Cholecystectomy also on rise in Alberta.
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Alberta↗
Biomedical subjects
E A Shaffer
Publications and source records attributed to E A Shaffer.
Slow intestinal transit: a motor disorder contributing to cholesterol gallstone formation in the ground squirrel.
Impaired gallbladder motility is an established factor in cholesterol gallstone formation. We assessed whether altered small intestinal smooth muscle contractility with slow transit might potentiate gallstone formation by further impeding enterohepatic cycling of bile acids. Ground squirrels were fed a 1% or a trace (controls) cholesterol diet. Small intestinal transit was evaluated from 51Cr distribution in conscious, fasted animals 20 minutes after infusion into the proximal jejunum. Small intestinal and gallbladder smooth muscle contractility was determined in vitro. Biliary lipid secretion was measured from the cannulated common duct and the bile salt pool size calculated by isotope dilution. Gas-liquid chromatography (GLC) assessed bile salt profile. In animals on the 1% cholesterol diet, aboral transit was significantly delayed, the maximal contractile response to bethanechol was markedly increased (P <.05) with no change in median effective concentration in either circular or longitudinal muscle strips from both the jejunum and ileum, and the gallbladder contractile responses to bethanechol and cholecystokinin (CCK) were decreased. Cholesterol saturation index and the fraction of deoxycholic acid in the pool doubled, whereas the total bile salt pool size remained unchanged in cholesterol-fed animals. In this model, a high-cholesterol diet is associated with altered small intestinal smooth muscle contractility and prolonged small intestinal transit, in addition to diminished gallbladder contractility. The resulting sluggish enterohepatic cycling of bile salts, associated with expanded deoxycholate pool, contributes to cholesterol gallstone formation.
Animals↗
The potential site of impaired gallbladder contractility in an animal model of cholesterol gallstone disease.
BACKGROUND & AIMS: Gallbladder contractility is decreased in cholesterol gallstone disease, but the mechanism underlining this defect is unclear. The aim of this study was to determine the cellular site of this defect in an animal model of cholesterol gallstone disease. METHODS: Ground squirrels were maintained for 28 days on either a control or a 1% cholesterol diet. Gallbladder contractile responses to several known agonists were measured in vitro using smooth muscle strips. RESULTS: Gallbladder contractility in response to cholecystokinin, bethanechol, and K+ was equally decreased in cholesterol-fed animals, in concert with an increased cholesterol saturation of gallbladder bile compared with controls. In contrast, the contractile responses to A-23187 (a calcium ionophore), cyclopiazonic acid (a selective, potent inhibitor of sarcoplasmic reticulum Ca2+ pump), and barium (a calcium analogue), which readily diffuse across the intact sarcolemmal membrane, remained the same in both groups. Dose responses to a G-protein activator, aluminum fluoride, were again not different between these two groups. CONCLUSIONS: The primary smooth muscle defect in this animal model of cholesterol gallstone disease does not reside in the intracellular signal transduction pathways or in the contractile apparatus but instead involves the sarcolemmal membrane.
Animals↗
Effects of liver transplantation on bile formation and biliary lipid secretion in the Sprague-Dawley rat.
Altered hepatic secretory function after orthotopic liver transplantation constitutes a major perioperative clinical problem. Cholestasis and cholesterol gallstone formation are among the most frequent complications reported. Such changes in the allograft secretory function can be secondary to many factors like graft injury due to preservation and marked rejection, surgical complications, immunosuppressive therapy, and sepsis. The effects of liver transplantation per se on bile formation and biliary lipid secretion are unknown. The rat model of orthotopic liver transplantation was used to characterize better the true effect of transplantation without the influence of these confounding variables. Twenty-four-hour bile collections were performed on nine transplanted versus nine liver-denervated (sham) rats 4 weeks after surgery, and nine normal Sprague-Dawley rats. The liver allografts showed mild lymphocytic infiltration in portal tracts and the serum alanine transaminase levels were not significantly elevated. Bile flow and the secretion of bile salts and bilirubin under basal conditions were unchanged. Bile salt pool size, synthesis rate, and bile acid composition did not differ among the three groups. However, cholesterol secretion was dramatically reduced (50%) in the transplanted rats and decreased 31% in the liver-denervated rats (P < .001 and .01, respectively), resulting in a more favorable cholesterol saturation index (CSI = 0.29 for transplanted and 0.32 for sham versus 0.45 for normal controls; P < .01). Thus, liver transplantation with its attendant denervation did not impair hepatic secretory function, but rather improved biliary lipid composition despite mild rejection.
