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PubMed1985

Evidence of a noncholecystokinin stimulant of gallbladder contraction: comparison of fasting serum concentrations in healthy subjects and in patients with gallstones.

Some investigators have reported that patients with gallstones empty their gallbladders more rapidly than do healthy subjects. This may contribute to the formation of lithogenic bile. To date, cholecystokinin is considered the prime mediator of gallbladder contraction. Evidence exists that cholecystokinin may not be the major hormone accounting for gallbladder emptying. The purpose of this study was to demonstrate the existence of this noncholecystokinin substance in healthy persons and to compare its concentration with that in patients with cholesterol gallstones. Fasting serum levels from 15 healthy human subjects (8 women and 7 men, mean age 32 +/- 8 years) and 10 patients with cholesterol gallstones (5 women and 5 men, mean age 48 +/- 16 years) were studied. Using rabbit in vitro gallbladder bioassay and cholecystokinin-8 as standards, serum bioactivity was measured and expressed as cholecystokinin-8 equivalent bioactivity. The effectiveness of serum to contract the gallbladder was tested before and after removal of cholecystokinin from the serum. Cholecystokinin was removed from the serum samples by affinity chromatography with Sepharose 4B beads coated with cholecystokinin 5135 antibody. Gallbladder contractility from this treated serum thus reflects the action of a noncholecystokinin stimulant. The cholecystokinin-8 bioactivity equivalents in untreated samples from healthy subjects and from patients with gallstones were 2.9 +/- 0.3 and 7.6 +/- 0.7 ng/ml, respectively. The fact that bioactivity of serum persisted after removal of cholecystokinin in both groups of subjects provides evidence that a noncholecystokinin stimulant of gallbladder contraction exists. This substance is found in significantly higher concentrations in the fasting serum of patients with gallstones compared with healthy subjects. This finding may explain, at least in part, the increased gallbladder emptying rate in patients with gallstones and may account for the reduced bile salt pool size and, thus, formation of lithogenic bile.

Adult↗

PubMed1988

Relationship between gallbladder contraction and progesterone receptors in patients with gallstones.

Stasis of bile within the gallbladder has long been suspected of having an important role in the pathogenesis of gallstone disease. We postulated that the female preponderance of gallstone disease might partly be related to the effects of progesterone, a known smooth muscle relaxant, on specific receptors in the gallbladder wall, leading to stasis of bile. A total of 42 patients with gallstone disease and 28 control subjects underwent radionuclide scan imaging and their gallbladder ejection fractions were calculated in response to intravenous infusion of cholecystokinin octapeptide. Patients then underwent cholecystectomy and a piece of gallbladder fundus was assayed for the presence of progesterone receptors. Receptors were present in 60 percent of patients. As a group, gallstone patients had a decreased ejection fraction compared with control subjects. The presence of progesterone receptors in the gallbladder wall was associated with a decreased percentage of ejection compared with both healthy control subjects and patients whose gallbladders were receptor-negative. We conclude that progesterone receptors are present in the gallbladder wall of gallstone patients and that their presence correlates with impaired gallbladder emptying.

Adult↗

PubMed1998

Surgical indications for small polypoid lesions of the gallbladder.

BACKGROUND: To determine which polyps of the gallbladder should be operated upon, we investigated the size and number of polyps in resected gallbladders, and studied changes in gallbladder polyps using ultrasonography (US). METHODS: We studied 74 resected gallbladders with small polypoid lesions less than 20 mm in diameter, and 60 patients with gallbladder polyps by US. The polyps in resected gallbladders were classified into four groups histologically, and clinical features, maximum diameter, and number of lesions were compared among the groups. In the followed-up cases with gallbladder polyps, the size and number of polyps were examined by US, and changes during the observation period were studied. RESULTS: The mean diameter of adenoma was 6.00 +/- 3.39 mm (mean +/- SD) and that of cancer 10.8 +/- 4.16 mm; 97% of cholesterol polyps were less than 10 mm in diameter (3.66 +/- 2.68 mm). Neoplastic polyps tended to be single (adenoma, n = 1.40 +/- 0.89; cancer, n = 1.16 +/- 0.40), whereas half of the cholesterol polyps were multiple (n = 3.09 +/- 3.31). However, when there were fewer than 3 lesions, the incidence of neoplasm was 37% among polyps 5 to 10 mm in diameter. A low incidence (6%) of neoplasm was also observed among polyps less than 5 mm in diameter. CONCLUSIONS: These data indicate that an aggressive surgical approach for small gallbladder polyps is warranted when there are fewer than 3 polyps, regardless of their size.

