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

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

doi:10.1097/ccm.0b013e31817d7f5c

Cited by 59 publications

(70 citation statements)

References 30 publications

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“…Basic amino acids, at doses of a few grams per kilogram body weight, trigger AP in rodents (8,23,46,53). Recently, it was suggested that L-arginine, which is most often used in these animal models of AP, may act through another basic amino acid L-ornithine (53).…”

Section: Characterizing Ros Responses Induced By L-ornithinementioning

confidence: 99%

Novel Lipophilic Probe for Detecting Near-Membrane Reactive Oxygen Species Responses and Its Application for Studies of Pancreatic Acinar Cells: Effects of Pyocyanin and L-Ornithine

Chvanov

Huang

Jin

et al. 2015

Antioxidants & Redox Signaling

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In our experimental conditions, the novel probe was more sensitive than 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein (CM-H2DCF) and dihydrorhodamine123 (H2R123) and allowed us to resolve ROS responses to secretagogues, pyocyanin, and L-ornithine. Changes in the fluorescence of the new probe were particularly prominent in the peripheral plasma membrane-associated regions. Our findings suggest that the new probe will be a useful tool in studies of the contribution of ROS to the pathophysiology of exocrine pancreas and other organs/tissues.

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Section: Characterizing Ros Responses Induced By L-ornithinementioning

confidence: 99%

Novel Lipophilic Probe for Detecting Near-Membrane Reactive Oxygen Species Responses and Its Application for Studies of Pancreatic Acinar Cells: Effects of Pyocyanin and L-Ornithine

Chvanov

Huang

Jin

et al. 2015

Antioxidants & Redox Signaling

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“…7 This finding suggested a major role for arginase (rather than NOS) in the catabolism of L-arginine. In the present study, we have shown that pretreatment Arginase is a key enzyme of the hepatic urea cycle, so it was not surprising that the highest enzyme activity was found in the liver of rats.…”

Section: Discussionmentioning

confidence: 84%

“…Most of the IP injected L-arginine is converted to Lornithine rather than L-citrulline, 7,8 therefore indicating a major role of arginase in the catabolism of this basic amino acid. Furthermore, we have recently shown that administration of Lornithine induces a more severe pancreatitis compared with Larginine.…”

mentioning

confidence: 99%

“…Furthermore, we have recently shown that administration of Lornithine induces a more severe pancreatitis compared with Larginine. 7 Therefore, we speculated that L-arginine produces a toxic effect on the pancreas, at least in part, via L-ornithine. The aim of this study was to test the effects of the irreversible arginase inhibitor (+)-S-2-amino-6-iodoacetamidohexanoic acid (AIHA) on L-arginineYinduced acute pancreatitis.…”

mentioning

confidence: 99%

“…Pancreatic tissue injury was evaluated as described previously. 7 Briefly, semiquantitative grading of interstitial edema (0Y3), vascular congestion (0Y1), leukocyte adhesion (0Y3) and infiltration (0Y4), and apoptosis (0Y3) and necrosis (0Y4) of acinar cells was determined in each animal. …”

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confidence: 99%

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Inhibition of arginase activity ameliorates L-arginine-induced acute pancreatitis in rats

Biczó¹,

Hegyi²,

Berczi³

et al. 2009

Z Gastroenterol

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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...

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Transgenic Rodents with Altered SSAT Expression as Models of Pancreatitis and Altered Glucose and Lipid Metabolism

Uimari

Hyvönen

Pirinen

et al. 2011

Methods in Molecular Biology

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Depletion of pancreatic acinar cell polyamines in response to activation of polyamine catabolism is associated with the development of acute pancreatitis in experimental rodent models. The disease is characterized by general hallmarks seen also in human pancreatitis, such as accumulation of intraperitoneal ascites, acinar cell necrosis, and pancreatic as well as remote organ edema and inflammation. Thus, these animals make useful models for the human disease. Determination of these hallmarks can be used to assess the severity of the disease and to evaluate the efficacy of any therapy applied. The metabolic changes seen in genetically modified mice with either accelerated or inactivated polyamine catabolism have revealed that polyamine catabolism is involved in the regulation of glucose and lipid metabolism. The simplest method to determine the metabolic phenotype of the animal is to assess the concentrations of blood metabolites. Fasting blood glucose level is an indicator of overall glucose homeostasis, whereas fasting insulin level is a useful marker of insulin sensitivity. A more detailed analysis of glucose homeostasis and insulin sensitivity can be obtained by intraperitoneal glucose and insulin tolerance tests. Blood lipid levels mainly reflect triglyceride, free fatty acid, and cholesterol metabolism. Altered blood glucose and/or lipid levels are associated with several diseases, e.g., diabetes, Cushing's syndrome, hyperthyroidism, atherosclerosis, pancreatitis, and dysfunction of the liver and kidneys.

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

Cited by 59 publications

References 30 publications

Novel Lipophilic Probe for Detecting Near-Membrane Reactive Oxygen Species Responses and Its Application for Studies of Pancreatic Acinar Cells: Effects of Pyocyanin and L-Ornithine

Novel Lipophilic Probe for Detecting Near-Membrane Reactive Oxygen Species Responses and Its Application for Studies of Pancreatic Acinar Cells: Effects of Pyocyanin and L-Ornithine

Inhibition of arginase activity ameliorates L-arginine-induced acute pancreatitis in rats

Transgenic Rodents with Altered SSAT Expression as Models of Pancreatitis and Altered Glucose and Lipid Metabolism

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