Alanine Transaminase↗
Inhibition of gallbladder emptying decreases cholesterol saturation in bile in the Richardson ground squirrel.
Impaired gallbladder emptying is frequent in cholesterol gallstone disease as well as in predisposing conditions like pregnancy and obesity. Gallbladder hypomotility is considered a pathogenic factor for gallstone formation, providing the residence time for cholesterol crystal nucleation, but any effect on the enterohepatic circulation of bile acids and subsequently on biliary lipid composition is unknown. Therefore, we studied the effect of prolonged suppression of gallbladder emptying with a cholecystokinin (CCK-A) receptor antagonist on bile formation in Richardson ground squirrels fed a trace versus a 1% cholesterol diet. Biliary lipid secretion was measured directly and bile acid pool size assessed by isotope dilution ([14C]-cholic acid). Gallbladder contraction was determined in vitro in response to CCK. The CCK-antagonist (MK-329) greatly inhibited gallbladder contraction in vitro and increased gallbladder fasting volume and bile acid pool size in vivo. It significantly lowered the cholesterol saturation index by 35% and 46% in hepatic bile and by 18% and 28% in gallbladder bile in the trace and cholesterol diet groups, respectively. Bile acid secretion and bile flow doubled with the CCK-receptor antagonist. Chronic CCK receptor antagonist-induced inhibition of gallbladder emptying increases bile acid secretion and thereby decreases cholesterol saturation in bile. Extensive biliary hypomotility thus leads to a more rapid cycling of bile acids by depriving the gallbladder of its function in the enterohepatic circulation.
Animals↗
Management of gastrointestinal hemorrhage.
Acute gastrointestinal hemorrhage is a common problem that requires prompt recognition and management to prevent serious morbidity and mortality. Management goals are stabilization of the patient with vigorous fluid resuscitation followed by investigation and definitive treatment of the bleeding source. Endoscopy is often the initial diagnostic test and allows therapeutic measures to be performed at the same time.
Acute Disease↗
Effects of obesity on bile formation and biliary lipid secretion in the genetically obese JCR:LA-corpulent rat.
Obesity, a known risk factor in cholesterol gallstone disease, is a favorable factor in the formation of bile supersaturated with cholesterol. Previous studies have been indirect and limited to human beings. To better define the hepatic secretory defect, we directly measured bile secretion and bile salt kinetics in a genetically obese rat. Common bile duct cannulations and 24-hr bile collections were performed on 11 obese (homozygous for the cp gene) and 11 lean (heterozygous cp) female rats of the JCR:LA-cp strain. In absolute terms, obese rats had normal bile salt secretion rates, 28% larger bile salt pools and 45% greater bile salt synthesis than lean controls. Obese rats had twice the total liver DNA content of lean controls, indicating twice the liver cell number. In terms relative to liver cell number, bile salt synthesis per milligram DNA was no different in the obese rats and controls. Biliary secretion under basal conditions, when expressed per total DNA content, was significantly decreased in the obese rats. Bile salt and phospholipid secretion per milligram DNA were decreased 54% and 49%, respectively, whereas a lesser 31% reduction in cholesterol secretion resulted in an increased cholesterol saturation index. The bile salt secretion rate and bile flow per milligram DNA were both decreased by half in obese rats, a cholestatic state likely reflecting the accumulation of intracellular microvesicular fat and mitochondrial damage. The secretory defect in this model of obesity is therefore less bile salt and phospholipid in relation to the cholesterol secreted per liver cell.
Animals↗
Bile salts determine leukotriene B4 synthesis in a human intestinal cell line (CaCo-2).