Adult↗

PubMed2000

Further evidence for the heterogeneity of functional muscarinic receptors in guinea pig gallbladder.

Previous studies have suggested the presence of multiple muscarinic receptor subtypes in guinea pig gallbladder smooth muscle, although the relative abundance and functional role of these subtypes remains an area of significant research efforts. The present study utilized both radioligand kinetic and functional experiments to further probe the nature of the muscarinic receptors in gallbladder smooth muscle and their mode of coupling to intra- and extra-cellular Ca(2+) sources. Dissociation kinetic studies using [3H]N-methylscopolamine ([3H]NMS) indicated that the binding profile in guinea pig gallbladder smooth muscle could not be reconciled with that expected for a single muscarinic receptor subtype, the latter determined in parallel experiments conducted on the cloned muscarinic M(1)-M(5) subtypes in Chinese hamster ovary (CHO) cells. Furthermore, comparison of the gallbladder data with the dissociation characteristics of [3H]NMS in guinea pig urinary bladder revealed a significantly different kinetic profile, with the urinary bladder, but not the gallbladder, demonstrating biphasic radioligand dissociation kinetics. In functional experiments, carbachol caused a concentration-dependent contraction of guinea pig gallbladder smooth muscle strips in Ca(2+)-free or 5 mM Sr(2+)-substituted physiological salt solutions (PSS) with amplitudes of the maximal contractions corresponding to 45.8+/-8.0% and 33.2+/-6.6% of control responses in normal PSS, respectively. Furthermore, the stimulus-response characteristics of carbachol-mediated contraction appeared significantly altered in Ca(2+)-free PSS relative to normal or Sr(2+)-substituted PSS. The antagonist, methoctramine (1x10(-7)-3x10(-5) M), exerted only a slight inhibition of carbachol (10(-5) M)-induced contractions in 5 mM Sr(2+)-substituted medium, whereas it was significantly more potent in antagonizing gallbladder contractions in response to 10(-5) M carbachol in the absence of extracellular Ca(2+). Both atropine and tripitramine were equipotent in antagonizing carbachol-induced contractions in Ca(2+)-free (pIC(50): 6.85+/-0.11 for atropine and 5.75+/-0.32 for tripitramine) and Sr(2+)-substituted media (pIC(50): 6.88+/-0.25 for atropine and 5.70+/-0.16 for tripitramine), and pirenzepine was only slightly more potent in Ca(2+)-free PSS (pIC(50): 5.66+/-0.23) than in Sr(2+)-substituted PSS (pIC(50): 5.33+/-0.21). Taken together, our data indicate that carbachol contracts guinea pig gallbladder by stimulating two distinct muscarinic receptor subtypes linked to extracellular Ca(2+) influx and intracellular Ca(2+) release. These two subtypes may represent the muscarinic M(3) and M(4) receptors, although the presence of the muscarinic M(2) receptor subtype is also suggested from the binding data.

Animals↗

PubMed1997

Inhibitory effect of bile salts on gallbladder smooth muscle contractility in the guinea pig in vitro.

