Nitric oxide and NK(1)-tachykinin receptors in cyclophosphamide-induced cystitis, in rats.

The present study was conducted to investigate the role of NK(1) receptors and of nitric oxide (NO) on the pathogenesis of cyclophosphamide-induced cystitis, in rats. This bladder toxicity was characterized by marked increases in protein plasma extravasation, urothelial damage, edema, white blood cell infiltrates, and vascular congestion. These changes were associated with appearance of Ca(2+)-independent NO-synthase (NOS) activity [characteristic of inducible NOS (iNOS)] in the bladder and with increases in urinary NO metabolites. GR205171, a selective NK(1) antagonist (10-20 mg/kg, i.p.) reduced cyclophosphamide-induced increases in protein plasma extravasation and in the urinary excretion of NO metabolites. N(G)-Nitro-L-arginine (L-NNA) (10 mg/kg, i.p.), a NOS inhibitor, reduced basal and cyclophosphamide-induced increases in NO metabolites and protected against cyclophosphamide-induced protein plasma extravasation. GR205171 had no effect, whereas L-NNA reduced basal NO metabolite excretion. Combined treatment with the NK(1) antagonist and the NO-synthesis inhibitor produced comparable reduction in protein plasma extravasation than that achieved with each drug given separately. Combined drug treatment ameliorated cyclophosphamideinduced urothelial damage, and the extent of edema, vascular congestion, and white blood cell infiltrates in the bladder. In summary, NK(1) receptors and iNOS play a role in NO formation and on cyclophosphamide-induced cystitis. Activation of NK(1) receptors mainly acts through the formation of NO. It is proposed that cyclophosphamide and/or its metabolites would stimulate primary afferent capsaicin-sensitive fibers in the bladder, releasing neuropeptides, which would activate NK(1) receptors. However, additional mechanisms are involved, because neither the NK(1) receptor antagonist nor the NO synthesis inhibitor, either alone or in combination, were able to completely prevent the toxicity.