Gallbladder Smooth Muscle Contractility Research Articles

PERSPECTIVES: A little humour relaxes the gallbladder

PERSPECTIVES: A little humour relaxes the gallbladder

A putative role of ribonuclear inclusions and MBNL1 in the impairment of gallbladder smooth muscle contractility with cholelithiasis in myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by expansion of unstable trinucleotide (CTG) repeats at 3′ untranslated region of the DMPK gene on chromosome 19q13.3. Mutant transcripts are retained in muscle nuclei as ribonuclear inclusions and interact with RNA-binding proteins, such as muscleblind-like protein 1 (MBNL1), leading to a reduction in their activity. The reduced MBNL1 activity has been associated to skeletal and cardiac muscle dysfunction. However, other organs and systems may be involved. It has been reported that 25–50% of DM1 patients have abdominal symptoms due to cholelithiasis or gallstones. Since impaired gallbladder motility plays an important role in gallstones formation, we have analyzed by FISH combined with MBNL1-immunofluorescence, the gallbladder obtained from a woman affected by DM1 who required a cholecystectomy at the age of 30. Gallbladders obtained from two no-DM1 subjects have been used as controls. Ribonuclear inclusions and MBNL1 foci accumulate and colocalize in nuclei of DM1 gallbladder smooth muscle cells. On the contrary, no ribonuclear inclusions are detectable in cell nuclei of control gallbladders and MBNL1 is uniformly distributed in smooth muscle cell nuclei. These results suggest that nuclear accumulation of MBNL1 and ribonuclear inclusions may have a direct adverse effect on gallbladder smooth muscle contractility and thus contribute to gallstones formation in DM1 patients.

Effect of peritonitis on gallbladder smooth muscle contractility in guinea pigs

Background The mechanisms involved in the impaired gallbladder contractile response in peritonitis are unknown. The aim of this study was to determine the effect of peritonitis on the contraction and relaxation responses to different agonists in gallbladder smooth muscle in guinea pig. Materials and methods Peritonitis was induced by cecal ligation and puncture (CLP) in 10 guinea pigs. Another group of 10 guinea pigs underwent a sham operation and acted as controls. Twenty-four hours after the operation, the guinea pigs were killed, and gallbladder strips were placed in organ bath. The contraction responses to KCl, carbachol, and histamine, and relaxation responses to cyclooxygenase inhibitors (indomethacin, nimesulide, and DFU) on KCl-induced contractions were recorded. Results There was no significant difference between the contractile responsiveness to KCl, but maximum contractile responses ( E max) to carbachol and histamine were significantly reduced. Indomethacin, nimesulide, and DFU concentration dependently inhibited on KCl-induced contractions of gallbladder smooth muscle. E max values of indomethacin, nimesulide, and DFU were significantly reduced in the peritonitis group compared with controls ( P < 0.05). The inhibitor effects of nimesulide and DFU were considerably similar, but inhibitor effect of indomethacin was significantly less than that measured for nimesulide and DFU in both control and peritonitis groups ( P < 0.05). Conclusions The contraction responses to carbachol and histamine and relaxation responses to COX inhibitors on gallbladder smooth muscle are significantly decreased by peritonitis. Although the mechanism of the decrease in contraction and relaxation responses in CLP-induced peritonitis is completely unknown, we speculate that impaired smooth muscle responses may be related to an alteration in the regulation of receptor/postreceptor excitation-response coupling and/or through changes on Ca 2+ influx.

Relaxant effect of omeprazole and lansoprazole in guinea pig gallbladder muscle strips in vitro.

The aim of this study was to investigate the role of omeprazole and lansoprazole, H(+)-K(+) ATPase inhibitors, in gallbladder smooth muscle contractility in vitro. Gallbladder muscle strips obtained from guinea pigs were mounted in an organ bath. The responses of both precontracted strips and strips under basal tension to omeprazole and lansoprazole were determined. Spontaneous contractile activity was blocked following omeprazole and lansoprazole administration. The agents also caused concentration-dependent relaxation in carbachol- and KCl-precontracted gallbladder muscle strips. Pretreatment with atropine (1 microM), N(W)-nitro L-arginine methyl ester (L-NAME; 30 microM), indomethacin (10 microM), ammonium chloride (7.5 mM), sodium acetate (7.5 mM), tetraethylammonium chloride (0.5 mM), glibenclamide (1 micro M), 4-aminopyridine (0.1 mM), or clotrimazole did not inhibit this relaxation. Gallbladder strips were placed in high-concentrtion potassium (80 mM), calcium-free solution. The contraction produced with the addition of Ca(2+) (2.5 mM) was completely relaxed by omeprazole, lansoprazole, and nifedipine separately. These results demonstrate that omeprazole and lansoprazole have potent inhibitory effects on spontaneous contractions and cause dose-dependent relaxation in precontracted gallbladder smooth muscle strips of guinea pig in vitro. This effect could be due to blockade of the calcium channels.

