title: Combination therapy of N-acetylcysteine, sodium nitroprusside and phosphoramidon attenuates ischemia-reperfusion injury in rat kidney.
abstract: Renal ischemia is of clinical interest because of its role in renal failure and also renal graft rejection. To evaluate the effect of the combination of N-acetylcysteine (NAC), a potent antioxidant, sodium nitroprusside (SNP), a nitric oxide donor, and phosphoramidon (P), an endothelin converting enzyme inhibitor, on tissue protection against ischemia-reperfusion injury, we studied the biochemical and morphological changes due to 90 min of renal ischemia-reperfusion in the rat model. Ninety min of ischemia caused very severe injury and the animals could not survive after 4 days without any treatment. Whereas, animals in the treated groups survived i.e. the NAC group (25%), NAC + SNP group (43%) and in the NAC + SNP + P group (100%), 2 weeks after 90 min of ischemia. A significant increase in the serum levels of creatinine and urea nitrogen was shown in the untreated group and to a much lesser extent in the treated group, especially in the NAC + SNP + P group. The protective effect was also supported by light microscopic studies on renal tissue sections. We also measured the activities of antioxidant enzymes in tissue homogenates. With the exception of Mn-superoxide dismutase, the activities of antioxidant enzymes (catalase, glutathione peroxidase, CuZn-superoxide dismutase) were decreased in the untreated kidney. The administration of NAC alone and NAC + SNP protected against the loss of activities. Treatment with a combination of NAC, SNP and P showed a synergistic effect as evidenced by the best protection. These results suggest that pre-administration of a combination of antioxidant (NAC) with endothelin derived vasodilators (sodium nitroprusside and Phosphoramidon) attenuates renal ischemia-reperfusion injury, e.g. in donor kidney for transplantation, by protecting cells against free radical damage.
authors.affiliation: Department of Pediatrics and Pathology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Dobashi
authors.forename: Inderjit
authors.initials: I
authors.lastname: Singh
authors.forename: John K
authors.initials: JK
authors.lastname: Orak
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Asayama
authors.forename: Avtar K
authors.initials: AK
authors.lastname: Singh
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants; D002374:Catalase / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005979:Glutathione Peroxidase / Q000378:metabolism; D006020:Glycopeptides / Q000494:pharmacology*; D019194:Ischemic Preconditioning; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors
chemical_list: D000975:Antioxidants; D006020:Glycopeptides; D009599:Nitroprusside; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C008890:phosphoramidon; D000111:Acetylcysteine