Pathophysiological role of cholecystokinin in humans

Abstract

Cholecystokinin (CCK) is a major gastrointestinal hormone that plays an important role in stimulation of pancreatic secretion and gall-bladder contraction, regulation of gastrointestinal motility and induction of satiety. Ingestion of fat and protein induces significant increases in plasma CCK. Intraluminal mediators of CCK secretion, luminal CCK releasing factor and diazepam-binding inhibitor, were purified from rat intestinal secretion. These CCK-releasing factors (RF) are secreted tonically by the small intestine and stimulate CCK release. Another kind of CCK-RF named 'monitor peptide' was purified from the rat pancreatic juice that stimulates CCK secretion when introduced into rat intestine. Bile exclusion from the duodenum causes an increase in basal CCK and enhances stimulated plasma CCK release, and bile salt replacement reverses these effects. Thus, the CCK-RF are spontaneously secreted into the intestinal lumen in humans, while the CCK-producing cells are under constant suppression by intraduodenal bile acids. In acute pancreatitis, plasma CCK levels are high in patients with gallstone pancreatitis, but not in patients with pancreatitis from other causes, such as alcoholic and idiopathic pancreatitis. A transient disturbance of bile flow into the duodenum by stones or oedema of the pancreas together with impairment of pancreatic exocrine function might cause the increase in plasma CCK release in gallstone pancreatitis. Patients with chronic pancreatitis with mild to moderate impairment of exocrine function and abdominal pain, had significantly higher plasma CCK concentrations, whereas patients with pancreatic insufficiency had a significantly lower plasma CCK response to a test meal than the healthy subjects. The increased CCK may further aggravate pancreatitis and worsen the prognosis of pancreatitis by stimulating the injured pancreas, resulting in the vicious circle via endogenous CCK release. The CCK-A receptor antagonist might be therapeutically useful in acute pancreatitis by stopping the vicious circle.

Pharmacological Study of IQM-97,423, a Potent and Selective CCK₁ Receptor Antagonist with Protective Effect in Experimental Acute Pancreatitis

“…The contribution of CCK to common BPDL-induced acute pancreatitis is not clear since the effects of CCK 1 receptor antagonists on this model are controversial [44,50]. High CCK levels have been however reported in patients with gallstone pancreatitis [51]. In this model, common BPDL caused an increase in plasma amylase activity, in line with most of previous data [44,47,50].…”

“…Increased CCK levels may further aggravate acute pancreatitis by stimulating the injured pancreas, resulting in a vicious circle via endogenous CCK release. CCK 1 receptor antagonists may then be therapeutically useful in acute pancreatitis by stopping this vicious circle [51].…”

Acute pancreatitis possible initial triggering mechanism and prophylaxis

“…Bilio-pancreatic hypertension is developed while the entero-pancreatic feedback is disrupted [39], because bilis and pancreatic juice are excluded from the intestinal lumen, inducing an increase in CCK blood level. This in Cosen-Binker/Binker/Negri/Tiscornia turn causes a supramaximal stimulation of acinar pancreocytes as cytosolic Ca 2+ concentration rises, leading to the desintegration of microtubules and microfilaments of acinar cells [40]. All this is a consequence of the increase in the intrapancreatic cholinergic tone, accompanied by a decrease in secretin.…”

Composition of Gastric Juice and Bile in Rats at the Experimental Chronic Pancreatitis

“…Усього за 3 год печінка дослідних щурів секретувала на 74,9 % (Р<0,001) жовчі більше, ніж контрольних тварин. Літератур-ні дані свідчать, що у хворих на хронічний панкреатит концентрація холецистокініну в плазмі крові значно підвищується, тоді як у пацієнтів з панкреатичною недостатністю вміст цього гормону знижується [25,26]. Оскільки відомо, що холецистокінін та секре-тин є стимуляторами не тільки підшлункової секреції, а й секреції жовчі [27,28], підви-щення рівня холерезу на 13-ту добу може бути результатом зростання концентрації цих гормонів у сироватці крові.…”