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REVIEW ARTICLE Table of Contents   
Year : 2000  |  Volume : 6  |  Issue : 1  |  Page : 3-17
The physiology of the biliary tree. Motility of the gallbladder - part 2


Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Click here for correspondence address and email

Date of Submission08-Feb-1999
Date of Acceptance10-Mar-1999
 

How to cite this article:
Ballal MA, Sanford PA. The physiology of the biliary tree. Motility of the gallbladder - part 2. Saudi J Gastroenterol 2000;6:3-17

How to cite this URL:
Ballal MA, Sanford PA. The physiology of the biliary tree. Motility of the gallbladder - part 2. Saudi J Gastroenterol [serial online] 2000 [cited 2017 May 23];6:3-17. Available from: http://www.saudijgastro.com/text.asp?2000/6/1/3/33499


In the second part of this review on the control of gallbladder motility emphasis will be given to:

­(a) The influence of the distal small intestine and colon,

(b) The emerging role of nitric oxide (NO),

(c) The contribution of afferent neurones releasing substance P (SP) and calcitonin gene-related peptide (CGRP) and

(d) The effects of cholesterol gallstones and inflammation, and the modified responses observed during pregnancy and diabetes mellitus.


   The ileum/colon and gallbladder function Top


The concept of events in the distal small intestine and colon significantly influencing gallbladder function is, perhaps surprising. An initial reaction might reasonably be that any interactions would be small. However, there are several ways by which gallbladder function could be dependent on ileal and colonic activity[105] For example, the composition and/or total content of the bile acid pool are likely to be different with the removal of the colon. Although bile acids are specifically transported across the distal ileum the colon also has an absorptive role to play. Furthermore, secondary bile acids, the result of colonic bacterial metabolism are produced in smaller amounts. Are these changes a problem? Their importance can be seen in those patients who have undergone a total or partial colectomy, the surgical treatment of choice for ulcerative colitis and familial adenomatous coli[106] Cholesterol gallstones (and their effects on gallbladder motility) are recognised as an annoying complication of colectomy. The molecular percentage of bile acids fell while those of phospholipid and cholesterol in bile increased. Rapid nucleation times were recorded. Increased prevalence of gallstone disease has led clinicians to wonder whether prophylactic cholecystectomy or litholytic agents might be considered after colectomy.

Another means by which the ileum/colon could affect the gallbladder is via the intestinal intraluminal contents. Nutrients in the proximal small intestine often stimulate gastrointestinal function. In contrast their presence in more distal regions produce inhibitory effects[107],[108],[109],[110],[111] Whereas intraduodenal infusion of oleic acid led to increased pancreatic secretion of proteins by conscious rats, the response to ileal perfusion was an immediate inhibition[112]. An anti-CCK factor was suspected when, in cross circulation experiments, the pancreatic protein secretion of animals not perfused, was also reduced. A similar picture has been described in anaesthetized cats[113],[114] Responses to infusion of oleic acid could still be recorded after extrinsic denervation of the gut and pancreas. Alcohol extraction of the colonic and ileal mucosae and subsequent precipitation with bile salts provided an inhibitor material. Appropriately the factor was named pancreotone, although it was also found to reduce the effects of CCK on the gallbladder. The peptide nature of the inhibitor was inferred because of its destruction by trypsin. Its chemical identity, however, could not be determined at the time. More recently it has been suggested that pancreatone is a mixture of several substances including peptide YY (PYY), enteroglucagon and endogenous opioids. PYY may be the original pancreatone, having similar effects [115] and found in highest concentrations in the colon and ileum. Interestingly it is structurally related to pancreatic polypeptide, another regulatory peptide causing relaxation of the gallbladder.

