Differential roles of dihydropyridine calcium antagonist nifedipine, nitrendipine and amlodipine on gentamicin-induced renal tubular toxicity in rats

In the present study, we investigated the antioxidative potencies of dihydropyridine calcium antagonists prototype nifedipine, the second generation drug nitrendipine, and the long acting, third generation drug amlodipine on gentamicin-induced renal tubular toxicity in Sprague–Dawley rats. In addition, we analyzed the relationship between renal tubular cell apoptosis and the antioxidative properties of these dihydropyridine calcium antagonists. Results showed that treatment with gentamicin alone caused significant changes in the levels of urinary protein, urinary N-acetyl-beta-d-glucosaminidase, serum creatinine, and blood urea nitrogen. Nifedipine and amlodipine effectively reversed the effect of gentamicin on these parameters. In contrast, nitrendipine either had no effect or worsened gentamicin-induced changes in the levels of urinary protein, urinary N-acetyl-beta-d-glucosaminidase, serum creatinine, and blood urea nitrogen. Furthermore, gentamicin treatment caused significant increases in the levels of malondialdehyde, nitric oxide, nitric oxide synthase and significant decreases in the levels of reduced glutathione, glutathione-S-transferase, and superoxide dismutase in kidney tissues. These effects were dramatically reduced by nifedipine and amlodipine but not affected by nitrendipine. In addition to the biochemical changes, histopathological studies showed that gentamicin caused structural damages in the kidneys; renal tubular cell apoptosis, a decrease in Bcl-2 expression and an increase in Bax expression were observed in all rats treated with gentamicin, nifedipine and amlodipine effectively reversed the effect of gentamicin while nitrendipine worsened them. In conclusion, this study clearly indicated that nifedipine and amlodipine protected against gentamicin-induced nephrotoxicity while nitrendipine had little effect, or even worsened.