INVOLVEMENT OF NITRIC-OXIDE IN THE PATHOGENESIS OF CYCLOPHOSPHAMIDE-INDUCED HEMORRHAGIC CYSTITIS

The involvement of nitric oxide (NO) and the potential modulation of N O synthase (NOS) activity by platelet-activating factor were investiga ted in a rat model of cyclophosphamide-induced hemorrhagic cystitis, M ale Wista rats received a single intraperitoneal injection of cyclopho sphamide, and cystitis was evaluated 6, 12, 24, 48, and 72 hours later by determining the changes in bladder wet weight and plasma protein e xtravasation and the macro- and microscopic morphological alterations. In addition, NOS activity and NADPH-diaphorase histochemistry were st udied in bladder tissues. Normal bladders showed extensizre NADPH-diap horase staining and a high level of constitutive NOS whereas the activ ity of inducible NOS was almost undetectable, Cyclophosphamide dose- a nd time-dependently increased the bladder wet weight and bladder plasm a protein extravasation. These events were accompanied at a microscopi c 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 inhibito rs L-N-G-nitroarginine methyl ester and L-N-G-nitroarginine significan tly reduced the cyclophosphamide-induced plasma protein extravasation and urothelial damage, This reduction was completely reversed by L-arg inine but not by D-arginine. The administration of the platelet-activa ting factor antagonist BN 52021 decreased the cyclophosphamide-induced plasma protein extravasation as well as the rise ill inducible NOS ac tivity but had no effect on the fall in constitutive NOS activity, The se results suggest that endogenous NO participates in the urothelial d amage and in the inflanzmirtory events leading to cyclophosphamide-ind uced hemorrhagic cystitis. Platelet-activating factor also seems to be involved in the pathogenesis of this condition, possibly by inducing NOS.