The ability of a human colonic epithelial cell line (CaCo-2) to synthesize leukotriene B4 (LTB4) in response to bile salt stimulation was examined, as was the dependency of such stimulation on the hydrophobic-hydrophilic balance of the bile salts. We demonstrate for the first time in this human intestinal epithelial cell line the ability of bile salts to stimulate synthesis of LTB4. CaCo-2 cell monolayers were incubated with a series of bile salts ranging in concentration from 0.5 microM to 1 mM. This resulted in a dose- and hydrophobicity-dependent increase in LTB4 synthesis. Hydrophobic bile salts (glycine and taurine conjugates of lithocholate and deoxycholate) caused LTB4 synthesis to be stimulated 27% and 35%, respectively, above control levels. In contrast, hydrophilic bile salts (glycine and taurine conjugates of ursodeoxycholate) increased LTB4 synthesis only 11.2% and 16.1%. Under basal conditions pretreatment with dexamethasone significantly inhibited bile salt-induced LTB4 synthesis by 38% compared to control. With more hydrophobic bile salts, chenodeoxycholate and deoxycholate, dexamethasone inhibited LTB4 synthesis to levels significantly below those observed with dexamethasone under basal conditions. Unlike A23187 calcium ionophore-induced LTB4 synthesis, bile salt-induced stimulation of LTB4 synthesis was not found to be dependent on the presence of extracellular calcium. Variations in bile salt stimulation of LTB4 by intestinal epithelial cells could be important in modulating cellular responses. The synthesis of chemotactic factors, such as LTB4, by the human colonic adenocarcinoma epithelial cell line now needs to be extended to normal human intestinal epithelium, as it may play a role in many of the functional disturbances which characterize intestinal inflammatory conditions.
Adenocarcinoma↗
Hydrophobic bile salt inhibits bacterial adhesion on biliary stent material.
Blockage of indwelling biliary stents is caused by biliary sludge, which forms as a result of bacteria adhering to the surface of the stent material and forming adherent biofilm. As the adherence of bacteria on plastic surface involves hydrophobic interaction of the plastic polymer and the bacterial cell wall, we tested if the detergent property of bile salts might retard bacterial adherence. Three common biliary pathogens isolated from the bile of patients suffering from acute suppurative cholangitis were used in this experiment: E. coli (O21:H25) which form pili and a glycocalyx; E. coli (O101:H9), non-piliated but with a glycocalyx, and Enterococcus fecalis without either pili or a glycocalyx. Polyethylene disks (1 cm2 diameter) were used for the in vitro adhesion study. They were continuously perfused by the bacterial suspension, flowing at 50 ml/hr at 37 degrees C for 24 hr. The suspending media used were sterile human bile and tryptic soy broth. Two different bile salts, taurocholate and taurodeoxycholate, were added to the perfusion media. The number of bacteria adhering to the surface was assessed by viable bacterial count, epifluorescence microscopy, and scanning electron microscopy. The results showed that E. coli (O21:H25) exhibited better adherence than the nonpiliated E. coli (O101:H9), which in turn was better than the non-pili-, non-glycocalyx-producing Enterococcus fecalis. When a more hydrophobic bile salt, taurodeoxycholate, was added at 25 or 50 mM to the tryptic soy broth or to the human bile, the adherence of the two E. coli strains were reduced 100- to 1000-fold (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Bacterial Adhesion↗
Mechanism of bile salt vasoactivity: dependence on calcium channels in vascular smooth muscle.
1. The vasoactive mechanisms of bile salts have been investigated in rat isolated portal venous and superior mesenteric arterial rings and perfused mesentery. 2. The isolated perfused mesentery was precontracted with a selective alpha 1-adrenoceptor agonist, cirazoline. Incremental doses of tauroursodeoxycholate (TUDC), taurochenodeoxycholate (TCDC) and taurodeoxycholate (TDC) caused a dose-dependent vasorelaxation. The order of potency of the vasodilator effect was TDC > TCDC > TUDC. 3. The effect of TDC (1.9 x 10(-8)-1.9 x 10(-6) mol) was examined before and after propranolol (3 microM), tetraethylammonium (5 mM), ouabain (10(-5) M), NG-nitro-L-arginine methyl ester (10(-4) M) and capsaicin (50 mg kg-1) to block, respectively, beta-adrenoceptors, K+ -channels, Na+, K+-ATPase, nitric oxide synthase, and primary sensory nerves. The vasodilator effect of TDC was not affected by any of these blocking agents or by denuding vascular endothelium with distilled water. 4. Infusion of TDC (1.9 x 10(-8)-1.9 x 10(-6) mol) with K+-free or high K+ (60 mM) physiological salt solution (PSS) did not affect the vasodilator effect of TDC. 5. Contractions induced by KCl (0.01-1.0 M), arginine vasopressin (AVP, 10(-10)-10(-7) M) or cirazoline (10(-7) x 10(-5) M) were all inhibited by TDC (300 microM). 6. TDC (10(-6) to 10(-3) M) also inhibited the basal tension and the development of spontaneous contractions in the isolated portal vein. 7. TDC (300 microM), however, did not affect noradrenaline-induced phasic contractions elicited in Ca(2+)-free PSS by Ca2+ release from intracellular stores. 8. We conclude that TDC inhibits Ca2+ entry through both voltage-operated and receptor-operated calcium channels, whereas intracellular Ca2+ release is not affected.