BACKGROUND & AIMS: Impaired gallbladder emptying occurs in patients undergoing bile salt therapy for cholesterol gallstone dissolution and in patients with cirrhosis who have elevated serum bile salt concentrations. To determine if bile salts directly inhibit gallbladder contractility, isometric contraction of the guinea pig gallbladder was examined in vitro. METHODS: Contractile responses to cholecystokinin (CCK), bethanechol, KCI, and field stimulation were constructed alone and in the presence of selected bile salts: taurodeoxycholate (TDC), taurochenodeoxycholate, taurocholate, and tauroursodeoxycholate (TUDC). RESULTS: More hydrophobic bile salts, such as TDC (as low as 5 micromol/L), concentration-dependently depressed (P < 0.05) both CCK- and field stimulation-induced gallbladder contractions. More hydrophilic bile salts, such as TUDC, only caused a modest depression up to a concentration of 500 micromol/L. When 5 or 50 micromol/L of TUDC was added to the organ bath before the application of equalmolar TDC, the TDC-induced impaired gallbladder contractility was reversed. Thus, this inhibitory effect on gallbladder contraction depended on the hydrophobicity of bile salts and was also specific for certain stimuli such as CCK and field stimulation (mediated by cholinergic nerves, being abolished by atropine and tetrodotoxin). CONCLUSIONS: Such direct bile salt inhibition of CCK- and cholinergic nerve-induced gallbladder contraction may contribute to the deteriorating gallbladder emptying in patients undergoing bile salt therapy for stone dissolution and in cirrhotic patients who are at risk for gallstone formation.

Animals↗

PubMed1997

Gallbladder relaxation in patients with pigment and cholesterol stones.

BACKGROUND & AIMS: Gallbladders with cholesterol stones show a defective contraction in response to agonists. The aim of this study was to investigate the muscle relaxation of human gallbladders with cholesterol or black pigment gallstones. METHODS: Gallbladder relaxation was measured in vitro using muscle strips and single muscle cells. Relaxation was expressed as percent inhibition of either basal active tension in strips or maximal cell contraction induced by diacylglycerol. The production of cyclic nucleotides was determined using a 125I-labeled radioimmunoassay kit. RESULTS: Frequency-dependent relaxation evoked by electrical field stimulation was significantly lower in gallbladders with cholesterol stones than in gallbladders with pigment stones. Relaxation and adenosine 3',5'-cyclic monophosphate (cAMP) production induced by isoproterenol, vasoactive intestinal peptide, and forskolin were also significantly decreased in gallbladders with cholesterol stones. However, the relaxation in response to 8-bromo-cAMP, nitric oxide (NO), and the NO donor S-nitroso-N-acetylpenicillamine (SNAP), which circumvent plasma membrane receptors and directly activate intracellular mechanisms, was similar in gallbladders with cholesterol and pigment stones. Guanosine 3',5'-cyclic monophosphate production induced by NO and SNAP was also similar. CONCLUSIONS: Human gallbladder muscle from specimens with cholesterol stones show an impaired relaxation and lower cAMP production compared with specimens with pigment stones. The muscle defect(s) responsible for this impairment seem to be in the plasma membranes.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1999

Prevalence and ethnic differences in gallbladder disease in the United States.

BACKGROUND & AIMS: Gallbladder disease is one of the most common conditions in the United States, but its true prevalence is unknown. A national population-based survey was performed to determine the age, sex, and ethnic distribution of gallbladder disease in the United States. METHODS: The third National Health and Nutrition Examination Survey (NHANES III) conducted gallbladder ultrasonography among a representative U.S. sample of more than 14, 000 persons. The diagnosis of gallbladder disease by detection of gallstones or cholecystectomy was made with excellent reproducibility. RESULTS: An estimated 6.3 million men and 14.2 million women aged 20-74 years had gallbladder disease. Age-standardized prevalence was similar for non-Hispanic white (8. 6%) and Mexican American (8.9%) men, and both were higher than non-Hispanic black men (5.3%). These relationships persisted with multivariate adjustment. Among women, age-adjusted prevalence was highest for Mexican Americans (26.7%) followed by non-Hispanic whites (16.6%) and non-Hispanic blacks (13.9%). Among women, multivariate adjustment reduced the risk of gallbladder disease for both Mexican Americans and non-Hispanic blacks compared with non-Hispanic whites. CONCLUSIONS: More than 20 million persons have gallbladder disease in the United States. Ethnic differences in gallbladder disease prevalence differed according to sex and were only partly explained by known risk factors.