Inhibition of upper gut motility by nutrients in the ileum was described as the ileal brake, a phenomenon slowing gastrointestinal transit and providing more time for digestion and absorption. Gallbladder relaxation, on the other hand, probably contributes to gallbladder refilling. The characteristics of a colonic brake are still being investigated[111]. Both volume- and nutrient­dependent effects on duodenal motility have been described in fasting dogs. Colonic infusion of 0.9% NaCl (producing distension) prolonged the length of duodenal MMCs by a mechanism involving extrinsic colonic nerves. A mixed nutrient solution (Ensure Plus, Ross Laboratories, Columbus, OH) on the other hand delayed duodenal MMC phase III contractions whether infused into innervated or extrinsically denervated colon loops. A role for PYY in this humorally-mediated response was suspected. As both increased PYY and delayed duodenal MMCs tend to reduce gallbladder contractile activity an ileocolonic contribution to gallbladder control should not be ignored.


   The nitric oxide (NO) story Top


It would, perhaps, have been surprising if evidence had not been forthcoming that NO contributes to the physiological control of gallbladder smooth muscle. This multifunctional messenger has many actions, one of which is to relax smooth muscle. Most of the effects of NO are mediated by activation of guanylate cyclase with the subsequent increase of cyclic GMP (cGMP) levels. However, NO is thought to provide a "double edged sword", having both beneficial and harmful effects[116],[117],[118],[119],[120]. Thus it is a scavenger of oxygen radicals and has antimicrobial activity, but can also damage DNA and is involved in apoptosis. Its ability to exert so many and varied effects depends presumably on the specific site, local concentration, quantity and duration of cGMP production.

NO is synthesized along with L-citrulline from L­arginine[121], a stereospecific reaction catalyzed by a ubiquitous family of nitric oxide synthases (NOS). Three isozymes, nNOS (neuronal, Type I), eNOS (endothelial, Type III) and iNOS (inducible, Type II) have been identified [122],[123]. They were intially purified and cloned from neuronal tissue, vascular endothelia and an immunoactivated macrophage line, respectively, although all of them are now known to be more widely distributed e.g. eNOS is associated with neutrophils. The first two forms are constitutive, Ca"-dependent enzymes. NO production occurs rapidly (within seconds to a few minutes) when an agonist causes elevation of intracellular [Ca ++ ]. When [Ca ++ ] returns to resting levels the release of NO is terminated[120]. As its name suggests iNOS can be induced. Numerous agents including bacterial lipopolysaccharide and the cytokines interleukin-1(3, interferon-y and tumor necrosis factor-a are able to increase iNOS activity. Thus when guinea pig gallbladder tissue was incubated with the endotoxin from S. typhosa extraordinary amounts of NO were generated[124] . Such findings have led to the suggestion that NO could account for the hypomotility associated with gallbladder infections. Clearly all, some or none of these isozymes could be significantly involved in gallbladder NO production under physiological conditions.

What then is the evidence that NO has a role to play in the control of normal gallbladder contractions? First of all NO-producing nerves have been demonstrated throughout the biliary tree. They are more abundant, however, in the  Sphincter of Oddi More Details than the gallbladder [125]. The greatest proportion of the NO-producing gallbladder neurones are found in the muscle layer with a sparser innervation to surrounding blood vessels and in the mucosa[126] . Furthermore, in vivo studies with guinea pigs have shown that inhibition of NOS using L­NAME increases gallbladder resting pressures and also the contractions induced by CCK and bethanechol[124]. In contrast treatment with L­-arginine, the normal source of NO, or sodium nitroprusside, an exogenous donor that spontaneously releases NO independent of enzymatic pathways, counteracts the effects of CCK. These results indicate an important physiological role for NO in the gallbladder. Data supporting the view that NO contributes to an intrinsic inhibitory gallbladder tone has been obtained in prairie dogs[127]. Using (a) L-NAME to inhibit NOS, or (b) methylene blue, a guanylate cyclase inhibitor preventing NO-induced increases in cGMP, 80 and 40% increases in tone, respectively, were observed. The questions remain as to what stimulates tonic NO production, and whether a continual release, in the absence of stimuli that would otherwise cause contractions, might relax the gallbladder and permit its filling without a build-up of intraluminal pressure.

