Effects of CCK on pancreatic function and morphology.
This report reviews the effects of CCK on the pancreas and in particular analyzes recent studies in which CCK antagonists were used to evaluate the physiological role of CCK in modulating pancreatic function and morphology. CCK is released from endocrine cells of the small intestine in response to a meal. In various animal species there are CCK receptors on pancreatic acinar cells with two sites; occupation of the high affinity site is thought to mediate pancreatic secretion and growth, whereas occupation of the low affinity site by high CCK concentrations is thought to be responsible for supramaximal inhibition of secretion and pancreatitis. Recently, CCK receptors were also found on postganglionic cholinergic neurons in the gastrointestinal tract. Administration of CCK agonists stimulates pancreatic secretion and growth. Although in some previous studies CCK was given at doses that mimic its postprandial increase in plasma, these studies did not prove that the actions of exogenous CCK were physiologically important. In addition, it was unclear if CCK primarily acts as a true hormone or as a neurotransmitter. The development of specific CCK receptor antagonists made it possible to better evaluate the physiological role of CCK. In humans, CCK-A antagonists like loxiglumide or L-364,718 at doses that completely inhibited the action of supraphysiological doses of exogenous CCK reduced meal-stimulated pancreatic enzyme secretion only by approximately 50%. On the other hand, atropine abolished the postprandial increase in pancreatic secretion and in addition markedly reduced the increase in pancreatic secretion due to infusion of "physiological" doses of CCK (i.e., CCK doses that mimic its postprandial increase in plasma). The increase in pancreatic bicarbonate secretion was only slightly reduced by CCK blockade. CCK antagonists failed to reduce the postprandial increase in plasma insulin, but markedly reduced the postprandial PP release. CCK-A antagonists caused slight hypotrophy and hypoplasia of the exocrine pancreas. However, even after 9 months of effective blockade of the CCK-A-receptor, mice had normal body weight and an almost normal pancreas. CCK antagonists were unable to alter short-term changes in pancreatic growth due to feeding and fasting. In some species, CCK agonists induced development of pancreatic nodules and increased the growth of malignant tumors. Studies about the effects of CCK antagonists on induction and growth of pancreatic tumors showed controversial results. In conclusion, CCK may act on the pancreas by three pathways: (1) At low doses it serves as a neurotransmitter by acting on cholinergic neurons.(ABSTRACT TRUNCATED AT 400 WORDS)
Niederau
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Department of Medicine, Heinrich-Heine-University of Düsseldorf, Germany.
Lüthen
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Heintges
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D000818:Animals; D002766:Cholecystokinin / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology*; D004435:Eating; D005704:Gallbladder / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D010179:Pancreas / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D011377:Proglumide / Q000031:analogs & derivatives / Q000494:pharmacology
C053737:loxiglumide; D002766:Cholecystokinin; D011377:Proglumide