Adult↗

PubMed2000

Endogenous prostaglandins modulate chloride secretion by prairie dog gallbladder.

In addition to concentrating bile, the gallbladder secretes chloride (Cl-) and mucus into its lumen. We recently observed that gallbladder Cl- secretion is increased in prairie dogs during the formation of cholesterol crystals, a period of altered mucosal prostaglandin synthesis. Pathologic Cl- secretion is characteristic of other epithelial disorders such as cystic fibrosis and hypercalciuric nephrolithiasis and may be important in gallstone pathogenesis. We hypothesized that concentrations of endogenous prostaglandin E2 (PGE2) found during experimental gallstone formation may mediate increased Cl- secretion by prairie dog gallbladder. Prairie dog gallbladders were harvested by cholecystectomy and mounted in Ussing chambers. Unidirectional transepithelial Cl-, Na+, and H20 fluxes were measured before and after inhibition of endogenous prostaglandin synthesis with 10 micromol/L indomethacin. Gallbladders were then exposed to increasing concentrations of PGE2 to a maximal dose of 1 micromol/L, as found in animals with gallstones. Standard electrophysiologic parameters were recorded simultaneously. Indomethacin increased mucosal resistance and stimulated gallbladder Na+ and Cl- absorption. These effects were rapidly reversed by PGE2. PGE2 promoted Cl- secretion and decreased mucosal Na+ absorption at concentrations found in the gallbladder bile of animals with gallstones. Endogenous prostaglandin metabolism modulates gallbladder Cl- secretion and may promote changes in Cl- transport associated with cholelithiasis.

Animals↗

PubMed1995

Protein kinase C regulates prairie dog gallbladder ion transport.

BACKGROUND: Gallstone formation is characterized by increased biliary calcium (Ca2+) level and altered gallbladder absorption. Recent studies suggest that luminal Ca2+ regulates gallbladder ion transport via intracellular calcium ([Ca2+]ic). Ca2+-calmodulin and protein kinase C (PKC) are two major systems through which [Ca2+]ic carries out second-messenger functions in many cell types. We have previously shown that Ca2+-calmodulin regulates basal gallbladder ion transport in prairie dog. The present study tests the hypothesis that PKC is also essential in regulation of gallbladder ion transport in this model. METHODS: The role of PKC in regulation of gallbladder ion transport was determined by studying the effects of phorbol esters, synthetic analogues of diacylglycerol, which directly activates PKC. Gallbladders were mounted in Ussing chambers, and standard electrophysiologic parameters were recorded after exposing tissues to either 10(-5) mol/L of 4-alpha-phorbol 12,13-didecanoate (PDD), 4-beta-phorbol 12-myristate 13-acetate, 4-beta-phorbol 12,13-dibutyrate (PDB), or 10(-4) mol/L serotonin. Unidirectional Na+, Cl-, and H2O fluxes were measured before and after treatment with only inactive PDD and most active PDB. RESULTS: Mucosal and serosal exposure of tissues to either 4-beta-phorbol 12-myristate 13-acetate or PDB resulted in a decrease in short-circuit current and transepithelial potential difference without any change in tissue resistance. Serotonin induced similar changes in gallbladder electrical properties. PDB caused an inhibition of mucosal to serosal fluxes of Na+, Cl-, and H2O, with a decrease in net Na+ absorption, an increase in net Cl- secretion, and a conversion of net H2O absorption to net H2O secretion. Serosal-to-mucosal fluxes of Na+, Cl-, and H2O did not change. Inactive PDD had no effect on either electrophysiologic parameters or ion and water fluxes. Pretreatment of tissues with PKC antagonist 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine blocked the phorbol ester-induced inhibition of ion transport. CONCLUSION: PKC regulates gallbladder ion transport in the prairie dog by inhibiting Na+ absorption and stimulating Cl- secretion.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2002

Hyperinsulinemia, dyslipidemia, and obesity as risk factors for hospitalized gallbladder disease. A prospective study.