Creatine increases gallbladder smooth muscle contractility

Creatine increases gallbladder smooth muscle contractility

Effect of Acalculous Cholecystitis on Gallbladder Neuromuscular Transmission and Contractility

Background. Impaired smooth muscle contractility is important in the pathophysiology of acalculous cholecystitis. Common bile duct ligation (CBDL) is a model of acalculous cholecystitis, producing acute inflammatory changes and decrease in gallbladder smooth muscle contractility. The aim of this study was to determine whether there is coexistent dysfunction of neural efferent motor pathways of the gallbladder after CBDL.Materials and methods. Gallbladder muscle contractility was studied in vitro in normal, CBDL, and sham-operated guinea pigs. Electric field stimulation (EFS; 2–16 Hz) was used to activate intrinsic nerves and exogenous acetylcholine (ACh) was used to directly stimulate the muscle. H&E-stained slides of muscle strips were scored for inflammatory changes.Results. After CBDL, there was a progressive increase in the inflammation score and decrease in gallbladder muscle contractility to ACh. There was also a progressive decline in EFS-induced contractility when expressed as absolute force or normalized to the maximal muscle contractile response to ACh. The nitric oxide synthase inhibitor l-NNA (10 μM) increased EFS-induced contractions by 50 ± 25% (P = 0.05) in CBDL animals but had no effect in sham surgical controls.Conclusions. CBDL with its acute gallbladder inflammation affects gallbladder contractility by two mechanisms: (1) decreased smooth muscle contractility, and (2) decreased neurally mediated contractions. The neurally mediated alterations result from dysfunction of cholinergic excitatory nerves and upregulation of nitric-oxide-mediated inhibition of smooth muscle contractility.

Effect of experimental acalculous cholecystitis on gallbladder smooth muscle contractility.

Gallbladder motility is impaired in chronic cholelithiasis but has not been studied in acute acalculous cholecystitis. The aim of this study was to determine the effects of acute acalculous inflammation on gallbladder contractility using the common bile duct ligation (CBDL) model in guinea pigs. Three groups of guinea pigs were studied: CBDL, normal, and sham surgical controls. Gallbladder dimensions were measured, and muscle strips were used for histology and in vitro contractility studies. CBDL resulted in progressive gallbladder distension, increased serum bilirubin, and gallbladder inflammation. There was a progressive decline in muscle contractility in the CBDL group as evidenced by a decrease in the contractile response to potassium and bethanechol with the duration of CBDL. In conclusion, CBDL in the guinea pig produces acute gallbladder inflammation and decreased gallbladder muscle contractility. Direct inhibition of muscle function is indicated by impaired contractile responses to potassium depolarization and bethanechol stimulation. Although the mechanism of the decrease in contractility with CBDL is unknown, we speculate that impaired muscle contractility is secondary to inflammation and may play a role in the clinicopathology of acute acalculous cholecystitis.

Effect of experimental acalculous cholecystitis on gallbladder smooth muscle contractility

Gallbladder motility is impaired in chroniccholelithiasis but has not been studied in acuteacalculous cholecystitis. The aim of this study was todetermine the effects of acute acalculous inflammation on gallbladder contractility using the commonbile duct ligation (CBDL) model in guinea pigs. Threegroups of guinea pigs were studied: CBDL, normal, andsham surgical controls. Gallbladder dimensions were measured, and muscle strips were used forhistology and in vitro contractility studies. CBDLresulted in progressive gallbladder distension,increased serum bilirubin, and gallbladder inflammation.There was a progressive decline in musclecontractility in the CBDL group as evidenced by adecrease in the contractile response to potassium andbethanechol with the duration of CBDL. In conclusion,CBDL in the guinea pig produces acute gallbladderinflammation and decreased gallbladder musclecontractility. Direct inhibition of muscle function isindicated by impaired contractile responses to potassiumdepolarization and bethanechol stimulation. Although themechanism of the decrease in contractility with CBDL isunknown, we speculate that impaired muscle contractilityis secondary to inflammation and may play a role in the clinicopathology of acute acalculouscholecystitis.

