title: A new severe acute necrotizing pancreatitis model induced by L-ornithine in rats.
abstract: OBJECTIVE
  Intraperitoneal administration of large doses of L-arginine is known to induce severe acute pancreatitis in rats. We therefore set out to determine whether metabolites of L-arginine (L-ornithine, L-citrulline, and nitric oxide) cause pancreatitis.
  
  
  METHODS
  The authors conducted an in vivo animal study.
  
  
  METHODS
  This study was conducted at a university research laboratory.
  
  
  METHODS
  Study subjects were male Wistar rats.
  
  
  METHODS
  Dose-response and time course changes of laboratory and histologic parameters of pancreatitis were determined after L-arginine, L-ornithine, L-citrulline, or sodium nitroprusside (nitric oxide donor) injection.
  
  
  RESULTS
  Intraperitoneal injection of 3 g/kg L-ornithine but not L-citrulline or nitroprusside caused severe acute pancreatitis; 4 to 6 g/kg L-ornithine killed the animals within hours. Serum and ascitic amylase activities were significantly increased, whereas pancreatic amylase activity was decreased after intraperitoneal injection of 3 g/kg L-ornithine. The increase in pancreatic trypsin activity (9-48 hrs) correlated with the degradation of IkappaB proteins and elevated interleukin-1beta levels. Oxidative stress in the pancreas was evident from 6 hrs; HSP72 synthesis was increased from 4 hrs after L-ornithine administration. Morphologic examination of the pancreas showed massive interstitial edema, apoptosis, and necrosis of acinar cells and infiltration of neutrophil granulocytes and monocytes 18 to 36 hrs after 3 g/kg L-ornithine injection. One month after L-ornithine injection, the pancreas appeared almost normal; the destructed parenchyma was partly replaced by fat. Equimolar administration of L-arginine resulted in lower pancreatic weight/body weight ratio, pancreatic myeloperoxidase activity, and histologic damage compared with the L-ornithine-treated group. L-ornithine levels in the blood were increased 54-fold after intraperitoneal administration of L-arginine.
  
  
  CONCLUSIONS
  We have developed a simple, noninvasive model of acute necrotizing pancreatitis in rats by intraperitoneal injection of 3 g/kg L-ornithine. Interestingly, we found that, compared with L-arginine, L-ornithine was even more effective at inducing pancreatitis. Large doses of L-arginine produce a toxic effect on the pancreas, at least in part, through L-ornithine.
authors.affiliation: First Department of Medicine, University of Szeged, Szeged, Hungary. raz@in1st.szote.u-szeged.hu
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Rakonczay
authors.forename: Péter
authors.initials: P
authors.lastname: Hegyi
authors.forename: Sándor
authors.initials: S
authors.lastname: Dósa
authors.forename: Béla
authors.initials: B
authors.lastname: Iványi
authors.forename: Katalin
authors.initials: K
authors.lastname: Jármay
authors.forename: György
authors.initials: G
authors.lastname: Biczó
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Hracskó
authors.forename: Ilona S
authors.initials: IS
authors.lastname: Varga
authors.forename: Eszter
authors.initials: E
authors.lastname: Karg
authors.forename: József
authors.initials: J
authors.lastname: Kaszaki
authors.forename: András
authors.initials: A
authors.lastname: Varró
authors.forename: János
authors.initials: J
authors.lastname: Lonovics
authors.forename: Imre
authors.initials: I
authors.lastname: Boros
authors.forename: Ilya
authors.initials: I
authors.lastname: Gukovsky
authors.forename: Anna S
authors.initials: AS
authors.lastname: Gukovskaya
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
authors.forename: Tamás
authors.initials: T
authors.lastname: Takács
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000097:blood / Q000633:toxicity; D002956:Citrulline / Q000097:blood / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008297:Male; D009952:Ornithine / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D055292:Pancreatic alpha-Amylases; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism; D000516:alpha-Amylases / Q000378:metabolism
chemical_list: D002956:Citrulline; D001120:Arginine; D009952:Ornithine; D009195:Peroxidase; C524801:Amy2a3 protein, rat; D055292:Pancreatic alpha-Amylases; D000516:alpha-Amylases; D014357:Trypsin