NO is also thought to influence the human gallbladder. It is probably the neurotransmitter of the recently described noncholinergic, nonadrenergic (NANC) innervation causing gallbladder relaxation. This innervation was exposed by subjecting human gallbladder smooth muscle strips to electrical field stimulation (EFS)[128], a procedure that specifically activates neurones. After contracting strips with (a) carbachol or (b) CCK or caerulein in the presence of atropine, EFS produced a relaxation. Caerulein is a CCK analogue, a decapeptide isolated from frog (Hyla caerulea) skin that can cause greater contractions than CCK. The response to EFS could be abolished by the NOS inhibitor L-nitroarginine, but was not by guanethidine, an agent blocking responses to postganglionic adrenergic nerve stimulation by interfering with noradrenaline release. Two other reports implicate NO in altering human gallbladder motility. In the earlier study[129] volunteers received infusions of the NO donor L­arginine that:

(a) increased by -30% the fasting gallbladder volume,

(b) reduced and retarded gallbladder emptying in response to a 600 Cal liquid meal, and

(c) prevented emptying induced by erythromycin. (N.B. this `macrolide antibiotic is an agonist of motilin[130], the 22 amino acid peptide released from the duodenojejunal mucosa and considered responsible for the onset of phase III MMCs. Motilin has been used as a model to induce motor patterns similar to those recorded during the interdigestive period, although the clock mechanism by which it is normally released remains unclear[131]. NO is converted to nitrite and nitrate. Increased plasma nitrite levels following arginine infusion lend support to the view that increased NO generation had occurred.

The more recent study[132] involved the use of glyceryl trinitrate (GTN), a further NO donor, and an established agent used in the treatment of ischaemic heart disease. Administered by buccal spray GTN also increased fasting gallbladder volumes and impaired gallbladder emptying resulting in a reduced ejection fraction and an increased residual volume [Figure 5]. As reduced emptying is one of the factors that can contribute to cholesterol stone pathogenesis patients with myocardial ischaemia who frequently take GTN may be at risk of developing gallstones. On the other hand GTN may have a therapeutic potential in the treatment of biliary colic resulting from excessive gallbladder contractions.


   Substance P (SP) and calcitonin gene-related peptide (CGRP) Top


Neurones activating gallbladder smooth muscle produce action potentials when they receive excitatory signals. Spontaneous activity is rarely recorded. Their major driving force is from efferent vagal cholinergic fibres. Clearly the ganglionic relay might be up- or down-regulated by physiological signals acting pre- or post-synaptically [Figure 6]. In other sections of this review the effects of CCK and noradrenaline on acetylcholine (ACh) release from vagal preganglionic neurones have been described. Two peptides thought to act postsynaptically are the tachykinin Sp[133] and CGRP[134],[135] Tachykinins can also act directly to contract gallbladder smooth muscle [136] . Both peptides can be detected together in what are likely to be extrinsic sensory neurones because CGRP is not expressed by gallbladder neurones [137],[138]. Two questions arise. Can neurones release more than one transmitter? Are extrinsic sensory neurones able to release neurotransmitters within the tissues they innervate?

The concept of co-localization of neurotransmitters is now well established. Many, if not all neurones, release more than one chemical agent. In the gallbladder of the toad (Bufo marinus), for example, four populations of nerve fibres with cell bodies outside the gallbladder were identified[139]. Three of these contained co-localized (a) SP and CGRP, (b) galanin, somatostatin and VIP and (c) catecholamines and neuropeptide Y. The fourth contained only adrenaline. The picture that is emerging, however, is both confusing and incomplete. The presence of a specific neurotransmitter within a particular network of neurones does not necessarily point to its functional significance. In recent models it has been proposed that single neurones may employ an amine, an amino acid and one or more peptides as messenger molecules[140],[141] The release of multiple transmitters from a single neurone would be more understandable if they were to be stored in separate vesicles and at different sites subcellularly. In some systems it has been shown that the discharge of different neurotransmitters is frequency coded, transmitters such as acetylcholine and NO being released at low frequency stimulation but peptides needing higher frequencies or bursting activity[142],[143] So what might be the physiological significance of neurones releasing multiple transmitters? Several possibilities can be suggested.

