A new severe acute necrotizing pancreatitis model induced by l-ornithine in rats

Zoltán Rakonczay, Péter Hegyi, Sándor Dósa, Béla Iványi, Katalin Jármay, György Biczó, Zsuzsanna Hracskó, Ilona S. Varga, Eszter Karg, József Kaszaki, András Varró, János Lonovics, Imre Boros, Ilya Gukovsky, Anna S. Gukovskaya, Stephen J. Pandol, Tamás Takács

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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. DESIGN: The authors conducted an in vivo animal study. SETTING: This study was conducted at a university research laboratory. SUBJECTS: Study subjects were male Wistar rats. INTERVENTIONS: 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. MEASUREMENTS AND MAIN 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 IκB proteins and elevated interleukin-1β 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.

Original languageEnglish
Pages (from-to)2117-2127
Number of pages11
JournalCritical care medicine
Volume36
Issue number7
DOIs
Publication statusPublished - Jul 2008

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Keywords

  • Acute pancreatitis
  • L-arginine
  • L-ornithine

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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