PURPOSE: Prospective studies of gallbladder disease have investigated a limited number of risk factors and have been conducted predominantly in women. Determinants of hospitalized gallbladder disease were examined in a large, population-based cohort of men and women. METHODS: Subjects, aged 45-64 years, were participants in the Atherosclerosis Risk in Communities (ARIC) Study who reported no history of gallbladder disease at baseline (n = 12,773). Incident cases of gallbladder disease were identified through surveillance of hospital discharges between the baseline visit (1987-1989) and 1996. RESULTS: The crude incidence rate of hospitalized gallbladder disease was 3.8 per 1000 person-years. In women, increasing risk was observed for increasing levels of body-mass index and waist-to-hip ratio, whereas in men, increased risk was observed only in the morbidly obese (BMI >or= 35). Fasting serum insulin, low HDL cholesterol, elevated triglycerides, and hormone replacement therapy were all positively associated with gallbladder disease risk. The relative risks associated with having one, two, or three or more components of the "multiple metabolic syndrome" in men were 1.45 (95% CI = 0.9-2.3), 2.17 (1.3-3.6), and 2.34 (1.3-4.3), respectively. CONCLUSIONS: In men, hyperinsulinemia and dyslipidemia may have some role in the etiology of gallbladder disease beyond their association with obesity, whereas in women, increased body size, central adiposity, and hormone replacement therapy may be more important determinants of gallbladder disease.

Age Factors↗

PubMedDate not supplied

Endothelins induce gallbladder contraction independent of elevated blood pressure in vivo in the Australian possum.

Endothelin levels are elevated in shock, sepsis, and cholestatic jaundice, and an effect on biliary motility may be postulated. The aim of this study was to determine whether (1) endothelin-1 and endothelin-3 induce gallbladder contraction in vivo, (2) the response is caused by changes in blood pressure, and (3) the response is nerve mediated. Gallbladder pressure and blood pressure were measured in 38 anesthetized possums. Endothelin-1 or endothelin-3 (5 to 200 pmol/kg) was administered by close intra-arterial injection. Tetrodotoxin (9 microg/kg) or the mixed endothelin antagonist tezosentan was infused at a rate of 10 or 100 nmol/kg/min (close intra-arterial injection). Maximum changes in gallbladder pressure (% of carbachol-induced contraction) and blood pressure (mm Hg) were determined. Statistical analysis was carried out by means of repeated-measures analysis of variance and Kruskal-Wallis test. Both endothelin-1 and endothelin-3 induced dose-dependent increases in gallbladder pressure and blood pressure (P < 0.05), which were unaffected by pretreatment with tetrodotoxin. The endothelin-1-induced gallbladder pressure but not blood pressure was reduced by the higher dose of tezosentan (P < 0.03). The lower dose of tezosentan also produced a decrease in the endothelin-3-induced gallbladder pressure (P < 0.02) but not in blood pressure, whereas the higher dose reduced the blood pressure with no further reduction in gallbladder pressure (P < 0.05). Endothelins increase gallbladder motility in vivo, acting directly on the smooth muscle and independent of changes in blood pressure.

Anesthetics, Local↗

PubMed2005

Biliary sludge is formed by modification of hepatic bile by the gallbladder mucosa.

BACKGROUND & AIMS: We studied 22 patients with symptomatic microlithiasis to determine whether a contributory role of the gallbladder in the early stage of cholesterol gallstone formation exists. We compared the merits of different methods (ultrasonography and microscopy) and sources (hepatic or gallbladder) of bile samples for diagnosing microlithiasis. METHODS: Paired hepatic and gallbladder bile samples were studied with polarizing microscopy. Nucleation time, bile salts, phospholipid, cholesterol, cholesterol saturation index (CSI), bilirubin, total protein, albumin and mucin concentration were measured. All patients had abdominal ultrasound examination. RESULTS: With polarizing microscopy as the standard, ultrasonography was positive in 13 patients (59%) and negative in 9 (41%). All gallbladder bile samples were positive for microlithiasis by microscopy. Only one hepatic bile sample was positive (P < .0001). There was a disproportional enrichment of total protein, albumin, and mucin (P < .05) in the gallbladder bile and a conversion of bilirubin diglucuronide to monoglucuronide (P < .01). Gallbladder samples had lower CSI but a faster nucleation time (P < .001), which correlates inversely with CSI, total protein, and mucin concentration. CONCLUSION: Biochemical composition and physical chemical behavior of hepatic bile are modified during residence in the gallbladder, contributing to sludge formation. Gallbladder bile has a lower calculated CSI, higher deconjugation of bilirubin, protein and mucin concentration and crystals were present. Hepatic bile samples are inappropriate for microscopic detection of microlithiasis.