A. Different neurotransmitters may be released in response to distinct patterns of action potentials producing similar effects but over different periods of time. The duration of the responses, dependent on the rate of removal of the transmitter may also be very different.

B. Different neurotransmitters may be released in sequence, the first exerting an effect antagonised, and, therefore, limited by those released subsequently.

C. Several neurotransmitters may be released simultaneously and not all act at the same sites. Thus, for example, ACh and SP might contract smooth muscle while VIP increases secretory activity of epithelial cells. Such a response would . depend on the availability of specific receptors on different target cells.

D. Several neurotransmitters may be released simultaneously and act at the same sites. Thus, for example, ACh and VIP might provide the means whereby smooth muscles could increase in length but retain their ability to contract effectively.

Perhaps the release of agents capable of producing effects locally in the region where the sensory nerve is stimulated should not be surprising. In certain types of inflammation the nervous system is involved in vascular in addition to sensory responses. Thus capsaicin, the pungent agent from hot peppers, a neurotoxin causing the marked depletion of neurotransmitters from sensory neurones, induces swelling and cutaneous vasodilatation as well as pain, although not in skin where the nerves have been cut and allowed to degenerate[144]. Sensory fibres within the gallbladder are also activated by inflammatory agents. Furthermore their discharges are increased with extreme pressure. Such fibres are thought to release SP (and other tachykinins) and CGRP within gallbladder ganglia. These peptides act directly on intrinsic neurones causing partial depolarization i.e. slow excitatory post synaptic potentials (slow EPSPs). Action potentials are not developed but postsynaptic neurones are "primed" and ganglionic transmission is facilitated[145],[146]

Such an intrinsic mechanism could provide a means of removing an obstruction or an irritating agent causing inflammation. Tachykinins exert 6their effects by acting on NK-3 receptors. Agonists of NK-1 ([Sar9,Met(O2 )11]-substance P) and NK-2 receptors ([β-ala8]-NKA(4,10)) produced no measurable depolarisations of neurones. In contrast the NK-3 agonist senkide depolarised neurones while the antagonist [Trp7, (β-alas]-NKA-(4-10) inhibited the responsiveness of gallbladder neurones to SP and depressed both capsaicin-induced depolarisations and stimulus-evoked EPSPs.

Slow EPSPs, although of smaller amplitude than those elicited with SP, have been recorded in response to CGRP[144]. However, CGRP may facilitate ganglionic transmission in another way. By inhibiting an endopeptidase hydrolyzing tachykinins CGRP may potentiate the actions of SP[147]. Other possible effects of CGRP have not been ignored. Thus a central contribution to gallbladder control is recognized. Cerebroventricular administration of CGRP induces gallbladder relaxation in rats as a result of activation of the sympathetic nervous system and the release of noradrenaline[148]. Thus CGRP conceivably could induce either gallbladder contraction or relaxation.

Direct effects of CGRP on the gallbladder might have been anticipated knowing that noxious stimulation of either the stomach or the urinary bladder results in local CGRP release[149],[150]

Disrupting the mucosal barrier of the rat stomach with 15% ethanol caused back diffusion of HCl and increased mucosal bloodflo[149] The hyperaemic response, an important protective mechanism and one which promotes tissue repair, was abolished by intraarterial infusion of hCGRP8-37, a CGRP antagonist with no effect on basal bloodflow. In addition to powerful vasodilatory properties, CGRP released from sensory neurones also relaxes smooth muscle of the mammalian urinary tract. These smooth muscle relaxatory responses are, perhaps, unexpected particularly as:

(a) CGRP can promote gallbladder motility by facilitating ganglionic transmission and

(b) SP, often co-localized and released with CGRP, has excitatory effects on gastrointestinal smooth muscle.

