Influence of glutathione synthesis on the course of acute experimental pancreatitis in the rat

Abstract

Introduction: Glutathione plays a central role as scavenger of reactive oxidative metabolites. L-Buthioninsulfoximine (BSO) is therefore, as inhibitor of /-glutamylcystein-synthetase and by the way of glutathione synthesis, a potent amplifier of oxidative stress. We investigated the influence of BSO on the experimentally induced cerulein pancreatitis of the rat and on the cerulein stimulation of isolated pancreatic acini as correlate to oxidative stress. Methods: Male Wistar rats had a bolus of 1 ml 0,9% NaC1 with or wihtout (control) 8 pmol/kg KG BSO injected intravenously. After anesthesia with ketanest/pentobarbital, an acute pancreatitis was induced by time and pressure dependent intraductal infusion of 0,125 ml 10 mMol glucodesoxychollic acid (GDOC) and subsequent intravenous application of 5 pg/kg/h cerulein. After a maximum observation period of 24 hrs the rats were euthanasised and the pancreas removed for histological analysis. For preparation of isolated pancreatic acini, male Wistar rats had their pancreas removed and collagenase digested in a standardised fashion. Isolated acini were stimulated over 45 Minuten with declining concentrations of cerulein (10 -7 to 10 -12 M). Lipase and Amylase were measured in the supernatant. Results: L-Buthioninsulfoximin (BSO) significantly increased mortality in experimentally induced pancreatitis. 7 of 8 BSO animals died versus 0 of 6 controls (p=0,036, Mann-Whitney-U-Test). On cellular level, BSO reduced secretory activity of stimulated acini concerning amylase as well as lipase (p < 0,01 with each; paired t-test). Conclusion: BSO increases mortality in experimentally induced pancreatitis. This is probably due to early local and systemic decompensation glutathionedependent scavenging systems. On cellular level, this mechanism is probably valid through reduction of energy dependent transport under oxidative stress (cerulein).