Combination therapy of N-acetylcysteine, sodium nitroprusside and phosphoramidon attenuates ischemia-reperfusion injury in rat kidney.
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.
Dobashi
Kazushige
K
Department of Pediatrics and Pathology, Medical University of South Carolina, Charleston, SC 29425, USA.
Singh
Inderjit
I
Orak
John K
JK
Asayama
Kohtaro
K
Singh
Avtar K
AK
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
D000975:Antioxidants; D006020:Glycopeptides; D009599:Nitroprusside; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C008890:phosphoramidon; D000111:Acetylcysteine