Human Gallbladder Motility Research Articles

1982-P: Glucagon-Like Peptide-2 Inhibits Postprandial Gallbladder Emptying in Healthy Male Individuals—A Randomized, Double-Blinded, Placebo-Controlled Study

A recent study in mice has demonstrated that the gut-derived hormone glucagon-like peptide-2 (GLP-2) may be involved in the regulation of gallbladder motility and induces gallbladder refilling. This study evaluated the effect of exogenous GLP-2 on postprandial gallbladder motility in humans. On three experimental days, 15 young healthy males ([mean±SEM] age 24.3±1.9 years, BMI 22.5±0.9 kg×m-2, HbA1c 4.8±0.1% (29.3±1.5 mmol/mol)) were subjected to a 3.5-hour 300 kcal mixed liquid meal-test. Continuous 4-hour intravenous infusions of placebo (saline), low-dose GLP-2 (1 pmol×kg-1×min-1) or high-dose GLP-2 (10 pmol×kg-1×min-1) were initiated 30 min before meal ingestion. Gallbladder volume was determined by ultrasonography, and gallbladder ejection fraction was calculated. Postprandial maximum gallbladder ejection fraction during saline infusion (76.3±2.8%) was significantly reduced by low-dose GLP-2 (65.5±3.5%, P=0.026) and completely abolished during high-dose GLP-2 infusion (4.0±3.7%, P<0.0001) (Figure). Postprandial peak plasma glucose was lower during high-dose GLP-2 infusion (6.4±0.2 mmol/l) compared to low-dose GLP-2 (6.9±0.2mmol/l, P=0.0004) and placebo infusion (7.2±0.2 mmol/l, P=0.008). In conclusion, exogenous GLP-2 dose-dependently inhibits postprandial gallbladder emptying in healthy male subjects. Disclosure N.L. Hansen: None. C.C. Nexøe-Larsen: None. A. Brønden: Other Relationship; Self; AstraZeneca. A.S. Christensen: None. D.P. Sonne: None. B. Hartmann: None. T. Vilsbøll: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S.

Estrogen and G protein-coupled estrogen receptor agonist G-1 cause relaxation of human gallbladder

ObjectiveEstrogen interacts with a membrane receptor, G protein-coupled estrogen receptor (GPER). It was reported that 17β-estradiol was able to inhibit contraction of the human colon and cause relaxation of the guinea pig gallbladder, however, the involvement of GPER was not clarified. The aim of the present study was to investigate the effect of estrogen on human gallbladder motility and the possible role of GPER. Materials and MethodsRelaxation of human gallbladder strips were measured using isometric transducers. Expression of GPER was evaluated by reverse transcription polymerase chain reaction (PCR), real-time PCR, and immunohistochemistry. ResultsIn human gallbladder strips, 17β-estradiol and G-1 elicited marked and rapid relaxation, whereas tamoxifen produced mild concentration-dependent relaxation. The relative efficacies to cause relaxation were as follows: 17β-estradiol = G-1 > tamoxifen. The relaxant response of 17β-estradiol was not attenuated by tetrodotoxin or conotoxin GVIA. This implies that nerve stimulation was not involved in the 17β-estradiol-induced gallbladder relaxation. Analysis by reverse transcription PCR and real-time PCR showed that GPER was expressed in the human gallbladder. Further analysis by immunohistochemistry revealed that GPER was expressed in the gallbladder muscle. This suggests that 17β-estradiol relaxes the human gallbladder via GPER. ConclusionThese results demonstrate for the first time that 17β-estradiol and GPER agonist G-1 cause relaxation of the human gallbladder, probably through GPER. Estrogen might play an important role in the control of human gallbladder motility.

Prokinetic effect of ??-adrenergic antagonist, and ??-adrenergic antagonist on gall-bladder motility in humans with gall-stone disease

