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

Introduction: Intraperitoneal (i.p.) injection of 3.5g/kg L-arginine (which induces experimental acute necrotizing pancreatitis in rats) will result in much greater increases in serum ornithine vs. citrulline level. This suggests that arginase is the key enzyme in the catabolism of L-arginine. Furthermore, equimolar L-ornithine induces a more severe acute pancreatitis compared to L-arginine. Aim: To test 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 in vitro on rat liver homogenate and purified bovine arginase. Male Wistar rats were administered 15mg/kg AIHA or its vehicle i.p.1h before the injection of physiological saline or 3.5g/kg L-arginine i.p. Laboratory and histological parameters of pancreatitis were determined 24h after the injection of physiological saline or L-arginine. Results: 60µM AIHA (equimolar to the in vivo dose) significantly inhibited arginase activity by about 25% in vitro. AIHA administration in itself significantly increased pancreatic TNF-α and heat shock protein (HSP72, HSP27) synthesis, Cu/Zn- and Mn-superoxide dismutase activities, significantly decreased pancreatic nonprotein sulfhydryl group content, but did not influence pancreatic weight/body weight ratio, and activities of serum and pancreatic amylase. AIHA administration significantly decreased pancreatic weight/body weight ratio, pancreatic myeloperoxidase activity, Cu/Zn- and Mn-superoxide dismutase and glutathione-peroxidase activities in the rats treated with L-arginine, but did not influence activities of serum and pancreatic amylase, pancreatic TNF-α level, nonprotein sulfhydryl group content and HSP levels. AIHA pretreatment also ameliorated pancreatic histological damage. Conclusions: AIHA pretreatment reduces the severity of L-arginine-induced pancreatitis, most likely by inhibiting arginase activity and induction of HSP synthesis. Supported by OTKA and MTA.