Adult↗

PubMed2000

Calmodulin regulation of gallbladder ion transport becomes dysfunctional during gallstone formation in prairie dogs.

Gallbladder absorption is increased prior to gallstone formation in prairie dogs and may promote cholesterol crystallization. Recent studies indicate that Ca2+-calmodulin (CaM) tonically inhibits gallbladder electrolyte absorption in prairie dogs fed a nonlithogenic diet. We hypothesized that dietary cholesterol alters CaM-dependent regulation of gallbladder ion transport, a possible link between increased gallbladder absorption and gallstone formation. Gallbladders from prairie dogs fed control (N = 24) or 1.2% cholesterol-enriched chow (N = 32) were mounted in Ussing chambers. Electrophysiology and ion flux were measured while exposing the epithelia sequentially to trifluoperazine (TFP), a CaM antagonist, followed by the calcium ionophore A23187. Animals fed the high cholesterol diet developed crystals and gallstones in a time-dependent fashion. Mucosal addition of 50 microM TFP decreased short-circuit current (Isc), transepithelial potential, and tissue conductance in control, crystal, and gallstone animals, but the magnitude of its effect was significantly decreased in animals fed cholesterol. TFP stimulated mucosa-to-serosa Na+ flux by 6.9 +/- 0.9 microeq/cm2/hr in control animals but only 3.1 +/- 0.8 microeq/cm2/hr in gallstone animals. Similarly, TFP increased mucosa-to-serosa Cl- flux by 11.9 +/- 1.4 microeq/cm2/hr in controls but only 4.9 +/- 1.4 microeq/cm2/hr in cholesterol-fed animals. TFP effects were not reversed by A23187, which caused differential effects on Isc and ion transport in cholesterol-fed animals. In conclusion, CaM-mediated inhibition of gallbladder Na+ and Cl- transport is diminished in prairie dogs fed cholesterol. We conclude that gallbladder ion transport is partially released from basal inhibition during gallstone formation and propose that dysfunctional CaM regulation may be a stimulus to increased gallbladder absorption.

Absorption↗

PubMed1998

Human gallbladder mucosal function: effects on intraluminal fluid and lipid composition in health and disease.

Gallbladder mucosal absorption of fluid during fasting is a well-known process. Indirect in vivo and recent in vitro evidence for physiologically relevant gallbladder absorption of cholesterol and phospholipids from bile has been observed in humans. The present study explored and compared by indirect means the relative efficiences of human gallbladder mucosal absorption of fluid and lipids in health and disease. Biliary lipids and pigment content were measured in fasting gallbladder bile samples obtained from gallstone-free controls and from four study groups: multiple and solitary cholesterol gallstone patients, and morbidly obese subjects with and without gallstones. Bile salts and pigment content were significantly greater in gallstone-free controls than in all other disease study groups. This was interpreted as evidence of more effective gallbladder mucosal fluid absorption in nonobese gallstone-free controls compared to that in all other groups. Correlation plot analyses of biliary lipids showed lower concentrations of phospholipids than expected from the index bile salt concentrations. The same was found for cholesterol concentrations but only in supersaturated samples. These findings were much more pronounced in gallstone free-controls and were accordingly interpreted as evidence of more efficient gallbladder absorption of both phospholipids and cholesterol in controls compared with that found in each of the disease study groups. Moreover, impaired gallbladder mucosal function, while invariably associated with cholesterol gallstone disease, was not found to be a necessary consequence of the physical presence of stones. It is concluded that efficient gallbladder mucosal absorption of both fluid and apolar lipids from bile is a normal physiological process that is often seriously impaired in the presence of either cholesterol gallstone disease or at least one of its precursor forms.

