Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in humans. Implications for the physiology of CCK.

Abstract

To explore the physiology of cholecystokinin (CCK) in humans, we investigated the effect on gallbladder contraction and gastric emptying of a recently developed CCK receptor antagonist, . In a double-blind, four-period crossover study eight subjects received single doses of 0.5, 2, or 10 mg MK-329, or placebo, followed by an intravenous infusion of CCK-8 (30 pmol/kg. h). In placebo-treated subjects gallbladder volumes decreased on average to 43% of initial volumes after 2 h of CCK infusion. MK-329 caused a dose-dependent inhibition of CCK-stimulated gallbladder contraction with 10 mg producing complete blockade (P < 0.01, cf. placebo).Gallbladder contraction and gastric emptying rates after a mixed meal were then measured in a two-period crossover study. Subjects received placebo or 10 mg of MK-329 2 h before eating. Gastric emptying of both solids and liquids was measured simultaneously by gamma scintigraphy. In placebotreated subjects plasma CCK levels increased postprandially to 2.3 pM, gallbladder volumes decreased 68.4±3.8% (SE), and the times for 50% emptying of liquids and solids from the stomach were 58±10 and 128±8 min, respectively. In MK-329-treated subjects there was a marked elevation in peak CCK levels to 13.8 pM (P < 0.01, cf. placebo), and gallbladder contraction was completely inhibited. Solid and liquid emptying rates were unaffected.These findings demonstrate that (a) MK-329 is a potent, orally active antagonist of CCK in humans, and (b) CCK is the major regulator of postprandial gallbladder contraction. These data also support the concept of negative feedback regulation of CCK secretion and suggest that mechanisms other than CCK play a dominant role in the regulation of postprandial gastric emptying rates.

Effect of CCK-1 receptor blockade on ghrelin and PYY secretion in men

“…This phenomenon has been observed before with CCK-1 receptor antagonists (6,20,26): the explanations include activation of a negative feedback mechanism due to low concentrations of bile and/or pancreatic juice constituents in the duodenal lumen and interference with autoregulating, inhibitory CCK-1 receptors on the I cell.…”

Cholestyramine Influences Meal-Stimulated Pancreaticobiliary Function and Plasma Cholecystokinin Independent of Gastric Emptying and Food Digestion

“…Because circulating CCK may induce PP release (22)(23)(24), the effect of cholestyramine on PP can at least in part be attributed to the increased CCK release. Similarly, the enhanced pancreaticobiliary response to the amino acid meal with cholestyramine may be explained by the increased plasma CCK levels (18,(25)(26)(27). However, in the present study we also found that cholestyramine tended to increase pancreatic enzyme secretion and significantly stimu lated gallbladder contraction under basal conditions.…”

“…Chenodeoxycholic acid inhibited CCK release in response to an intraduodenal mixed liquid meal in humans and prevented the enhancement effect of cholestyr amine (3). Administration of CCK receptor antagonists in humans results in a marked exaggeration of meal-stimulated plasma CCK levels (25)(26)(27). Because CCK receptor antago nists inhibit gallbladder contraction to a greater extent than pancreatic enzyme secretion in humans, this suggests that the effect is primarily due to a decreased amount of bile salts in the small bowel (27,32).…”

Sucrose polyester does not inhibit gastric acid secretion or stimulate cholecystokinin release in men

“…Digestible fat is a powerfu 1 stiinu 1 us for plasma cholecysto kinin (CCK) release and subsequently for gallbladder contrac tion and pancreatic enzyme secretion (11)(12)(13)(14)(15)(16)(17). It has been suggested that the inhibition of gastric acid secretion is also mediated at least in part by CCK (8)(9)(10)(18)(19)(20)(21)(22).…”