This study was aimed at an assessment of the role of oxygen-derived free radicals, cytokines and endogenous cholecystokinin (CCK) in the pathogenesis of L-arginine (Arg)-induced acute pancreatitis in rat. We measured the levels of malonyl dialdehyde (MDA), glutathione peroxidase (GPx), catalase and superoxide dismutase (Mn- and Cu, Zn-SOD) in pancreatic tissue, the serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and CCK, and evaluated the protective effect of the xanthine oxidase inhibitor allopurinol and a novel CCK receptor antagonist KSG-504. Acute pancreatitis was induced in male Wistar rats by injecting 2x 250 mg/100 g body weight of Arg intraperitoneally in an 1-h interval, as a 20% solution in 0.15 M NaCl. Control rats received the same quantity of glycine. 200 mg·kg-1 allopurinol 30 min before the first Arg treatment or 50 mg·kg-1 KSG-504 30 min before and 6, 18 and 36 h after the first Arg injection was administered subcutaneously. Rats were killed at 6, 12, 24 and 48 h following Arg administration, and acute pancreatitis was confirmed by a serum amylase level elevation and typical inflammatory features observed microscopically. The serum level of amylase reached the peak level at 24 h after the Arg injection (30 800 ± 3 813 versus 6 382 ± 184 U·L-1 in the control) and normalized at 48 h. The tissue concentration of MDA was significantly elevated at 24 h, and reached the peak value at 48 h (5.00 ± 1.75 versus 0.28 ± 0.0.5 nM·mg-1 protein in the control). The catalase and Mn-SOD activities were significantly decreased throughout the study, while the GPx activity was significantly reduced at 6 and 12 h, and the Cu, Zn-SOD activity was significantly lower at 12 h after the Arg injection as compared with the controls. Both the TNF-α and the IL-6 levels were already elevated significantly at 12 h and peak at 24 h versus the controls (19.1 ± 7.9 U·mL-1 and 57.6 ± 11.2 pg·mL-1 versus 3.1 ± 0.8 U·mL-1 and 15.2 ± 3.1 pg·mL-1, respectively). No significant changes in plasma CCK levels were observed. Allopurinol treatment markedly reduced the serum amylase elevation (12.631 ± 2.257 U·L-1 at 24 h), prevented the increase in tissue MDA concentration (0.55 ± 0.09 nM·mg-1 protein at 48 h) and significantly ameliorated the pancreatic edema, necrosis and inflammation at 48 h after Arg administration. KSG-504 administration did not exert any beneficial effect on the development of histopathological changes neither modified the serum amylase or cytokine levels. Oxygen-derived free radicals and cytokines are involved, while endogenous CCK does not seem to play a role in the pathogenesis of Arg-induced acute pancreatitis. (C) 2000 Elsevier Science Ltd.
- Cholecystokinin receptor antagonist
- L-arginine-induced acute pancreatitis
- Oxygen-derived free radicals
ASJC Scopus subject areas
- Physiology (medical)