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. (Gastroenterology 1997 May;112(5):1699-706)

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.

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. (Hepatology 1996 Jun;23(6):1664-72)

Gallbladder contractility in aspirin- and cholesterol-fed prairie dogs

Background/Aims: Whether aspirin prevents cholesterol gallstone formation is controversial. This study aimed to investigate this issue and determine the depression of gallbladder smooth muscle contractility associated with cholesterol feeding in the prairie dog. Methods: Prairie dogs were divided into four subgroups. Animals were fed control or 1.2% cholesterol diet and treated with placebo or aspirin for 2 weeks. The presence of crystals and stones was determined, and contractile force in response to cholecystokinin octapeptide (CCK-8) of gallbladder muscle strips was measured. Results: Maximal stress of 2.66 ± 0.23 × 104 N/m2 was measured in muscle strips from animals on control diet. Maximal stress was significantly lower in strips from animals on high-cholesterol diet, being 1.49 ± 0.16 × 104 N/m2 with placebo and 1.62 ± 0.23 × 104 N/m2 with aspirin. The difference in maximal stress between aspirin-treated and placebo-treated animals was not significant. Although none of the animals on control diet had crystals or stones, all animals on the high-cholesterol diet, whether receiving placebo or aspirin, had crystals in the bile, and more than 65% had cholesterol stones. Conclusions: Aspirin has no effect on stone formation, nor does it prevent the decrease in contractility despite a profound decrease in endogenous gallbladder prostanoid synthesis.

Effect of bile diversion and sphincterotomy on gallbladder muscle contractility and gallstone formation

Feeding prairie dogs a diet rich in cholesterol induces gallstone formation that is preceded by a sustained decrease in gallbladder smooth muscle contractility. Sphincterotomy is known to prevent gallstone formation in cholesterol-fed prairie dogs. Experiments were designed to determine whether the effect of Sphincterotomy is a consequence of hepatic bile diversion, and whether bile diversion prevents the altered contractility. Following sham operation, surgical biliary enteric bypass, or sphincterotomy, prairie dogs were fed a high-cholesterol or a regular diet. Gallbladder muscle contractility and the presence of crystals and stones were determined. In sham-operated animals, the cholesterol diet induced a decrease in gallbladder muscle contractility and caused the formation of cholesterol gallstones. In animals with bile diversion and sphincterotomy, the effects of cholesterol feeding were reduced or prevented. Thus, these procedures may prevent stone formation by preventing a reduction in gallbladder contractility. Contractility was depressed in animals with bile diversion fed a regular diet, compared with animals with a sham operation fed a regular diet. The mechanism for this depression may differ from that induced by the cholesterol diet. Diversion, and perhaps sphincterotomy, impairs gallbladder filling. Thus, gallbladder muscle is not stretched and does not contract against a load. This could result in a “disuse atrophy.” If the results from our study apply to humans, sphincterotomy may reduce stone formation by preventing the effects of lithogenic bile on gallbladder muscle contractility and by enhancing the ability of the muscle to empty the lithogenic bile.

Monochloramine induces contraction of guinea pig gallbladder via two different pathways.

