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.
ASJC Scopus subject areas
- Critical Care and Intensive Care Medicine