Effects of a specific cholecystokinin receptor antagonist in a traumatic model of pancreatitis

Acute traumatic or iatrogenic (post-surgical) induced pancreatitis remains a major clinical problem. In order to investigate the early events associated with this form of pancreatitis we have developed an animal model which mimics many of the pathological changes seen in man. The usefulness of this model in evaluating potential new therapeutic modalities was examined using L-364,718, a potent and highly specific CCK receptor antagonist. Female guinea pigs (500-550 g) underwent a midline laparotomy with pancreatic trauma induced in three areas of the gland by a modified Spencer Wells vascular clamp. This resulted in acute edematous changes (40% increase in pancreatic wt), intraparenchymal hemorrhage and necrosis as well as saponification of the pancreas, surrounding fat and mesentery. Serum lipase was increased 9-fold at 24 and 48 hours after pancreatic injury. Continuous administration of L364,617 (25 nmol/kg/hr via an implanted osmotic pump), initiated either 24 hours prior to insult or 4 hours after, resulted in a marked amelioration of pancreatic inflammation and necrosis (quantified by morphometric analysis) and a significant reduction in serum lipase (p < 0.001). This experimental model of traumatic pancreatitis is highly reproducible and progressive over a 24 to 72 hour interval. These important aspects have allowed us to evaluate CCK-receptor blockade as a potential therapeutic modality in the treatment of pancreatitis.