The effects of cholinergic agents and vagal control on gall-bladder motility are well defined. Alpha adrenergic antagonists have been found in previous studies to have a prokinetic effect on gall-bladder motility in normal human patients. Their effects have not, however, been fully elucidated in patients with gall-stone disease. Our aim was to determine the effects of alpha-antagonists and beta-antagonists on gall-bladder motility in human patients with gall-stone disease. In this single-blind, three-way crossover study, a slow release formulation of 80 mg propranolol (beta-antagonist), and 25 mg indoramin (alpha-antagonist), and placebo were administered separately to 10 patients with gall-stone disease on three separate days 8 h before assessment of gall-bladder volumes by ultrasonography. Gall-bladder volumes were assessed in the fasting state and at 5 min intervals for 50 min after a standard proprietary enteral feed (Ensure 180 ml, Abbott). Differences between the placebo and postadrenergic antagonist scan volumes were tested using the Wilcoxon-signed rank test. There were no significant differences in the mean fasting gall-bladder volumes after receiving propranolol, indoramin and placebo (23.6+/-3.9, 22.3+/-4.3, 26.8+/-7.2 ml, mean+/-SEM, respectively). In the postprandial period, however, indoramin significantly enhanced postprandial gall-bladder emptying compared with placebo between 5 and 30 min (P<0.05) after which refilling commenced. There were no significant postprandial gall-bladder volume differences between propranolol and placebo. Indoramin, an alpha-adrenergic antagonist, acts as a prokinetic agent enhancing postprandial gall-bladder emptying in patients with gall-stone disease. This effect is similar to its effect on postprandial gall-bladder emptying in healthy individuals.

Effect of somatostatin on human gallbladder motility: an in vitro study.

In vivo studies have demonstrated that somatostatin induces human gallbladder relaxation. To determine whether this polypeptide acts directly on the gallbladder muscle, its effect on strips of human gallbladder was studied in vitro. Strips of gallbladder were set up isometrically in an organ bath containing oxygenated Krebs' solution. Dose-response curves to cholecystokinin-octapeptide and carbachol were first established. The ability of somatostatin to cause relaxation under basal conditions and during 50% maximal stimulation by cholecystokinin-octapeptide (7.2 x 10(-8) M) and carbachol (3.5 x 10(-6) M) was assessed in 32 strips at 4.3 x 10(-6) M concentration which mimics the plasma concentrations found in patients with somatostatinoma and in 12 additional strips at 4.3 x 10(-8) M concentration. Somatostatin action on the intrinsic innervation by using electrical field stimulation (EFS) (200 mA 5 msec in duration, 30 Hz; 400 mA, 1 msec in duration, 10 Hz) was also evaluated in 39 strips. Somatostatin had no effect on the basal or carbachol-generated tensions. On the contrary, somatostatin (4.3 x 10(-6) M) reduced cholecystokinin-octapeptide-generated tensions by 8% (P < 0.001) and reduced EFS-generated tensions at 30 Hz by 7.7% (P < 0.01) and those at 10 Hz by 41.2% (P < 0.01). All responses to cholecystokinin-octapeptide and carbachol were abolished by dibutyryl-guanosine 3', 5'-cyclic monophosphate (5 x 10(-3) M) and atropine (10(-5) M), respectively (P < 0.0002 and P < 0.0002). All responses to electrical field stimulation were reduced or abolished by tetrodotoxin (2 x 10(-6) M) (P < 0.001 and P < 0.0001, respectively). Our findings show that somatostatin exerts its inhibitory action on the response to cholecystokinin-octapeptide and on the intrinsic innervation of the gallbladder smooth muscle. The probable neurotransmitter is the acetylcholine.

Hepatocyte growth factor effects on motility of stone-diseased and stone-free human gallbladders.

Hepatocyte growth factor (HGF) has unique morphogenic activity for several cell types. Besides its major effect upon liver regeneration, its motogenic activity to enhance motility has not been verified for smooth muscles. Therefore we evaluated the impact of HGF in an in-vitro model of human gallbladder motility. Twelve stone-diseased and eight stone-free muscle strips were preincubated with HGF (100 ng/ml, 200 ng/ml). For the analysis of motility, cholecystokinin (CCK) was added (0.1 nM, 0.5 nM, 2 nM, 10 nM, and 100 nM). Twelve stone-diseased and eight stone-free strips without HGF incubation served as the control group. The tone of healthy (tone/100 nM CCK: control group, 12.4 +/- 3.6 mN; HGF group, 19.5 +/- 4.5 mN) and stone-diseased (tone/100 nM CCK: control group, 10.8 +/- 3.8 mN; HGF group, 17.3 +/- 4.8 mN) muscle strips, preincubated with HGF, was increased, with a higher sensitivity to CCK. Our results suggest that there is a clear motogenic response of stone-diseased human gallbladders to HGF.