Animals↗
Sulfasalazine revisited: a meta-analysis of 5-aminosalicylic acid in the treatment of ulcerative colitis.
PURPOSE: To assess the effectiveness of the newer 5-aminosalicylic acid (5-ASA) delivery systems compared with placebo or sulfasalazine for the treatment of active ulcerative colitis and for the maintenance of remission. DATA SOURCES: Pertinent studies were selected using the MEDLINE and BIOS (1981 to 1992) data bases, reference lists from published articles, reviews, symposia proceedings, and abstracts from major gastrointestinal meetings. STUDY SELECTION: Randomized controlled trials of 5-ASA compared with placebo or sulfasalazine of a minimum of 4 weeks duration for active disease and a minimum of 6 months for maintenance of disease remission. Sixteen trials of 5-ASA for active disease, published either in abstract or full manuscript, were available. Eleven trials of 5-ASA for maintenance of remission were also reviewed. DATA EXTRACTION: Crude rates for either induction of remission (active disease studies) or maintenance of remission (relapse-prevention trials) based on the intention-to-treat principle were extracted from the studies by two independent observers. Each study was given a quality score, based on predetermined criteria. RESULTS: Studies were placed in three groups: 5-ASA compared with placebo, 5-ASA compared with sulfasalazine for active disease, and 5-ASA compared with sulfasalazine for maintenance of remission. 5-Aminosalicylic acid was superior to placebo in the treatment of active ulcerative colitis (pooled odds ratio, 2.02; 95% CI, 1.50 to 2.72). A dose-response effect for 5-ASA existed (P < 0.001). For active disease, the pooled odds ratio for 5-ASA compared with sulfasalazine was 1.15 (CI, 0.83 to 1.61). When 5-ASA was compared with sulfasalazine for maintenance of disease remission, the pooled odds ratio was 0.85 (CI, 0.64 to 1.15). Withdrawal rates and reported side effects were similar for 5-ASA compared with placebo- or sulfasalazine-treated patients. CONCLUSIONS: Although the newer 5-ASA preparations in a dose of at least 2 g/d are more effective than placebo in the treatment of ulcerative colitis, insufficient evidence exists to suggest that they are superior to sulfasalazine. Although they offer a benefit to the sulfasalazine-sensitive patient, use of 5-ASA preparations instead of sulfasalazine in the treatment of ulcerative colitis cannot yet be substantiated.
Aminosalicylic Acids↗
Involvement of L-arginine-nitric oxide pathways in neural relaxation of the sphincter of Oddi.
To evaluate if L-arginine-nitric oxide-pathways are involved in the neural relaxation of the sphincter of Oddi, we studied the effect of nitric oxide synthase inhibition on electrical field stimulation-induced relaxation of the sphincter of Oddi in the guinea pig in vitro. After incubation with atropine (1 microM), phentolamine (1 microM) and propranolol (1 microM), histamine (50 microM) and cholecystokinin-octapeptide (25 nM) produced similar increases in sphincter tone. Subsequent field stimulation induced sphincteric relaxation, that was significantly greater when the initial tone had been raised by cholecystokinin (5 Hz, 59 +/- 9%; 10 Hz, 79 +/- 9%) compared to histamine (5 Hz, 27 +/- 3%; 10 Hz, 40 +/- 7%). N-omega-Nitro-L-arginine methyl ester (L-NAME, 100 microM), which competitively inhibits nitric oxide synthase, markedly suppressed this relaxation. The subsequent addition of L-arginine (1 mM), but not D-arginine (1 mM), restored the relaxation. Hexamethonium (100 microM) did not affect the relaxation, but tetrodotoxin (1 microM) completely abolished it. Sodium nitroprusside caused a dose-dependent relaxation of the sphincter (ED50 13 nM), which was unaffected by L-NAME. In conclusion, endogenous nitric oxide synthase products represent a major transmitter of non-adrenergic non-cholinergic relaxation of the sphincter of Oddi in the guinea pig. This relaxation is partially facilitated by cholecystokinin.
Amino Acid Oxidoreductases↗
Spontaneous obesity and increased bile saturation in the ground squirrel.
