The role of cholecystokinin in the pathogenesis of acute pancreatitis in the isolated pancreas preparation.
In a variety of animal models of acute pancreatitis, cholecystokinin-receptor antagonists have ameliorated the injury response. These results suggest that cholecystokinin may play a primary role in the pathogenesis of pancreatitis initiated by multiple stimuli. In an effort to test this theory, a sensitive and high affinity cholecystokinin-receptor antagonist L364,718 was administered to four different models of acute pancreatitis that were produced in the ex vivo perfused canine pancreas preparation. The four models of pancreatitis were initiated by cerulein infusion, partial duct obstruction with secretin stimulation, oleic acid infusion, and a 2-hour period of ischemia. In each model, pancreatitis was manifest by edema formation, weight gain, and hyperamylasemia during a 4-hour perfusion. In cerulein infusion-induced pancreatitis L364,718 inhibited edema formation and weight gain (31 +/- 5 gm versus 7 +/- 6 gm; p less than 0.05) and significantly decreased plasma amylase activity (36,605 +/- 21,216 U/dl versus 9421 +/- 5149 U/dl; p less than 0.05). The acute pancreatitis induced by the other three stimuli was not ameliorated by L364,718 treatment. We conclude that in the ex vivo-perfused canine pancreas preparation cerulein-induced pancreatitis is mediated at least in part by the cholecystokinin receptor. Early blockade of the cholecystokinin receptor was of no benefit in treating the other models of pancreatitis, suggesting that cholecystokinin is not involved in the early pathogenesis.
Nordback
I H
IH
Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21209.
Clemens
J A
JA
Cameron
J L
JL
D000208:Acute Disease; D000681:Amylases / Q000097:blood / Q000378:metabolism; D000818:Animals; D001570:Benzodiazepinones / Q000494:pharmacology*; D002108:Ceruletide; D002766:Cholecystokinin / Q000037:antagonists & inhibitors* / Q000502:physiology; D020109:Devazepide; D004285:Dogs; D066298:In Vitro Techniques; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D010183:Pancreatic Ducts / Q000502:physiology; D010195:Pancreatitis / Q000139:chemically induced / Q000503:physiopathology*; D010477:Perfusion; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values
D001570:Benzodiazepinones; D011949:Receptors, Cholecystokinin; D002108:Ceruletide; D002766:Cholecystokinin; D000681:Amylases; D020109:Devazepide