Absorption↗

PubMed1997

Impaired gallbladder and gastric motility and pathological gastro-oesophageal reflux in gallstone patients.

Impaired gallbladder motility is common in gallstone patients and might be associated with other gastrointestinal defects. Twenty patients with small stones in an opacified gallbladder at oral cholecystography and 20 healthy subjects homogeneous for sex, age and body size were studied by ultrasonography to assess gallbladder and gastric emptying simultaneously in response to a standard liquid meal (120 kcal, 11 g fat, 200 mL). The same subjects underwent ambulatory 24-h gastro-oesophageal pH monitoring. Dyspeptic symptoms were specifically investigated using a questionnaire. Gallstone patients had a significantly larger fasting (P < 0.05) and residual (P < 0.005) gallbladder volume with slower (P < 0.05) and less complete (ANOVA, 0.001 < P < 0.05) gastric emptying than healthy control subjects. The speed of antral emptying was significantly correlated with the speed of gallbladder emptying (n = 40, r = +0.31, P < 0.05). Pathological gastro-oesophageal reflux was present in 75% and 15% of patients and control subjects respectively (P < 0.05). Overall, 95% of gallstone patients had abnormal pH profiles resulting from pathological gastro-oesophageal reflux and/or prolonged gastric alkalinization. The speed of post-prandial antral emptying was significantly correlated with the duration of the longest gastro-oesophageal reflux episode (r = +0.30, P < 0.03) and duodeno-gastric reflux episode (r = +0.80, P < 0.02). Best predictors for gastric alkalinization were the following indices of gallbladder function: large fasting volume (P = 0.03), large ejection volume (P = 0.009) and slower emptying (P = 0.032). Gallbladder and gastric motility were similar in patients with (n = 12) and without (n = 8) dyspeptic symptoms. Pathological gastro-oesophageal reflux was found in 83% of dyspeptic patients and in 25% of patients without dyspepsia (P < 0.01). When reflux was present, it was significantly less in asymptomatic than in dyspeptic patients [time at pH < 4, median (range): 6.4% (3.2-22.6%) vs. 47.8% (2.1-87%), P < 0.05]. This study shows that a subgroup of gallstone patients with small-mainly asymptomatic-stones have impaired gallbladder and gastric motility as well as abnormal gastro-oesophageal pH-profiles. These findings point to the existence of multiple functional defects of the upper gastrointestinal tract in gallstone disease.

Adult↗

PubMed1998

Evidence for the presence of muscarinic M2 and M4 receptors in guinea-pig gallbladder smooth muscle.

1. The affinities of 10 selective muscarinic receptor antagonists against [3H]-quinuclidinyl benzilate (QNB) binding were determined to characterize the muscarinic receptors present in guinea-pig gallbladder smooth muscle. The highest correlation was obtained for the comparison between the pKi values for the gallbladder smooth muscle and M2 sites. Pirenzepine revealed two binding sites with affinities indicating the presence of muscarinic M2 receptors in abundance and a minor population of an additional site(s). 2. Carbachol produced gallbladder contractions, stimulated phosphoinositide (PI) hydrolysis and inhibited cAMP formation concentration-dependently with pD2 values of 6.12 +/- 0.11, 5.18 +/- 0.33 and 7.19 +/- 0.15, respectively. 3. Pirenzepine, 4-DAMP, HHSiD, pF-HHSiD, AF-DX 116, methoctramine, AQ-RA 741, guanylpirenzepine and AF-DX 384 showed competitive antagonism against carbachol-induced gallbladder contractions. There was no correlation between the pA2 values for the gallbladder and pKi values for the M2 sites, whereas significant correlations were found for the M1, M3 and M4 sites, the best correlation being between the pA2 values for the gallbladder and M4 subtypes. 4. Finally, the presence of both m2 and m4 receptor proteins were demonstrated by Western blot analysis. It is concluded that guinea-pig gallbladder smooth muscle has both muscarinic M2 and M4 receptors, which are coupled to adenylate cyclase inhibition and PI hydrolysis. 5. Although it seems likely that M2 receptors do not play a primary role in carbachol-induced guinea-pig gallbladder contraction, the characterization of the muscarinic subtypes which mediate these contractile responses needs further evidence.

