Differential effects of dihydropyridine calcium antagonists on doxorubicin-induced nephrotoxicity in rats

The aim of this study was to compare the roles of dihydropyridine calcium antagonists nifedipine, nitrendipine, amlodipine on doxorubicin (DXR)-induced nephrotoxicity in rats using biochemical, histopathological and immunohistochemical approaches. Male Sprague–Dawley rats were randomly divided into five experimental groups: control; DXR; DXR + nifedipine (15 mg/kg); DXR + nitrendipine (10 mg/kg); DXR + amlodipine (5 mg/kg). Results showed that treatment with DXR alone caused significant changes in the levels of urinary protein, serum creatinine (SCr), and blood urea nitrogen (BUN). Co-administration with amlodipine effectively reversed the effect of DXR on these parameters. In contrast, nifedipine and nitrendipine either had no effect or worsened DXR induced changes in the levels of urinary protein, SCr and BUN. Furthermore, DXR treatment caused significant increases in the levels of malondialdehyde (MDA), nitric oxide (NO), nitric oxide synthase (NOS) and significant decreases in the levels of reduced glutathione (GSH), glutathione-S-transferase (GST), and superoxide dismutase (SOD). These effects were significantly reduced by co-administration with amlodipine but not affected by nifedipine and worsened by nitrendipine. In addition to the biochemical changes, histopathological studies showed that DXR caused significant structural damages in the kidneys. Glomerular cell apoptosis, a decrease in Bcl-2 expression and an increase in Bax expression were observed in all rats treated with DXR. Co-administration with amlodipine effectively reversed the effect of DXR while nifedipine and nitrendipine had no effect. In conclusion, this study clearly indicated that amlodipine protected against DXR-induced nephrotoxicity while nifedipine and nitrendipine had no effect.