzyme activity were measured.
  
  
  RESULTS
  The levels of the OSP and the inflammatory proteins were higher in the EA-administered groups. The ratio of phosphorylated PSP was higher in the EA-administered groups and the protective effect of PC did not develop.
  
  
  CONCLUSIONS
  Inhibition of GST by EA augmented the IR damage. GST inhibition was associated with a different activation of the mitogen-activated protein kinases and the PSP, regulating these pathways in the process of apoptosis and PC.
authors.affiliation: Departments of Surgical Research and Techniques, Medical School, University of Pécs, Pécs, Hungary.
authors.forename: Tibor
authors.initials: T
authors.lastname: Nagy
authors.forename: Viktória
authors.initials: V
authors.lastname: Kovács
authors.forename: Péter
authors.initials: P
authors.lastname: Hardi
authors.forename: Tünde Gyöngyvér
authors.initials: TG
authors.lastname: Veres
authors.forename: Ildikó
authors.initials: I
authors.lastname: Takács
authors.forename: Gábor
authors.initials: G
authors.lastname: Jancsó
authors.forename: László
authors.initials: L
authors.lastname: Sinay
authors.forename: Gábor
authors.initials: G
authors.lastname: Fazekas
authors.forename: Örs
authors.initials: Ö
authors.lastname: Pintér
authors.forename: Endre
authors.initials: E
authors.lastname: Arató
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004976:Ethacrynic Acid / Q000633:toxicity*; D005978:Glutathione / Q000097:blood; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply*; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood; D057775:Ischemic Postconditioning; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011183:Postoperative Complications / Q000201:enzymology / Q000473:pathology*; D052097:Quadriceps Muscle / Q000098:blood supply / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000097:blood; D013482:Superoxide Dismutase / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D015850:Interleukin-6; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D005982:Glutathione Transferase; D005978:Glutathione; D004976:Ethacrynic Acid