Sildenafil Ameliorates Gentamicin-Induced Nephrotoxicity in Rats: Role of iNOS and eNOS

Abstract

Gentamicin, an aminoglycoside antibiotic, is used for the treatment of serious Gram-negative infections. However, its usefulness is limited by its nephrotoxicity. Sildenafil, a selective phosphodiesterase-5 inhibitor, was reported to prevent or decrease tissue injury. The aim of this study is to evaluate the potential protective effects of sildenafil on gentamicin-induced nephrotoxicity in rats. Male Wistar rats were injected with gentamicin (100 mg/kg/day, i.p.) for 6 days with and without sildenafil. Sildenafil administration resulted in nephroprotective effect in gentamicin-intoxicated rats as it significantly decreased serum creatinine and urea, urinary albumin, and renal malondialdehyde and nitrite/nitrate levels, with a concomitant increase in renal catalase and superoxide dismutase activities compared to gentamicin-treated rats. Moreover, immunohistochemical examination revealed that sildenafil treatment markedly reduced inducible nitric oxide synthase (iNOS) expression, while expression of endothelial nitric oxide synthase (eNOS) was markedly enhanced. The protective effects of sildenafil were verified histopathologically. In conclusion, sildenafil protects rats against gentamicin-induced nephrotoxicity possibly, in part, through its antioxidant activity, inhibition of iNOS expression, and induction of eNOS production.

Nitric oxide metabolite changes in gentamicin-induced nephrotoxicity; the effects of antioxidant vitamins

“…Another study has reported that antioxidant vitamins can elicit NO level and improve endothelial functioning (28). Contrary to our findings, Morsy at al, documented that GM could increase NO level (20). Other studies reported that NO does not have any important role in renal hemodynamic.…”

“…Enormous studies have shown some contradictory effects on serum and kidney level of NO. For example, Sadeghi et al reported that after administration of GM, serum and kidney levels of NO decreased (19), while Morsy et al documented that GM increased nitrite levels (20).…”

Phosphodiesterase type 5 inhibitors and kidney disease

“…In gentamicin-induced nephrotoxicity in rats, sildenafil significantly decreased serum creatinine, urea, urinary albumin excretion, renal malondialdehyde, and nitrite/nitrate levels, with a concomitant increase in renal catalase and superoxide dismutase activities and an improvement in histological injury, compared to gentamicin-treated control rats [44].…”

The role of activation of KАTP channels on hydrogen sulfide induced renoprotective effect on diabetic nephropathy

“…Regarding the level of total renal tissue (NO), the results obtained in this study displayed that it was significantly higher in diabetic rats than in the control rats. (Morsy et al, ) reported that NO production induced by inducible NO synthase (iNOS) increased by hyperglycemia, and increased the accumulation of the extracellular matrix in mesangial cells. At toxic concentrations that is produced by the iNOS, its “bad face” appears as leading to the renal inflammatory state through peroxynitrite (ONOO − ) formation, a proinflammatory cytokine, by reacting with superoxide anion (O 2 •− ).…”