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.