Aminoguanidine, selective nitric oxide synthase inhibitor, ameliorates cyclophosphamide-induced hemorrhagic cystitis by inhibiting protein nitration and PARS activation.

OBJECTIVES: To elucidate the mechanism by which aminoguanidine (AG) protects against cyclophosphamide (CP)-induced hemorrhagic cystitis.

METHODS: Hemorrhagic cystitis was induced in the rats by administration of a single injection of CP at a dose of 150 mg/kg body weight intraperitoneally. For the AG pretreatment studies, the rats were injected intraperitoneally with AG at a dose of 200 mg/kg body weight 1 hour before administration of CP. The control rats received AG or saline alone. All the rats were killed 16 hours after the administration of CP or saline.

RESULTS: Pretreatment with AG ameliorated CP-induced bladder damage. Pretreatment with AG prevented CP-induced elevation in nitrate levels, nitration of protein tyrosine, poly (adenosine diphosphate ribose) polymerase (PARP) activation, and restored the activity of superoxide dismutase, the peroxynitrite-sensitive enzyme. The results of the present study have confirmed that AG is effective in preventing CP-induced cystitis and have also demonstrated that the protective effect is from its ability to inhibit nitric oxide-induced protein nitration and poly (adenosine diphosphate ribose) polymerase activation.

CONCLUSIONS: AG can prevent CP-induced urotoxicity and lead to better tolerance of the drug. Thus, a more efficient and comfortable therapy can be achieved for patients in need of CP treatment. AG appears to be a promising drug for the prevention of the urotoxicity of CP.