Inhibition of arginase activity ameliorates L-arginine-induced acute pancreatitis in rats.
OBJECTIVE
Intraperitoneal (IP) injection of 3.5 g/kg L-arginine (known to induce acute pancreatitis) in rats will result in much greater increases in serum ornithine versus citrulline concentration (Crit Care Med. 2008;36:2117-2127). These data indicate a major role of arginase in the catabolism of L-arginine. Therefore, we tested the effects of the irreversible arginase inhibitor (+)-S-2-amino-6-iodoacetamidohexanoic acid (AIHA) on L-arginine-induced acute pancreatitis.


METHODS
The inhibitory effect of AIHA on arginase activity was tested on rat liver homogenate and purified bovine arginase. Male Wistar rats were administered 15 mg/kg AIHA or its vehicle IP 1 hour before the injection of physiological saline or 3.5 g/kg L-arginine IP. Laboratory and histological parameters of pancreatitis were determined 24 hours after the last injection.


RESULTS
Sixty micromolars of AIHA (equimolar to an in vivo dose of 15 mg/kg) significantly inhibited arginase activity by about 25%. Pretreatment with AIHA significantly ameliorated pancreatic damage caused by L-arginine administration. It decreased pancreatic weight/body weight ratio, pancreatic glutathione peroxidase and myeloperoxidase activities, and histological damage. Administration of AIHA in itself significantly increased levels of pancreatic heat shock proteins.


CONCLUSIONS
Pretreatment with AIHA reduces the severity of L-arginine-induced pancreatitis most likely by inhibiting arginase activity.
Biczó
György
G
First Department of Medicine, University of Szeged, Hungary.
Hegyi
Péter
P
Berczi
Sándor
S
Dósa
Sándor
S
Hracskó
Zsuzsanna
Z
Varga
Ilona S
IS
Iványi
Béla
B
Venglovecz
Viktória
V
Wittmann
Tibor
T
Takács
Tamás
T
Rakonczay
Zoltán
Z
D000208:Acute Disease; D000614:Aminocaproates; D015119:Aminocaproic Acid / Q000627:therapeutic use; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors*; D001120:Arginine / Q000633:toxicity; D002417:Cattle; D002956:Citrulline / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000032:analysis; D006360:Heat-Shock Proteins / Q000032:analysis; D008297:Male; D009952:Ornithine / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D009195:Peroxidase / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index
D000614:Aminocaproates; D006360:Heat-Shock Proteins; D002956:Citrulline; C079268:2-amino-6-iodoacetamidohexanoic acid; D001120:Arginine; D009952:Ornithine; D009195:Peroxidase; D005979:Glutathione Peroxidase; D001119:Arginase; D015119:Aminocaproic Acid