Adenylyl Cyclases↗

PubMed1996

Role of nitric oxide in induction of inflammatory fluid secretion by the mucosa of the feline gallbladder.

BACKGROUND & AIMS: Nitric oxide is synthesized from L-arginine and is metabolized to nitrate and nitrite. This study evaluates the effects of a pharmacological blockade of NO synthesis on fluid transport by the inflamed gallbladder mucosa. METHODS: Experiments were performed in cats with cholecystitis and in control animals. NO synthase activity was measured in gallbladder tissue; the enzyme was characterized by immunoblotting techniques and localized by immunofluorescence. Fluid transport and release of nitrate and nitrite by the gallbladder mucosa and bile and bile salt secretion from the liver were registered simultaneously in vivo. RESULTS: Fluid secretion in inflamed gallbladders was reversed to a net absorption in response to the NO synthase blockers N omega-nitro-L-arginine and aminoguanidine, and formation of nitrate was reduced. The effects were reversed by L-arginine. Increased levels of inducible NO synthase in inflamed gallbladders were shown by immunoblotting, by immunofluorescence (mainly in macrophages), and by Ca(2+)-independent [3H]citrulline formation from [3H]arginine. The NO synthase blockers had no effect on gallbladder fluid transport in normal gallbladders. CONCLUSIONS: Increased levels of inducible NO synthase activity are shown in inflamed gallbladders, and a pharmacological blockade of this enzyme blocks fluid secretion and decreases nitrate release from the mucosa.

Analysis of Variance↗

PubMed2000

p27(Kip1) expression in normal epithelia, precancerous lesions, and carcinomas of the gallbladder: association with cancer progression and prognosis.

p27(Kip1) is a cyclin-dependent kinase inhibitor that negatively regulates cell proliferation. This study was designed to evaluate the roles of p27(Kip1) in gallbladder carcinogenesis and the prognostic value of p27(Kip1) in patients with gallbladder carcinoma. p27(Kip1) expression was examined immunohistochemically in surgically resected specimens of 8 normal epithelia, 8 adenomyomatosis lesions, 6 precancerous adenomas, and 37 carcinomas of the gallbladder. Decreased p27(Kip1) expression (<50% nuclear staining) was observed in 16 of the 37 (43%) gallbladder carcinomas, but not in any specimen of normal epithelium, adenomyomatosis, or adenoma. The fact that all of the adenomas showed normal p27(Kip1) expression suggests that decreased p27(Kip1) expression is probably not an early event in gallbladder carcinogenesis. Decreased p27(Kip1) expression was significantly associated with less marked tumor cell differentiation (P =.017), lymphatic invasion (P =.046), lymph node metastasis (P =.007), and advanced TNM stage (stage IV vs. stage I, P =.026; stage IV vs. stage II, P =.005). This suggests that down-regulation of p27(Kip1) expression is a late event in gallbladder carcinogenesis, possibly promoting tumor progression and metastasis. Kaplan-Meier curves showed that decreased p27(Kip1) expression was significantly associated with shorter overall survival (P =.001) in patients with gallbladder carcinomas who had undergone radical surgery. Cox's proportional hazards model revealed decreased p27(Kip1) expression to be an independent predictor for death (P =.034; risk ratio, 3.9; 95% confidence interval, 1.1-13.7). In conclusion, decreased p27(Kip1) expression significantly correlates with tumor progression and predicts poor prognosis in gallbladder carcinomas.

Adenoma↗