Can Trimetazidine, Vinpocetine or Isosorbide Dinitrate Ameliorate Cyclosporine-Induced Nephrotoxicity in Rats?

BACKGROUND: The present study was conducted to investigate the effect of concurrent administration of trimetazidine (a mitochondrial stabilizing anti-anginal agent), vinpocetine (a phosphodiesterase-1 inhibitor) and isosorbide dinitrate (a NO donor) on nephrotoxicity induced by cyclosporine A (CsA) treatment. METHODS: Female albino rats were divided into eight groups. Group1 rats were treated with corn oil and served as normal control. Group2 received CsA (15mg/kg, s.c. for 4 weeks) and served as control. Groups 3 and 4 received CsA along with trimetazidine (5 & 10mg/kg, p.o). Groups 5 and 6 received CsA along with vinpocetine (5 & 10mg/kg, p.o). Groups 7 and 8 received CsA along with isosorbide dinitrate (3.6, and 7.2mg/kg p.o). Blood urea nitrogen (BUN), serum creatinine, serum uric acid and blood glucose were measured. Creatinine clearance (Ccr) and proteinuria were estimated. Reduced glutathione (GSH), lipid peroxides, nitric oxide (NO), and hydroxyproline contents were measured in kidney tissues. RESULTS: Injection of CsA increased BUN, serum creatinine, and blood glucose levels as well as renal hydroxyproline content. It also decreased C-cr and renal NO content. Only isosorbide dinitrate (3.6mg/kg) could partially improve CsA-dependent changes in renal function as shown by decrease in elevated serum creatinine and renal hydroxyproline content as well as improvement of C-cr. However, administration of isosorbide dinitrate at a higher dose (7.2mg/kg) along with CsA deteriorated the renal function reflected by decreased C-cr and renal NO content associated with proteinuria, increased BUN and uric acid levels. CONCLUSION: The current study demonstrates that isosorbide dinitrate at the dose of 3.6mg/kg could protect against CsA-induced nephrotoxicity, whereas both trimetazidine and vinpocetine are of unclear utility.