The effect of sildenafil on cisplatin nephrotoxicity in rats

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 [5 mg/kg, intraperitoneally (i.p.) once], sildenafil (0.4 mg/kg/day, i.p. for 5 days), sildenafil (0.4 mg/kg/day i.p. for 5 days) plus CP (5 mg/kg, i.p., once), sildenafil [10 mg/kg/day, subcutaneous (s.c.) for 5 days] or sildenafil (10 mg/kg/day, s.c. for 5 days) plus CP (5 mg/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 (0.4 mg/kg/day, i.p. for 5 days) 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 (10 mg/kg/day, s.c. for 5 days) did not affect CP nephrotoxicity, suggesting the importance of dose and route selection of sildenafil as a nephroprotectant.     

Time-course effects of systemically administered diesel exhaust particles in rats

Nanosized fraction of particulate air pollution has been reported to translocate from the airways into the bloodstream and act on different organs. However, the direct effect of these translocated particles is not well understood. In this study, we determined the time-course (6h, 18 h, 48 h and 168 h) effects of the systemic administration of 0.02 mg/kg diesel exhaust particles (DEP) on systolic blood pressure (SBP), systemic inflammation, oxidative status, and morphological alterations in lungs, heart, liver and kidneys in Wistar rats. SBP was significantly decreased at 6 h (P < 0.05) but no significant effects have been observed at later time points. The leukocyte numbers were increased at 6 h (P < 0.05) and 18 h (P < 0.05). However, the platelet numbers were significantly decreased (P < 0.05) 6 h following the systemic administration of DEP. The IL-6 concentrations in plasma was increased at 6 h (P < 0.05) and 18 h (P < 0.05). Similarly, superoxide dismutase activity was significantly increased at 6 (P = 0.01) and 18 h (P < 0.05) following DEP exposure. The direct addition of DEP (0.1–1 μg/ml) to untreated rat blood significantly induced in vitro platelet aggregation in a dose-dependent fashion. The activation of intravascular coagulation was confirmed by a dose-dependent shortening of activated partial thromboplastin time and the prothrombin time following in vitro exposure to DEP (0.25–1 μg/ml). Histological analysis revealed the presence of DEP in the lungs, heart, liver and kidneys. However, the morphological changes were only observed in the lungs, where the presence of infiltration of inflammatory cells was observed as early as 6 h, increased at 18 h, and decreased in intensity at 48 h and at 168 h. We conclude that the direct systemic administration of DEP caused acute effect on SBP (6 h) and systemic inflammation and oxidative stress mainly at 6 h and 18 h. Despite the presence of DEP in lungs, heart, liver and kidneys, the histopathological changes were only seen in the lung which suggests that, at the dose and time-points investigated, DEP cause inflammation and have a predilection for pulmonary tissue.