Role of CCK in regulation of pancreaticobiliary functions and GI motility in humans: effects of loxiglumide

Abstract

To evaluate the physiological role of cholecystokinin (CCK) in humans, we studied the influence of the specific CCK receptor antagonist loxiglumide (CR 1505) on gallbladder contraction, pancreatic enzyme output, plasma CCK concentrations, mouth-to-cecum transit time (MCTT), stool weight, and fecal fat excretion. Infusion of CCK-8, producing CCK plasma levels of 10-12 pmol/l, decreased gallbladder volume to 21% of the initial volume (P less than 0.01) and increased bilirubin output 8- to 10-fold and pancreatic enzyme secretion 2- to 4-fold. Infusion of loxiglumide (10 mg.kg-1.h-1 iv) abolished CCK-8-stimulated enzyme and bilirubin output. Basal gallbladder volume increased 68% during loxiglumide infusion (P less than 0.001) and 137% (P less than 0.001) after 7 days of oral loxiglumide treatment (3 x 1.6 g/day). Gallbladder contraction and bilirubin output in response to the intraduodenal instillation of a liquid meal (382 kcal) was completely inhibited by loxiglumide; gallbladder volume even increased 45% postprandially during loxiglumide infusion (P less than 0.02) and 145% after long-term loxiglumide treatment (P less than 0.001). Meal-stimulated pancreatic enzyme output was diminished 46-53% after acute and 25-29% after chronic administration of loxiglumide. Meal-stimulated integrated plasma CCK-immunoreactive (CCK-ir) concentrations, determined by RIA, were 3.2-fold higher during loxiglumide infusion (P less than 0.02); plateau CCK levels were markedly elevated (10.1 +/- 1.4 vs. 3.7 +/- 0.5 pM). Plasma CCK-like bioactivity, measured by a sensitive bioassay, was identical to CCK-ir levels in the absence of loxiglumide; in the presence of loxiglumide, no circulating CCK-like bioactivity was detectable, indicating complete inhibition of plasma CCK. MCTT was augmented 24% (P less than 0.05). Oral treatment with loxiglumide increased stool weight 72% (P less than 0.01) and fecal fat excretion 186% (P less than 0.001). In conclusion, 1) meal-induced gallbladder contraction and fasting tone are primarily controlled by CCK; 2) the contribution of CCK to the intestinal phase of postprandial pancreatic enzyme secretion is 40-50%; 3) GI motility and absorption are partially controlled by CCK; and 4) postprandial CCK secretion is substantially augmented by loxiglumide via an unknown mechanism.

Cholecystokinin and Gastrin Receptors

“…As observed in vitro, experiments with the CCK1 receptor antagonist loxiglumide indicate that CCK affects human colonic motility in vivo. Indeed, this compound accelerates colonic transit in normal volunteers (313,438,449,538). Moreover, demonstration that small intestinal motility is in part mediated by CCK1R-induced signaling was recently supported by significantly lower transit rates in CCK1R null mice (553).…”

Pharmacological profile of TP‐680, a new cholecystokininA receptor antagonist

“…Recent clinical and experimental studies have indicated the possible involvement of endogenous CCK in pancreatic and gastrointestinal physiology and pathophysiology (Meyer et al, 1989;Rovati, 1991;Schmidt et al, 1991;Beglinger et al, 1992a,b;Niederau et al, 1992;Tani et al, 1993;Herrington & 1 Author for correspondence. Adrian, 1995).…”

“…However, further studies using other CCKA receptor antagonists may be helpful in elucidating the physiological role of CCK. Thus, the development of CCKA receptor antagonists with higher selectivity for CCKA versus CCKB receptors or -with different characteristics is desirable in order to investigate new insights into digestive physiology and pathophysiology, to distinguish further CCK receptor substypes, and to examine the role of CCK in the treatment of gastrointestinal disorders (Meyer et al, 1989;Beglinger et al, 1991;1992a;Rovati, 1991;Schmidt et al, 1991;Niederau et al, 1992;Tani et al, 1993;Herrington & Adrian, 1995).…”

Cholecystokinin Receptor Antagonist Loxiglumide: Influence on Bilio-Pancreatic Secretion and Gastrointestinal Hormones in Man

“…Pancreatic secretion in response to a liquid test meal (382 kcal) was assessed by aspiration of duode nal juice via a multiple-lumen tube, as described [17,18]. Loxiglumide (30 mg/kg/h for 10 min, 10 mg/kg/h thereafter) or saline was administered intravenously.…”

“…Plasma CCK concentrations were determined in duplicate by a specific and sensitive radioimmunoas say using the Gottingen antiserum G-160 which rec ognizes the sulfated tyrosine group of CCK-8 [23], Details have been described elsewhere [ 17], Isolated rat pancreatic acini were used for the measurement of plasma CCK-like bioactivity by bioassay, as described with some modifications [7,9,39], Briefly, CCK and loxiglumide were ex tracted simultaneously from a plasma sample using RP-18 cartridges (Merck, Darmstadt, FRG). Rat pancreatic acini were prepared by collagenase diges tion.…”