The effects of intraduodenal bile on Interdigestive gastrointestinal and gallbladder motility in humans

The effects of intraduodenal bile on Interdigestive gastrointestinal and gallbladder motility in humans

Gall bladder motility after endoscopic sphincterotomy

Editor,—We read with interest the article by Sugiyama and Atomi ( Gut 1996; 39 :856–9) on the effect of endoscopic sphincterotomy (ES) on gall bladder motility. These authors have proved conclusively that ES causes a significant improvement in gall bladder motility in humans. We have assessed gall bladder motility in patients who underwent ES for common bile duct (CBD) stones and compared these with patients with gall bladder calculi but without CBD stones. We found significantly lower fasting and residual gall bladder volumes in the patients who had undergone ES, indicating reduced filling after ES.1 However, the ejection fraction and the rate constant of gall bladder emptying in these patients was increased significantly, suggesting increased gall bladder emptying. In another study2 we found a significant decrease in fasting volume (mean (SD) 18.3 (8.5) v 13.9 (7.3) ml), residual volume (12.0 (8.0) v 4.4 (3.2) ml) and an increase in the ejection fraction (54.3 (9.8) v 83.5 (5.4)) after ES, suggesting decreased stasis and increased gall bladder emptying. In Sugiyama and Atomi’s this study, all patients in whom gall bladder motility was assessed before ES had CBD stones; all stones were extracted before … Dr Sugiyama.

Effect of insulin on basal and cholecystokinin-stimulated gallbladder motility in humans

Background/Aims: Acute hyperglycemia inhibits gallbladder contraction. In non-diabetic subjects this inhibitory effect may result from endogenous hyperinsulinemia. Therefore we investigated the effects of acute hyperglycemia and euglycemic hyperinsulinemia on basal and cholecystokinin-stimulated gallbladder motility. Methods: Gallbladder volume (ultrasonography) and duodenal bilirubin output were studied simultaneously in nine healthy volunteers (age 20–52 years) on 3 separate occasions in random order during: (a) saline infusion (control), (b) hyperglycemic hyperinsulinemic clamping (HG; plasma glucose at 15 mmol/l), and (c) euglycemic hyperinsulinemic clamping (HI; plasma insulin at 150 mU/l, glucose at 4–5 mmol/l). After a 2-h basal clamp period, cholecystokinin was infused intravenously for 60 min at 0.25 IDU · kg −1 · h −1, followed by another 60 min at 0.5 IDU · kg −1 · h −1. Results: HI and HG significantly ( p<0.05) reduced basal duodenal bilirubin output compared to control, while basal gallbladder volume did not change. At the low dose cholecystokinin, gallbladder emptying during HG (25±3%) and HI (39±4%) was significantly ( p<0.01) reduced compared to control (61±4%). The inhibitory effect of HG was significantly ( p<0.05) stronger compared to HI. Duodenal bilirubin output during the low dose cholecystokinin was significantly ( p<0.05) reduced by HG, but not by HI. No inhibitory effect of HG and HI on gallbladder emptying and duodenal bilirubin output was observed with the high dose of cholecystokinin. Conclusions: In healthy subjects acute hyperglycemia and euglycemic hyperinsulinemia reduce basal duodenal bilirubin output and inhibit gallbladder emptying stimulated by low dose cholecystokinin. These results suggest that insulin is involved in the inhibitory effect of hyperglycemia on basal and cholecystokinin-stimulted gallbladder motility.

Effect of insulin on cholecystokinin-stimulated gallbladder motility in humans

Effect of insulin on cholecystokinin-stimulated gallbladder motility in humans

Effect of the nitric oxide donor, glyceryl trinitrate, on human gall bladder motility

Background—Nitric oxide is a major neurotransmitter in non-adrenergic, non-cholinergic (NANC) pathways. NANC inhibitory innervation has been shown in human gall bladder muscle in vitro; the role of nitric oxide in...

Effect of endoscopic sphincterotomy on gallbladder motility.

In experimental animals, sphincterotomy facilitates passage of solids from the gallbladder and inhibits gallstone formation apparently by improvement in gallbladder emptying. In humans, however, gallbladder emptying has not been studied following endoscopic sphincterotomy (ES) in patients with gallstones. We therefore prospectively studied resting and cerulin-stimulated gallbladder volumes by real time ultrasonography in 15 patients of choledocholithiasis with gallbladder in situ (eight with and seven without gallbladder calculi) before and after (after bile duct clearance) ES. ES significantly lowered resting gallbladder volume (21.2 +/- 10.6 vs 11.1 +/- 5.0; P < 0.0001) and cerulin-stimulated residual gallbladder volume (10.8 +/- 5.6 vs 4.4 +/- 2.1; P < 0.0001). ES also significantly increased the gallbladder ejection fraction (47.3 +/- 12.1% vs 58.8 +/- 11.1%; P < 0.0001). The rate constant for gallbladder emptying after cerulin infusion also increased significantly after ES (-0.022/min vs -0.031/ min; P < 0.0001). Significant improvement in gallbladder motility was observed in both groups of patients with and without gallbladder calculi. ES significantly improves gallbladder motility in humans.

