Salvage of cyclosporine A-induced oxidative stress and renal dysfunction by carvedilol.
BACKGROUND
Cyclosporine A (CsA) is the first-line immunosuppressant employed for the management of solid organ transplantation and autoimmune diseases. Nephrotoxicity is the major limitation of CsA use. Recent evidence suggests that reactive oxygen species (ROS) play an important role in mediating CsA nephrotoxicity. The present study was designed to investigate effects of carvedilol, a third-generation beta-blocker with potent free radical-scavenging activity on CsA-induced oxidative stress and resultant renal dysfunction in a rat model of chronic CsA nephrotoxicity.


METHODS
Carvedilol (2.0 and 4.0 mg/kg i.p.) and propranolol (10 mg/kg i.p.) were administered to separate group of animals 24 h before and concurrently with CsA (20 mg/kg s.c.) for 21 days. Renal function was assessed by estimating plasma creatinine, blood urea nitrogen (BUN), creatinine and urea clearance. Tissue lipid peroxidation was measured as thiobarbituric acid-reacting substances (TBARS). Renal morphological alterations were assessed by histopathological examination of hematoxylin-eosin, PAS and Masson's trichrome stained sections of the kidneys.


RESULTS
CsA (20 mg/kg s.c) administration for 21 days produced elevated levels of TBARS and deteriorated renal function as assessed by increased plasma creatinine, BUN and decreased creatinine and urea clearance as compared to vehicle-treated rats. The kidneys of CsA-treated rats showed severe striped interstitial fibrosis, arteriolopathy, glomerular basement thickening, tubular vacuolization and hyaline casts. Propranolol neither decreased TBARS nor improved the renal dysfunction and morphological changes induced by CsA. Both doses of carvedilol markedly reduced elevated levels of TBARS, whereas the higher dose of carvedilol significantly attenuated renal dysfunction and morphological changes in CsA-treated rats.


CONCLUSIONS
These data clearly indicate the renoprotective potential of carvedilol in CsA-induced nephrotoxicity and suggest a significant contribution of its antilipoperoxidative property in this beneficial effect.
Padi
Satyanarayana S V
SS
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India.
Chopra
Kanwaljit
K
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004326:Drinking / Q000187:drug effects; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014556:Urine
D000975:Antioxidants; D002227:Carbazoles; D007166:Immunosuppressive Agents; D011412:Propanolamines; D000077261:Carvedilol; D016572:Cyclosporine