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Abstract
This study is the first to investigate the role of the KATP channel in the possible protection mediated by nicorandil against cyclophosphamide-induced lung and testicular toxicity in rats. Animals received cyclophosphamide (150 mg/kg/day, i.p.) for 2 consecutive days and then were untreated for the following 5 days. Nicorandil (3 mg/kg/day, p.o.) was administered starting from the day of cyclophosphamide injection with or without glibenclamide (5 mg/kg/day, p.o.). Nicorandil administration significantly reduced the cyclophosphamide-induced deterioration of testicular function, as demonstrated by increases in the level of serum testosterone and the activities of the testicular 3β- hydroxysteroid, 17β-hydroxysteroid and sorbitol dehydrogenases. Furthermore, nicorandil significantly alleviated oxidative stress (as determined by lipid peroxides and reduced glutathione levels and total antioxidant capacity), as well as inflammatory markers (tumour necrosis factor-α and interleukin-1β), in bronchoalveolar lavage fluid and testicular tissue. Finally, the therapy decreased the levels of fibrogenic markers (transforming growth factor-β and hydroxyproline) and ameliorated the histological alterations (as assessed by lung fibrosis grading and testicular Johnsen scores). The co-administration of glibenclamide (a KATP channel blocker) blocked the protective effects of nicorandil. In conclusion, KATP channel activation plays an important role in the protective effect of nicorandil against cyclophosphamide-induced lung and testicular toxicity.
Highlights
May be key features of the maintenance and progression of fibrosis, where the inhibition of proteases that degrade the extracellular matrix modulates profibrogenic and proinflammatory cytokines, such as transforming growth factor-β (TGF-β ) and tumour necrosis factor-α (TNF-α )[12,13]
The reduction in body weight might be attributed to the cytotoxic and wasting effect of CP32, whereas the increase in lung weight could be due to hyperplasia, inflammation, interstitial fluid accumulation, oedema and increased collagen synthesis, as confirmed by the biochemical and histological results
Atrophy of the testis is an index of drug toxicity and was shown by a significant decrease in the serum testosterone level and testicular 3β -hydroxysteroid dehydrogenase (HSD), 17β -HSD and sorbitol dehydrogenase (SDH) activities
Summary
May be key features of the maintenance and progression of fibrosis, where the inhibition of proteases that degrade the extracellular matrix modulates profibrogenic and proinflammatory cytokines, such as transforming growth factor-β (TGF-β ) and tumour necrosis factor-α (TNF-α )[12,13]. Nicorandil has previously been shown to inhibit the development of experimentally induced prostatic hyperplasia and mesangioproliferative glomerulonephritis[15,16]. Nicorandil, as a KATP channel opener, has been shown to inhibit monocrotaline-induced inflammation and proliferation in lung tissue in rats[17]. The administration of nicorandil has been found to reduce oxidative stress by stimulating KATP channel opening, independently of its ability to donate NO18. The aim of the present study was to investigate the protective effect of nicorandil on CP-induced lung and testicular toxicity. It examined the role of KATP channel opening in the possible protection mediated by nicorandil
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