Obesity is a well-known risk factor for developing cholesterol gallstones, but only indirect human studies are available. Presently available animal models of cholesterol gallstone disease do not become obese under normal conditions, while genetically obese or dietarily manipulated rats lack a gallbladder. The Richardson ground squirrel on a high-cholesterol diet develops impaired gallbladder contractility, excess cholesterol in its bile, and then cholesterol gallstones. To determine if ground squirrels would spontaneously become obese and serve as an appropriate model, animal weights were followed over several months while being maintained under a regulated laboratory environment. The five obese animals were twice the body weight of the five lean controls and also had a 20% rise in body fat. Plasma cholesterol levels were markedly increased and liver histology revealed mild microvesicular steatosis. Cholesterol saturation rose in the gallbladder bile of the obese group. This alteration was primarily due to a significant increase in phospholipid (33%) and cholesterol (86%) levels. Such a laboratory environment interrupts the natural annual rhythm of the ground squirrel and prevents hibernation. Animals continued to eat and develop severe obesity and abnormal gallbladder bile. These spontaneously obese animals provide an excellent means for examining altered hepatobiliary secretion and gallbladder motility relative to cholesterol gallstone disease.
Animals↗
Antibacterial activity of bile salts against common biliary pathogens. Effects of hydrophobicity of the molecule and in the presence of phospholipids.
In vitro studies have demonstrated that bile salts have cytotoxic and bacteriostatic properties. The cytotoxic effect of bile salts is reduced when lecithin is added. The effect of lecithin on the bacteriostatic property of bile salts is not known. In this report, we test the hypotheses that (1) the bacteriostatic activity of bile salts is a function of the hydrophobicity of the molecules, and (2) lecithin, by engaging the hydrophobic component of bile salts, attenuates the bacteriostatic property of these molecules. Two common biliary pathogens, Escherichia coli and Enterococcus fecalis, were tested in this experiment. The results demonstrate that hydrophobic bile salts (sodium taurodeoxycholate, sodium deoxycholate) have more significant inhibition on the growth of bacteria when compared with the hydrophilic bile salts (sodium taurocholate, sodium chenodeoxycholate, and sodium tauroursodeoxycholate). When lecithin is added, creating a mixed micellar solution and mimicking the in vivo conditions, the antibacterial activities of even the more potent bacteriostatic bile salts are significantly reduced. The finding that lecithin significantly attenuates the bacteriostatic property of even the hydrophobic bile salts raises questions about the clinical significance of such bacteriostatic effect in vivo; as bile salts in the bile exist in mixed micellar solution.
Bile↗
Cisapride improves gallbladder contractility and bile lipid composition in an animal model of gallstone disease.
BACKGROUND: The hepatic secretion of supersaturated bile and gallbladder stasis are key events in cholesterol gallstone formation. The therapeutic value of cisapride, a prokinetic agent, was assessed in ground squirrels on a 1% cholesterol diet. METHODS: Biliary lipid secretion was measured directly and bile salt pool size assessed by isotope dilution ([14C]cholic acid). Gallbladder contraction was measured in vitro in response to cholecystokinin (CCK). RESULTS: Cholesterol-fed animals had a combined hepatic secretory defect (a 53% decrease in bile salt secretion and also a 31% increase in cholesterol secretion). Adding cisapride restored bile salt secretion to control levels but did not affect cholesterol secretion. In cholesterol-fed animals, the cholesterol saturation index of gallbladder bile more than doubled and cholesterol crystals developed; cisapride markedly reduced cholesterol saturation, thus preventing crystal formation. Gallbladder contractility, measured in vitro in response to CCK, decreased 23% in animals on the 1% cholesterol diet; cisapride restored the CCK dose-response curve to normal. The bile salt pool as assessed by isotope dilution was similar in all groups. CONCLUSIONS: Thus, lithogenic bile develops in this model because of reduced bile salt secretion and increased cholesterol secretion. Cisapride renders biliary lipid composition towards normal by enhancing gallbladder (and possibly intestinal) motility and cycling of the bile salt pool, thereby increasing bile salt secretion.
Animals↗
The effect of cyclosporine and liver autotransplantation on bile flow and composition in dogs.
