The Effect of Sildenafil on Cisplatin Nephrotoxicity in Rats

Abstract

Sildenafil, the first drug for erectile dysfunction, has cardiopulmonary protective actions. A recent study has reported that sildenafil given intraperitoneally (i.p.) attenuated cisplatin (CP)-induced nephrotoxicity. Here, we evaluated whether sildenafil, given by two different routes and at two different doses, can attenuate CP-induced nephrotoxicity and would also affect renal haemodynamics in CP-treated rats. Six groups of rats were treated with saline (controls), CP [5mg/kg, intraperitoneally (i.p.) once], sildenafil (0.4mg/kg/day, i.p. for 5days), sildenafil (0.4mg/kg/day i.p. for 5days) plus CP (5mg/kg, i.p., once), sildenafil [10mg/kg/day, subcutaneous (s.c.) for 5days] or sildenafil (10mg/kg/day, s.c. for 5days) plus CP (5mg/kg, i.p. once). Five days after the end of the treatments, urine was collected from all rats, which were then anaesthetized for blood pressure and renal blood flow monitoring. This was followed by intravenous (i.v.) injection of norepinephrine for the measurement of renal vasoconstrictor responses. Thereafter, blood and kidneys were collected for measurement of several biochemical, functional and structural parameters. CP reduced body-weight and renal blood flow but did not affect norepinephrine-induced renal vasoconstriction. It increased the plasma concentrations of urea and creatinine, and reduced creatinine clearance. CP caused extensive renal tubular necrosis, increased urine volume and N-acetyl-β-d-glucosaminidase activity. When sildenafil (0.4mg/kg/day, i.p. for 5days) was combined with cisplatin, there was a dramatic improvement in renal histopathology, reduction in N-acetyl-β-d-glucosaminidase and increase in renal blood flow. However, sildenafil (10mg/kg/day, s.c. for 5days) did not affect CP nephrotoxicity, suggesting the importance of dose and route selection of sildenafil as a nephroprotectant. © 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.