However, if CGRP and SP can elicit variable responses there is the potential for them to produce different responses in different parts of the same organ depending on:

(i) the relative concentrations of the peptides accumulating in the tissue to be stimulated and

(ii) the numbers of receptors for these peptides on target cells.

In the urinary bladder a model has been developed of responses to noxious stimuli which illustrates this concept. Distension, hypertonicity or chemicals such as K + , H + , bradykinin and chemotactic peptides of bacterial origin activate primary afferents in the guinea pig urinary tract[150] These stimuli could be the result of mechanical trauma, inflammation, cancer, stones or some intrinsic defect of the epithelial (urothelial) barrier that makes it leaky to urinary solutes (interstitial cystitis). The prevailing response in the bladder dome and renal pelvis is contraction accounted for by tachykinins, while in the bladder neck and ureter relaxation is dominant for which CGRP is responsible. Such motility changes, and concomitantly, local increases in bloodflow, might facilitate the removal of noxious stimuli.

In the gallbladder CGRP can also induce relaxation [151],152] This has been demonstrated using guinea pig gallbladder strips precontracted by CCK. The responses were inhibited by TTX and L-NAME suggesting that CGRP can exert effects, partially at least through NANC neurones, although direct effects on gallbladder smooth muscle involving cAMP-dependent mechanisms have been reported[152]

The question remains as to whether penetration of noxious stimuli in bile (e.g. hydrophobic bile acids) or excessive distension induce similar responses in the gallbladder to those described in stomach and urinary bladder [Figure 7]. Certainly CGRP and SP are released from extrinsic afferent neurones and can increase the excitability of intrinsic fibres causing gallbladder contraction. A valuable means of expelling potentially harmful agents might, therefore, be available. However, because of the multiple responses to SP and CGRP that have been recorded a final picture has yet to emerge. Does the gallbladder, like the urinary bladder, possess regions with different sensitivities to the peptides to ensure more effective removal of noxious stimuli? What is the importance of these peptides under physiological situations?


   Cholesterol gallstones Top


Three types of gallstone are recognized in which the major constituents are cholesterol (cholesterol stones), bilirubin pigment polymer (black pigment stones) and calcium bilirubinate (brown pigment stones)[153],[154]. In the Western world most are cholesterol stones. Three major factors contribute to cholesterol stone formation. These are (i) hepatic bile supersaturated with cholesterol, (ii) agents altering cholesterol nucleation and (iii) impaired gallbladder motility.

Cholesterol must be kept in solution after its secretion in unilamellar phospholipid vesicles by hepatocytes. Reacting with bile acids the vesicles are solubilized into mixed micelles, the cholesterol incorporated into the hydrophobic interiors. When bile becomes supersaturated with cholesterol (or bile acid concentrations are low) mixed micelles are unable to hold all the cholesterol and unstable unilamellar vesicles fuse to produce multilamellar aggregates from which cholesterol monohydrate crystals may nucleate. Supersaturation is a prerequisite for stone formation. Thus the increased prevalence of gallstones in the elderly and the obese have been explained, at least in part, by increased bile cholesterol concentrations. Similarly slow intestinal transit, providing more time for bacterial metabolism and the generation of more lithogenic bile acids e.g. deoxycholic acid, has been recognized as a possible explanation of gallstones in women of normal weight[155]. Although a prerequisite for gallstone formation, supersaturation of bile results in cholesterol stones in only a small percentage of the population. In developed countries -50% have supersaturated bile but only -10% develop cholesterol stones[156]