Inositol trisphosphate restores impaired human gallbladder motility associated with cholesterol stones

Background: Gallbladder motility is impaired in specimens with cholesterol stones but normal with pigment stones. Methods: Muscle cells obtained from 19 human gallbladders with cholesterol stones and 11 with pigment stones were enzymatically digested and contracted with cholecystokinin octapeptide (CCK-8), acetylcholine, and KCl. Results: Muscle cells from pigment stones had a greater contraction than cells from cholesterol stones. CCK-8-induced contraction was unaffected by calcium-free media but was blocked by strontium. Potassium-evoked contraction was blocked by a calcium-free media and unaffected by strontium. Inositol triphosphate (IP-3)-induced contraction was similar to the contraction caused by CCK-8 in permeable cells from pigment stones but was greater than the response to CCK-8 in cells from cholesterol stones. Conclusions: Muscle cells from gallbladders with cholesterol stones contract less than cells from gallbladders with pigment stones; CCK-8-induced contraction only uses stored calcium; and IP-3 causes contractions of equal magnitude in cells from gallbladders with cholesterol and pigment stones. These abnormalities could result from an impaired receptor activation of the mechanism for IP-3 generation and release of stored calcium.

Effect on human gallbladder motility of a physiological substance : L-propionil-carnitine

Effect on human gallbladder motility of a physiological substance : L-propionil-carnitine

Sex Steroid Hormone Receptors and Human Gallbladder Motility in vitro

This study was designed to investigate the relationship between estrogen and progesterone receptor levels and in vitro contractile response of gallbladder muscle strips to stimulation by carbachol and cholecystokinin-octapeptide (CCK-OP). Seventeen female postmenopausal patients cholecystectomized for gallstones were studied. Samples of the gallbladder wall were used for histological examination; motility was studied by Keane et al. [Surg Gynecol Obstet 1986; 163:555-560]; the estrogen and progesterone receptor levels were evaluated by immunoenzymatic assay. Positive correlations were found between the progesterone receptor level and the carbachol concentration that produced half the maximal response (ED50), and between the estrogen receptor level and the ED50 of CCK-OP. Our data confirm the presence of estrogen and progesterone receptors in the gallbladder and suggest that sex steroid hormones act on gallbladder motility by modulating the affinity of gallbladder receptors to CCK-OP and carbachol.

The role of neurotensin in human gallbladder motility.

Gallbladder contraction in response to a fatty meal is thought to be caused by release of cholecystokinin (CCK). We have previously demonstrated a close correlation between circulating concentrations of CCK and contraction of the gallbladder in normal humans and in gallstone patients. Recent studies in animals, however, have shown that other potentially cholecystokinetic hormonal agents are released by a fatty meal, which suggests that other hormones may be involved in postprandial gallbladder contraction. Neurotensin, a 13-amino acid peptide, is released by fat; we have shown it to cause gallbladder contraction in dogs. In the present study, we measured release of neurotensin in seven normal adult volunteers. We determined the effects of infused neurotensin (4 pmol/kg-min) on gallbladder contractility, measured by ultrasonography in 10 adult volunteers, and we evaluated release of neurotensin in eight patients with gallstones. After ingestion of fat, we found significant release of neurotensin in normal volunteers from a mean basal concentration of 15.9 +/- 3.5 pg/ml to a maximum of 34.7 +/- 0.2 pg/ml. In the gallstone patients after fat ingestion, neurotensin rose from a basal of 16.8 +/- 3.1 pg/ml to a maximum of 53.4 +/- 28.1 pg/ml, which was a significantly greater release than in controls. Intravenous infusion of neurotensin produced dilatation of the gallbladder (from a mean basal volume of 13.7 +/- 2.3 cc to 20.0 +/- 1.8 cc). Neurotensin causes relaxation of the gallbladder in humans and, by contributing to stasis, may be involved in the formation of gallstones.