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American Journal of Pathology, Vol 150, 247-256, Copyright © 1997 by American Society for Investigative Pathology

REGULAR ARTICLES

Involvement of nitric oxide in the pathogenesis of cyclophosphamide- induced hemorrhagic cystitis

MV Souza-Fiho, MV Lima, MM Pompeu, G Ballejo, FQ Cunha and A Ribeiro R de
Department of Physiology and Pharmacology, Federal University of Ceara, Fortaleza, Ribeirao Preto, Brazil.

The involvement of nitric oxide (NO) and the potential modulation of NO synthase (NOS) activity by platelet-activating factor were investigated in a rat model of cyclophosphamide-induced hemorrhagic cystitis. Male Wistar rats received a single intraperitoneal injection of cyclophosphamide, and cystitis was evaluated 6, 12, 24, 48, and 72 hours later by determining the changes in bladder wet weight and plasma protein extravasation and the macro- and microscopic morphological alterations. In addition, NOS activity and NADPH-diaphorase histochemistry were studied in bladder tissues. Normal bladders showed extensive NADPH-diaphorase staining and a high level of constitutive NOS whereas the activity of inducible NOS was almost undetectable. Cyclophosphamide dose- and time-dependently increased the bladder wet weight and bladder plasma protein extravasation. These events were accompanied at a microscopic level by urothelial necrosis, sloughing, ulceration, hemorrhage, and leukocyte infiltration. Cyclophosphamide also increased the levels of inducible NOS but reduced those of constitutive NOS. The NOS inhibitors L-NG-nitroarginine methyl ester and L-NG-nitroarginine significantly reduced the cyclophosphamide- induced plasma protein extravasation and urothelial damage. This reduction was completely reversed by L-arginine but not by D-arginine. The administration of the platelet-activating factor antagonist BN 52021 decreased the cyclophosphamide-induced plasma protein extravasation as well as the rise in inducible NOS activity but had no effect on the fall in constitutive NOS activity. These results suggest that endogenous NO participates in the urothelial damage and in the inflammatory events leading to cyclophosphamide-induced hemorrhagic cystitis. Platelet-activating factor also seems to be involved in the pathogenesis of this condition, possibly by inducing NOS.

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