The number of cholesterol pro- and anti-nucleating factors continues to grow. Agents accelerating nucleation include mucus, which also immobilizes and traps cholesterol crystals[157], and the recently added alpha s -acid glycoprotein[158]. Inhibition of mucus production by aspirin (and other NSAIDs) provides an explanation as to how gallstone formation can be reduced[159] . Agents in bile slowing nucleation include apoproteins A l and A2. More recently attention has been focused on a heterodimeric glycoprotein (120 kD)[156] and immunoglobulin A (IgA)[160]. The former is the first glycoprotein in human bile with cholesterol crystal growth-inhibiting activity. Each of its two subunits have at least twice the potency of apoprotein Al. The latter can prevent crystallization at physiological and even lower concentrations although at high concentrations IgA loses its capacity, perhaps by contributing to heterogenous nucleation, the non- specific seeding of the crystallization process. The antinucleating properties of IgA provide an interesting additional function for these immunoglobulins. They have been shown to prevent adherence and penetration of bacteria, viruses and other injurious agents to mucosal surfaces and are regarded as a first line of defence in the biliary tract. Their presence in a lactating mother's milk following antigen challenge may be particularly useful to neonates where intestinal barriers are immature. Bile is a particularly rich source of IgA in the intestinal lumen with up to 90% of the newly synthesized specific antibodies reaching the intestine via hepatic secretions. IgA can be formed after sampling of luminal macromolecules within the intestines by thin membranous M cells and their presentation to the closely associated lymphocyte population[161]

The relationship between gallbladder motility and cholesterol stone formation provides a chicken and egg situation. Hypomotility limits mixing and emptying of gallbladder contents. Stasis increases the risk of cholesterol precipitation. Cholesterol supersaturation and stones impair gallbladder motility. A viscious circle appears to have been produced. How might cholesterol and/or the presence of cholesterol stones cause changes in contractile activity? Evidence gathered from both animal models and human studies indicate that dysfunction of gallbladder muscle is the result of excessive incorporation of cholesterol in the plasma membrane and resides in the steps before G protein activation[162],[163]. Defects in membrane receptors or receptor-G protein coupling were proposed because the intracellular signal transduction pathways after G protein activation and the contractile apparatus were functionally intact. Indeed, the contractile responses of ground squirrel gallbladder strips to the G protein activator, aluminum fluoride[163], were not significantly different in cholesterol fed and control animals[162]. Aluminum fluoride, by interacting with GDP can mimic GTP. Preliminary reports have indicated decreased CCK binding capacity and CCK-activated binding of GTPy S (a GTP analogue which cannot be hydrolysed, and is widely used a G protein stimulator) to G protein in gallbladders from patients with cholesterol stones[165],[166] A further complicating factor has been the finding that the pathway of signal transduction is altered[163] in gallbladder isolated muscle cells from patients and prairie dogs with cholesterol stones. In controls (gallbladders without stones in prairie dogs, but with pigment stones in humans considered to be reacting "normally" to CCK) the maximum contraction to CCK was blocked by the calmodulin antagonist CGS9343B but not by the PKC inhibitor H-7. Conversely, the responses of gallbladders with cholesterol stones to CCK was inhibited by H-7 but not by CGS9343B. Thus high CCK concentrations may activate the calmodulin-dependent pathway in functionally normal muscle but the PKC-dependent pathway in muscles from gallbladders with cholesterol stones.

The lipid 'bilayer of the plasma membrane is considered a fluid matrix in which protein molecules are able to move within the plane of the membrane, rotate in position or possibly flip-flop from one interface or lipid leaflet to the other[167]. Excess cholesterol may exert its effects by reducing membrane fluidity. Support for this possibility has been the reversibly defective gallbladder muscle contractions recorded after incubating normal cells with cholesterol-rich liposomes[168]

If gallbladder contraction is compromised by excess cholesterol, what happens to relaxation? A recent study has addressed this question[169] A comparison was made of responses of gallbladder muscle taken from patients with cholesterol and pigment stones. Relaxations evoked by EFS and VIP were smaller in muscle from gallbladders with cholesterol stones. Furthermore, in contrast to its effects on contraction, cholesterol produced responses beyond receptor and receptor-G protein interactions. Relaxation induced by forskolin, the adenylate cyclase activator, was also diminished. However, responses to 8-bromo-cAMP (an analogue of cAMP, an intracellular mediator of VIP) and NO, which circumvent plasma membrane receptors and activate intracellular mechanisms directly, were similar. Thus, as with contraction. gallbladder relaxation is impaired in patients with cholesterol stones and the defect(s) responsible appear to be in the plasma membrane.

