title: Cyclophosphamide induced cystitis: role of nitric oxide synthase, cyclooxygenase-1 and 2, and NK(1) receptors.
abstract: OBJECTIVE
  The role of substance P, inducible nitric oxide synthase, and cyclooxygenase-1 and 2 on the pathogenesis of cyclophosphamide induced cystitis was investigated in rats.
  
  
  METHODS
  Sprague-Dawley male rats received 1 of certain treatments, including 1) 0.9 weight per volume saline (0.10 ml/100 gm intraperitoneally), 2) cyclophosphamide (75 mg/kg intraperitoneally), 3) cyclophosphamide plus the NK(1) receptor antagonist Win-51.708 (20 mg/kg intraperitoneally), 4) cyclophosphamide plus the inducible nitric oxide synthase inhibitor S-methylthiourea (20 mg/kg intraperitoneally), 5) cyclophosphamide plus the highly selective cyclooxygenase-2 inhibitor rofecoxib (15 mg/kg intraperitoneally), 6) cyclophosphamide plus the selective cyclooxygenase-2 inhibitor meloxicam (15 mg/kg intraperitoneally), 7) cyclophosphamide plus the nonselective cyclooxygenase inhibitor ketoprofen (20 mg/kg intraperitoneally) or 8) cyclophosphamide plus methylthiourea plus meloxicam. Parameters were evaluated 6 hours after cyclophosphamide administration, including plasma protein extravasation, histological changes, myeloperoxidase and inducible nitric oxide synthase activities in the bladder, plasmatic nitric oxide metabolites and urinary nitric oxide metabolites, and prostaglandin E(2) levels.
  
  
  RESULTS
  Cyclophosphamide produced inflammatory and cytotoxic changes in the bladder, accompanied by increased nitric oxide metabolites, urinary prostaglandins, myeloperoxidase and inducible nitric oxide synthase activity. Pretreatment with Win-51.708 and with methylthiourea prevented all of these effects except myeloperoxidase activity, which was only prevented by Win-51.708. All inducible cyclooxygenases were able to prevent prostaglandin synthesis and increases in myeloperoxidase activity. Combined inhibition of inducible nitric oxide synthase and cyclooxygenase-2/cyclooxygenase-1 (methylthiourea plus meloxicam) did not provide any additional protection against bladder damage, increased inducible nitric oxide synthase activity or prostaglandin E(2) synthesis. Additionally, this combination was unable to prevent increased myeloperoxidase activity.
  
  
  CONCLUSIONS
  The results of this study suggest that there is crosstalk between nitric oxide and the cyclooxygenase enzyme with cyclooxygenase-1/cyclooxygenase-2 isoforms having an important role in this relationship. Augmented myeloperoxidase activity seems to be associated with NK(1) receptor activation and low levels of nitric oxide with cyclooxygenase-1 having an important role.
authors: Department of Physiology, School of Medicine "Dr. Luis Razetti", Central University of Venezuela, Caracas, Venezuela.
authors: Beatriz E
authors: BE
authors: Linares-Fernández
authors: Anna B
authors: AB
authors: Alfieri
mesh_terms: D000818:Animals; D051545:Cyclooxygenase 1 / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003520:Cyclophosphamide / Q000008:administration & dosage*; D003556:Cystitis / Q000139:chemically induced* / Q000201:enzymology*; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D013373:Substance P / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D013373:Substance P; D003520:Cyclophosphamide; D019001:Nitric Oxide Synthase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2