Taken together, early mitochondrial injury caused by large doses of L-lysine may lead to the development of acute pancreatitis independently of pancreatic trypsinogen and NF-κB activation.

No abstract

Objectives: 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; 36:2117Y2127). 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-arginineYinduced 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 LarginineYinduced pancreatitis most likely by inhibiting arginase activity.Key Words: arginase, L-arginine, (+)-S-2-amino-6-iodoacetamidohexanoic acid, acute pancreatitis (Pancreas 2010;00: 00Y00) L arge doses (2.5Y5 g/kg) of intraperitoneally (IP) injected L-arginine are known to induce acute necrotizing pancreatitis in rats and mice. 1Y4 The pathomechanism of L-arginine pancreatitis is unknown, especially concerning the early events leading to the disease.Two key enzymes that are involved in the metabolism of L-arginine are nitric oxide synthase (NOS) and arginase ( F1 Fig. 1).5 Nitric oxide synthase has 3 isoforms: the constitutive endothelial (eNOS) and neuronal (nNOS) and an inducible form (iNOS). They catalyze the conversion of L-arginine to nitric oxide and L-citrulline. Arginase, which has 2 isoforms (types I and II), hydrolyzes L-arginine to L-ornithine and urea. These 2 arginase isoforms are encoded by 2 different genes and differ in molecular properties, tissue distribution, subcellular location, and regulation of expression. Arginase I is localized in the cytosol and is highly expressed in the liver and to a much less extent in a few other tissues. Arginase II is a mitochondrial enzyme, which is widely distributed in extrahepatic tissues.In arginine-induced pancreatitis, pancreatic constitutive NOS activity was depleted at 6 hours then gradually increased to significantly higher level than the control at 24 hours. 6 The activity of pancreatic iNOS was significantly increased at 24 hours after L-arginine injection.Most of the IP injected L-arginine is converted to Lornithine rather than L-citrulline, 7,8 therefore indicating a major ro...

l-Ornithine-induced pancreatitis was associated with activation of pancreatic polyamine catabolism. However, administration of a metabolically stable polyamine analogue did not affect disease severity.

Objectives: 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; 36:2117Y2127). 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-arginineYinduced 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 LarginineYinduced pancreatitis most likely by inhibiting arginase activity.Key Words: arginase, L-arginine, (+)-S-2-amino-6-iodoacetamidohexanoic acid, acute pancreatitis (Pancreas 2010;00: 00Y00) L arge doses (2.5Y5 g/kg) of intraperitoneally (IP) injected L-arginine are known to induce acute necrotizing pancreatitis in rats and mice. 1Y4 The pathomechanism of L-arginine pancreatitis is unknown, especially concerning the early events leading to the disease.Two key enzymes that are involved in the metabolism of L-arginine are nitric oxide synthase (NOS) and arginase ( F1 Fig. 1). 5 Nitric oxide synthase has 3 isoforms: the constitutive endothelial (eNOS) and neuronal (nNOS) and an inducible form (iNOS). They catalyze the conversion of L-arginine to nitric oxide and L-citrulline. Arginase, which has 2 isoforms (types I and II), hydrolyzes L-arginine to L-ornithine and urea. These 2 arginase isoforms are encoded by 2 different genes and differ in molecular properties, tissue distribution, subcellular location, and regulation of expression. Arginase I is localized in the cytosol and is highly expressed in the liver and to a much less extent in a few other tissues. Arginase II is a mitochondrial enzyme, which is widely distributed in extrahepatic tissues.In arginine-induced pancreatitis, pancreatic constitutive NOS activity was depleted at 6 hours then gradually increased to significantly higher level than the control at 24 hours. 6 The activity of pancreatic iNOS was significantly increased at 24 hours after L-arginine injection.Most of the IP injected L-arginine is converted to Lornithine rather than L-citrulline, 7,8 therefore indicating a major r...