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Inducible nitric oxide synthase inhibition in cyclophosphamide induced hemorrhagic cystitis in rats

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Abstract

Cyclophosphamide (CP) is an antineoplastic agent used alone or in combination with other chemotherapeutic agents for the treatment of many neoplastic diseases. Hemorrhagic cystitis (HC) is a major potential toxicity and dose limiting side effect of CP. Recently, it has been shown that endogenous inflammatory mediators are involved in cystitis by increasing nitric oxide (NO) production in target tissue. The aim of this study was to evaluate the relationship between NO and CP induced hemorrhagic cystitis HC in rats. A total of 30 female Spraque-Dawley rats were divided into 4 groups. Group 1 served as control, three groups received single dose of CP (100 mg/kg) intraperitoneally (i.p.): group 2 received CP only. Group 3 received the NO precursor L-arginine (80 mg/kg/day), and group 4 received the selective inducible NO synthase (iNOS) inhibitor S-methylisothiourea (SMT; 20 mg/kg/day) before and the day after cyclophosphamide injection. CP injection resulted in severe cystitis. SMT but not L-arginine produced marked inhibition of CP induced bladder damage. We concluded that NO produced by iNOS, is an important mediator in the pathogenesis of CP induced cystitis.

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References

  1. Levine LA, Richie JP (1989) Urological complications of cyclophosphamide. J Urol 141:1063–1069

    CAS  PubMed  Google Scholar 

  2. Philips FS, Sternberg SS, Cronin AP, Vidal PM (1961) Cyclophosphamide and urinary bladder toxicity. Cancer Res 21:1577–1589

    CAS  PubMed  Google Scholar 

  3. Brock N, Pohl J, Stekar J (1981) Studies on the urotoxicity of oxazaphosphorine cytostatics and its prevention. I.Experimental studies on the urotoxicity of alkylating compounds. Eur J Cancer 17:595–607

    CAS  PubMed  Google Scholar 

  4. West NJ (1997) Prevention and treatment of hemorrhagic cystitis. Pharmacotherapy 17:696–706

    CAS  PubMed  Google Scholar 

  5. Brock N, Pohl J (1983) The development of mesna for regional detoxification. Cancer Treat Rev 10[suppl A]:33–43

  6. Gomes TN, Santos CC, Souza-Filho MV, Cunha FQ, Ribeiro RA (1995) Participation of TNF-α and IL-1 in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis. Braz J Med Biol Res 28:1103–1108

    CAS  PubMed  Google Scholar 

  7. Souza-Filho MV, Lima MV, Pompeu MM, Ballejo G, Cunha FQ, Ribeiro RA (1997) Involvement of nitric oxide in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis. Am J Pathol 150:247–256

    CAS  PubMed  Google Scholar 

  8. Ribeiro RA, Feritas HC, Campos MC, Santos CC, Figueiredo FC, Brito GA, Cunha FQ (2002) Tumor necrosis factor-α and interleukin-1β mediate the production of nitric oxide involved in the pathogenesis of ifosfamide induced hemorrhagic cystitis in mice. J Urol 67:2229–2234

    Article  Google Scholar 

  9. Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharm Rev 43:109–142

    CAS  PubMed  Google Scholar 

  10. Hibbs JB, Taintor RR, Vavrin Z (1987) Macrophage cytotoxicity: role forL-arginine deiminase and imino nitrogen oxidation to nitrite. Science 235:473–476

    CAS  PubMed  Google Scholar 

  11. Tracey WR, Tse J, Carter G (1995) Lipopolisaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors. J Pharmacol Exp Ther 272:1011–1015

    CAS  PubMed  Google Scholar 

  12. Xu X, Cubeddu LX, Malave A (2001) Expression of inducible nitric oxide synthase in primary culture of rat bladder smooth muscle cells by plasma from cyclophosphamide-treated rats. Eur J Pharmacol 416:1–9

    Article  CAS  PubMed  Google Scholar 

  13. Alfieri AB, Cubeddu LX (2000) Nitric oxide and NK1-tachykinin receptors in cyclophosphamide-induced cystitis, in rats. J Pharmacol Exp Ther 295: 824–829

    CAS  PubMed  Google Scholar 

  14. Alfieri AB, Malave A, Cubeddu LX (2001) Nitric oxide synthases an cyclophosphamide-induced cystitis in rats. Naunyn Schmiedebergs Arch Pharmacol 363:353–357

    Article  CAS  PubMed  Google Scholar 

  15. Moncada S, Higgs A, Furchgott R (1997) International union of pharmacology nomenclature in nitric oxide research. Pharm Rev 49:137–142

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Gulhane Military Medical Academy Research and Progress Center (AR-2001/48).

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Authors and Affiliations

  1. Gulhane Military Medical Academy, Department of Physiology, Ankara, Turkey

    Sukru Oter, Ahmet Korkmaz, Turgut Topal & Hayati Bilgic

  2. Gulhane Military Medical Academy, Department of Histology and Embryology, Ankara, Turkey

    Emin Oztas

  3. Gulhane Military Medical Academy, Department of Urology, Ankara, Turkey

    Ibrahim Yildirim

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  1. Sukru Oter
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  2. Ahmet Korkmaz
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  3. Emin Oztas
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  4. Ibrahim Yildirim
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  5. Turgut Topal
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  6. Hayati Bilgic
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Correspondence to Sukru Oter.

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Oter, S., Korkmaz, A., Oztas, E. et al. Inducible nitric oxide synthase inhibition in cyclophosphamide induced hemorrhagic cystitis in rats. Urol Res 32, 185–189 (2004). https://doi.org/10.1007/s00240-003-0398-y

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  • DOI: https://doi.org/10.1007/s00240-003-0398-y

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