Ab. Alfieri et Lx. Cubeddu, Nitric oxide and NK1-tachykinin receptors in cyclophosphamide-induced cystitis, in rats, J PHARM EXP, 295(2), 2000, pp. 824-829
Citations number
20
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
The present study was conducted to investigate the role of NK1 receptors an
d of nitric oxide (NO) on the pathogenesis of cyclophosphamide-induced cyst
itis, 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 a
ppearance of Ca2+-independent NO-synthase (NOS) activity [characteristic of
inducible NOS (iNOS)] in the bladder and with increases in urinary NO meta
bolites. GR205171, a selective NK1 antagonist (10-20 mg/kg, i.p.) reduced c
yclophosphamide-induced increases in protein plasma extravasation and in th
e 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 incr
eases in NO metabolites and protected against cyclophosphamide-induced prot
ein plasma extravasation. GR205171 had no effect, whereas L-NNA reduced bas
al NO metabolite excretion. Combined treatment with the NK1 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 cyclophosphamide-induced urothelial damage, and
the extent of edema, vascular congestion, and white blood cell infiltrates
in the bladder. In summary, NK1 receptors and iNOS play a role in NO format
ion and on cyclophosphamide-induced cystitis. Activation of NK1 receptors m
ainly acts through the formation of NO. It is proposed that cyclophosphamid
e and/or its metabolites would stimulate primary afferent capsaicin-sensiti
ve fibers in the bladder, releasing neuropeptides, which would activate NK1
receptors. However, additional mechanisms are involved, because neither th
e NK1 receptor antagonist nor the NO synthesis inhibitor, either alone or i
n combination, were able to completely prevent the toxicity.