Supramaximal Cholecystokinin-58 Does Not Induce Pancreatitis in the Rat: Role of Pancreatic Water Secretion Running Title: CCK58 and Pancreatitis in the Rat

In contrast to supramaximal CCK8 or caerulein, acute or prolonged supraphysiological levels of endogenous cholecystokinin (CCK58) do not cause pancreatitis. Compared to CCK8, CCK58 is a much stronger stimulant of pancreatic chloride and water secretion, equivalent to maximally effective secretin, but with a chloride to bicarbonate ratio characteristic of acinar fluid. Because supraphysiological endogenous cholecystokinin does not cause pancreatitis and because co-administration of secretin ameliorated caeruleinor CCK8-induced pancreatitis, coincident with restoring pancreatic water secretion, we hypothesized that supramaximal CCK58 would not induce pancreatitis. Conscious rats were infused i.v. with 2 or 4 nmol•kg-1•h-1 of CCK8 or synthetic rat CCK58 for 6 h and pancreases examined for morphological and biochemical indices of acute pancreatitis. A second group was treated as above while monitoring pancreatic protein and water secretion. CCK8 at 2 nmol•kg-1•h-1 caused severe edematous pancreatitis as evidenced by morphological and biochemical criteria. CCK58 at this dose had minimal or no effect on these indices. CCK58 at 4 nmol•kg-1•h-1 increased some indices of pancreatic damage but less than either the 2 or 4 nmol•kg-1•h-1 dose of CCK8. Pancreatic water and protein secretion were nearly or completely abolished within 3 hr of onset of CCK8 infusion, whereas water and protein secretion were maintained near basal levels in CCK58-treated rats. We hypothesize that supramaximal CCK58 does not induce pancreatitis because it maintains pancreatic acinar chloride and water secretion, which are essential for exocytosis of activated zymogens. We conclude that CCK-58 may be a valuable tool for investigating events that trigger pancreatitis. Page 2 of 44