The purpose of the present investigation was to examine the effect and mechanism of action of the reactive oxygen metabolites monochloramine (NH2Cl), hypochlorous acid (HOCl), and hydrogen peroxide (H2O2) on gallbladder smooth muscle contractility. All oxidants caused concentration-dependent increases in resting tension of gallbladder muscle; the rank order of potencies (half-maximal concentration) was NH2Cl (30 microM) greater than HOCl (70 microM) greater than H2O2 (100 microM). The oxidant concentrations employed are those found to exist in inflamed tissue. Tetrodotoxin (0.5 microM) had no effect on gallbladder muscle contraction caused by the oxidants, suggesting a direct, nonneural action. The maximal response induced by NH2Cl, HOCl, or H2O2 was significantly (P less than 0.05) inhibited by 5 microM indomethacin and 5 microM piroxicam. The calcium channel blocker verapamil partially inhibited the contractile effect of NH2Cl but had no effect on the contraction induced by exogenous cyclooxygenase products. Monochloramine induced significant prostaglandin E2 release from the gallbladder, which was blocked by indomethacin. Furthermore, the effect of NH2Cl on the smooth muscle was blocked by 5-aminosalicylic acid (1 mM). We conclude that reactive oxygen metabolites induce contraction of gallbladder smooth muscle by a direct action. The effect is mediated via cyclooxygenase metabolites and activation of calcium influx.

Actin and myosin isoforms in gallbladder smooth muscle following cholesterol feeding in prairie dogs

Gallbladder smooth muscle contractility decreases after high-cholesterol feeding in prairie dogs. This decrease is not associated with alterations in the total amounts of the contractile proteins actin and myosin. The present study was designed to determine if cholesterol feeding results in alterations in the isoforms of actin and/or myosin heavy chain in gallbladder smooth muscle. Control prairie dogs were fed a trace-cholesterol diet and test animals were fed a high (1.2 %)-cholesterol diet for 8 days. Although the proportion of β-actin was unchanged, the proportion of α-actin in the gallbladder was less in the animals fed the high-cholesterol diet (32.6% ± 1.5% in the control animals and 24.6% ± 0.4% in the diet animals). On the other hand, the proportion of γ-actin was significantly greater in the cholesterol-fed animals. There were no significant differences in the proportions of the myosin heavy-chain isoforms between the two groups. Also, there was no change in the volume fraction of smooth muscle in the gallbladders from the two groups. Thus, cholesterol feeding induces a shift in actin isoforms at the same time that there is a decrease in contractility. Whether the altered pattern of actin isoforms is related to the functional changes remains to be determined.

Response to Calcium of Skinned Gallbladder Smooth Muscle from Newborn and Adult Guinea Pigs

Guinea pig gallbladder smooth muscle contractility undergoes a period of postnatal maturation. Because tissues from adult animals contract more forcefully than tissues from newborn animals when stimulated with agonists that activate the contractile process through different mechanisms (receptor activation, membrane depolarization), we proposed that factors unrelated to the mechanism of action of the agonist may contribute to the difference in force development between the age groups. Our study tested this hypothesis by examining the in vitro contractile response to calcium of membrane skinned muscle preparations from newborn and adult guinea pigs. Cell membranes were permeabilized using a Triton X-100 (0.5%) skinning solution. The muscle strips were rinsed in relaxing solution then contracted with calcium. The contracting solution contained either 1, 5, 10, or 20 microM calcium. Each muscle strip was stimulated with a single concentration of calcium. The results can be summarized as follows: 1) the maximal response of the skinned preparations did not differ from that of membrane intact preparations; 2) tissues from each age group contracted in a dose-response manner with the maximal response occurring at 10 microM calcium; and 3) at each calcium concentration, tissues from adult animals developed more active force than tissues from newborn animals. The data suggest that the postnatal maturation of gallbladder smooth muscle contractility includes factors involved in calcium activation of the excitation-contraction coupling process.

Effect of pregnancy on gallbladder contractility in the guinea pig

The effect of pregnancy on the in vitro contractility of the guinea pig gallbladder was examined by stimulating tissues from pregnant and nonpregnant guinea pigs with acetylcholine, cholecystokinin-octapeptide, and elevated extracellular potassium. Pregnancy was characterized by significant decreases in the magnitude of the contractile responses to acetylcholine and cholecystokinin-octapeptide at each point along their respective dose-response curves. The decrease in tension development was not associated with any change in the sensitivity of the gallbladder to either of the agonists. The contractile response to increased extracellular potassium was unaffected by pregnancy. This latter point suggests that pregnancy is not characterized by a generalized decrease in gallbladder smooth muscle contractility, but rather that it may affect a step in the excitation-contraction coupling process common to acetylcholine and cholecystokinin-octapeptide stimulation. The data suggest that the sluggish behavior of the gallbladder in vivo during pregnancy may be due to a decrease in the magnitude of the contractile responses to cholinergic and hormonal stimulation.