Following liver transplantation bile formation may be influenced by hepatic denervation and cyclosporine therapy. To better establish any effect of liver transplantation on bile secretion, 6 mongrel dogs were studied: 3 underwent liver denervation by a modified autotransplantation procedure and insertion of a Thomas cannula to create a chronic duodenal fistula; 3 others had cholecystectomy and the duodenal cannula placement without manipulating the liver. One month after surgery, two control studies were done, one week apart. Then oral cyclosporine was given in doses of 5, 15, and 50 mg/kg/day for consecutive 1-week periods each. Twice on each cyclosporine regimen, after 4 and 7 days of therapy, the common duct was cannulated and bile collected for 5 h; animals were awake and fasted. The first 3 h of bile collection established basal conditions; flow was then stimulated with consecutive hour-long taurocholate infusions at 1 and 2 mumol/kg/min. In all dogs, bile flow increased as the cyclosporine dose increased, under both basal and bile salt-stimulated conditions. The increased flow primarily resulted from increased bile salt-independent flow. Cyclosporine had no effect on bile salt, bilirubin, or cholesterol secretion. Phospholipid secretion, however, decreased significantly in a dose-related manner with increasing cyclosporine in the dogs with autotransplanted livers, but not in the nontransplanted dogs. This decrease in phospholipid secretion resulted in a significant increase in the calculated cholesterol saturation of bile. Thus, cyclosporine administered orally is not cholestatic but rather increases bile flow independent of any change in bile salt secretion. Cyclosporine reduced phospholipid secretion in autotransplanted dogs, possibly related to denervation of the liver. The resultant change in biliary composition may pose a risk factor for gallstone formation.
Animals↗
Efficacy of bile acid therapy for gallstone dissolution: a meta-analysis of randomized trials.
To define better the efficacy of bile acid therapy for dissolution of radiolucent gallstones, we performed a meta-analysis of published trials from January 1966 to September 1992. Studies were identified using a MEDLINE computer search followed by an extensive manual search. The inclusion criteria used were: randomized trial, radiolucent gallstones in a visualizing gallbladder on oral cholecystography, and complete stone dissolution confirmed by oral cholecystography or ultrasound. Study results were pooled into 6 groups: placebo: high- and low-dose chenodeoxycholic acid (CDCA) (> or = 10 mg.kg/day and < 10 mg.kg/day); high- and low-dose ursodeoxycholic acid (UDCA) (> or = 7 mg.kg/day and < 7 mg.kg/day) and combined CDCA plus UDCA. Homogeneity calculations were performed and the percentage of complete stone dissolution calculated for each group with 95% confidence intervals. Of 66 trials identified, 23 comprising 1949 patients met the inclusion criteria. A total of 1062 patients were treated with CDCA, 819 with UDCA and 78 combination therapy. In studies > 6 months' duration, high-dose UDCA completely dissolved stones in 37.3% of patients (95% C.I. 33-42%), low-dose UDCA in 20.6%) and high-dose CDCA 18.2% (95% C.I. 15-21%). Based on only two studies, combination therapy achieved dissolution in 62.8% (95% C.I. 51-74%) of patients. Stones less than 10 mm dissolved significantly more frequently than stones larger than 10 mm. This analysis shows that UDCA in doses greater than 7 mg.kg/day taken for greater than 6 months will dissolve radiolucent gallstones in 38% of patients. The combination of UDCA and CDCA may be more efficacious but this observation is based upon only 78 patients and requires confirmation in further randomized trials.
Chenodeoxycholic Acid↗
Characterization of leukotriene-induced contraction of the guinea-pig gallbladder in vitro.
Metabolites of arachidonic acid like prostaglandins have an established role in the pathogenesis of gallstone formation and cholecystitis, but any contribution by leukotrienes is less clear. Leukotrienes might contribute to the disease process by contracting the inflamed and (or) obstructed gallbladder, resulting in further inflammatory damage and biliary pain. To better define the role of leukotrienes, we assessed their effects on gallbladder contractility in vitro. Both leukotriene C4 (LTC4) and D4 (LTD4) had a concentration-dependent excitatory effect on guinea-pig gallbladder smooth muscle. The LTD4-receptor antagonist MK-571 (1 microM) competitively depressed the contractile response, to both LTD4 and LTC4. The source of calcium was defined using ryanodine to deplete intracellular calcium stores and nifedinine to block extracellular entry. Ryanodine (10 microM) antagonized gallbladder contraction at low concentrations of LTD4 (10(-10) and 10(-9) M). Nifedipine (1 microM) had a greater inhibitory effect on the contractile response at high concentrations of LTD4 (10(-8)-10(-6) M). LTD4-induced contractions were unaffected in tissues pretreated with the neural blocker tetrodotoxin or the muscarinic antagonist atropine. Thus, leukotrienes act directly on the gallbladder smooth muscle, causing contraction at concentrations found in models of cholecystitis, suggesting that these inflammatory mediators contribute to the symptoms and morbidity associated with gallbladder disease.
Animals↗