A new severe acute necrotizing pancreatitis model induced by L-ornithine in rats.
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.
Rakonczay
Zoltán
Z
First Department of Medicine, University of Szeged, Szeged, Hungary. raz@in1st.szote.u-szeged.hu
Hegyi
Péter
P
Dósa
Sándor
S
Iványi
Béla
B
Jármay
Katalin
K
Biczó
György
G
Hracskó
Zsuzsanna
Z
Varga
Ilona S
IS
Karg
Eszter
E
Kaszaki
József
J
Varró
András
A
Lonovics
János
J
Boros
Imre
I
Gukovsky
Ilya
I
Gukovskaya
Anna S
AS
Pandol
Stephen J
SJ
Takács
Tamás
T
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
D002956:Citrulline; D001120:Arginine; D009952:Ornithine; D009195:Peroxidase; C524801:Amy2a3 protein, rat; D055292:Pancreatic alpha-Amylases; D000516:alpha-Amylases; D014357:Trypsin