Scavenging of peroxynitrite reduces renal ischemia/reperfusion injury.
BACKGROUND
Nitric oxide (NO) and peroxynitrite (OONO-) are implicated in the pathophysiology of renal ischemia/reperfusion (I/R). The aim of this study was to investigate and compare the efficiency of S-methylisothiourea (SMT), an iNOS inhibitor, and mercaptoethylguanidine (MEG), a scavenger of peroxynitrite, on renal dysfunction and injury induced by I/R of rat kidney.


METHODS
Thirty-two male Sprague-Dawley rats were divided into four groups: sham-operated, I/R, I/R+SMT, and I/R+MEG. Rats were given SMT (10 mg/kg i.p.) or MEG (10 mg/kg i.p.) 6 h prior to I/R and at the beginning of reperfusion. All rats except sham-operated underwent 60 min of bilateral renal ischemia followed by 6 h of reperfusion. After reperfusion, kidneys and blood were obtained for evaluation. Superoxide dismutase, glutathione peroxidase, malondialdehide, protein carbonyl content, and nitrite/nitrate level (NO(x)) were determined in the renal tissue. Serum creatinine (S(Cr)), blood urea nitrogen (BUN), and aspartate aminotransferase (AST) were determined in the blood. Additionally, renal sections were used for histological grade of renal injury.


RESULTS
SMT and MEG significantly reduced the I/R-induced increases in S(Cr), BUN, and AST. Both SMT and MEG attenuated the tissue NO(x) levels, indicating reduced NO production. In addition, SMT and MEG markedly reduced elevated oxidative stress product, restored decreased antioxidant enzymes, and attenuated histological alterations. Interestingly, MEG exerted a greater renoprotective effect than SMT.


CONCLUSIONS
These data support the finding that iNOS and peroxynitrite are involved in the renal I/R injury, and suggest that a scavenger of peroxynitrite might be more effective than iNOS inhibitors as a therapeutic intervention.
Guven
Ahmet
A
Department of Pediatric Surgery, Gulhane Military Medical Academy, Ankara, Turkey. drahmetguven@yahoo.com
Uysal
Bulent
B
Akgul
Ozgur
O
Cermik
Hakan
H
Gundogdu
Gokhan
G
Surer
Ilhami
I
Ozturk
Haluk
H
Korkmaz
Ahmet
A
D058186:Acute Kidney Injury / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D003404:Creatinine / Q000652:urine; D004195:Disease Models, Animal; D006146:Guanidines / Q000494:pharmacology*; D007150:Immunohistochemistry; D019194:Ischemic Preconditioning / Q000379:methods*; D007550:Isothiuronium / Q000031:analogs & derivatives* / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D030421:Peroxynitrous Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D012680:Sensitivity and Specificity
D006146:Guanidines; D030421:Peroxynitrous Acid; D007550:Isothiuronium; D009569:Nitric Oxide; D003404:Creatinine; D019001:Nitric Oxide Synthase; C027744:S-methylisothiopseudouronium; C100078:2-mercaptoethylguanidine