Nitric oxide synthases and cyclophosphamide-induced cystitis in rats

The role of inducible (iNOS) and neuronal nitric oxide (nNOS) synthases and of tachykinin NK, receptors on the pathogenesis of cyclophosphamide (CYP)- induced cystitis was investigated, in rats. CYP-induced cystitis was charac terized by large increases in bladder-protein plasma extravasation (PPE), i ncreases in the urinary excretion of nitric oxide (NO) metabolites and hist ological evidences of urothelial damage, edema, extensive white blood cell infiltrates and vascular congestion of the bladder. The specific iNOS inhib itor, S-methylthiourea (MITU), produced marked inhibition (>90%) of CYP-ind uced increases in PPE associated with amelioration of tissue inflammatory c hanges. Treatment with 7-nitroindazole (7-NI; 20, 40 and 80 mg/kg), a selec tive nNOS inhibitor, did not significantly reduce CYP-induced increases in PPE and failed to produce histological improvement. In addition, treatment with MITU, but not with 7-NI, inhibited the increases in the urinary excret ion of NO metabolites induced by CYP treatment. WIN 51,708 (17-beta -hydrox y-17-alpha -ethynyl-androstano[3,2-b]pyrimido[1,2-a] benzimidazole; WIN), a selective NK1-receptor antagonist, reduced the increases in EPP and amelio rated the inflammatory changes in the bladder induced by CYP. However, the maximal degree of protection achieved with WIN was significantly less than that produced by MITU. Combined treatment with the iNOS inhibitor and the N K, antagonist produced no greater effect than that produced by the iNOS inh ibitor alone. Our results suggest that NO plays a fundamental role in the p roduction of the cystitis associated with CYP treatment. The iNOS, and not nNOS, seems responsible for the inflammatory changes. Part of the increases in NO may due to activation of NK1 receptors by neuropeptides such as subs tance P possibly released from primary afferent fibers.