The concept of impaired contraction and relaxation of gallbladder smooth muscle providing an environment with a greater risk of cholesterol nucleation is easy to appreciate. However, less than a quarter of patients with cholesterol stones have been classified as pathological (weaker) contractors[170]~.

The remainder have relatively normal contracting gallbladders, although fasting and residual volumes were greater than those recorded in healthy controls [Figure 8]. Increased residual volumes could result in less complete washout of concentrated gallbladder contents, including cholesterol crystals[171]. (N.B. gallbladders thought to be contracting normally as regards amplitude may not contract as frequently and/or empty normally. Thus, in obese subjects, secreting greater amounts of cholesterol and with no detectable defect of motility, emptying was slower and the minimum residual volume was reached 20 minutes later than in non-obese * controls[172]. Interestingly, the ejection fractions of cholesterol stone patients with normal contracting gallbladders were closely correlated with fasting volumes, suggesting that gallbladder smooth muscle may respond to stretch in a way similar to that described in cardiac muscle (the Starling mechanism). This possibility was supported by an earlier finding that opossum gallbladder reacts to CCK with the development of greater pressures as its volume increases[17.3]. It would be worth knowing whether normal contractors eventually develop into pathological contractors as greater amounts of cholesterol are incorporated into smooth muscle membranes[170]

Numerous strategies have been proposed to correct gallbladder hypomotility[174]. These include:­ (i) stimulation of CCK receptors either directly by treatment with caerulein or CCK-8 (the biologically active COOH-terminal octapeptide of CCK, initially synthesized but subsequently found in brain and p ripheral neurones including those of the gut[175], indirectly by increasing endogenous CCK output. Two means have been used to stimulate the latter. One has involved the use of cholestyramine that interrupts the negative feedback inhibition of duodenal bile acids on CCK release. The other depends on administration of intravenous amino acids which produce (a) substantial gallbladder emptying and (b) similar plasma CCK concentrations to those recorded after a standard liquid meal. (The response to intravenous amino acids is surprising, particularly bearing in mind the major effects of CCK on gallbladder and pancreatic enzyme secretion. The value of this approach in promoting emptying in patients receiving total intravenous nutrition and in whom sludge and gallstones often develop has been recognized[176].

(ii) the use of motilin-like drugs e.g. erythromycin. These agents have powerful prokinetic effects although their mode of action is controversial. Motilin, as discussed earlier, is a peptide considered responsible for the onset of phase III MMCs, and is associated with gallbladder contractions in the interdigestive but not postprandial periods[177]. Some have suggested that erythromycin produces its effects by reacting with motilin receptors[130]) although there are no structural similarities between the two. In contrast others have proposed that erythromyin acts indirectly by releasing motilin[178] . The clinical value of motilin-like drugs remains to be determined because of their frequent adverse gastrointestinal reactions.

(iii) altering the production of prostaglandins. Chronic administration of indomethacin has been found to improve postprandial emptying in gallstone patients. Why this might occur has been the subject of speculation. One suggestion has been that indomethacin, by inhibiting the cyclo-oxygenase pathway, may cause the elaboration of more prokinetic prostaglandins or leukotrienes[179]. An alternative possibility is that indomethacin removes the sustained hyperpolarisation of ganglionic neurons (and resultant hypomotility) that is associated with prostaglandin production during chronic inflammation.


   Inflammation Top


The previous section on cholesterol stones leads conveniently to a consideration of gallbladder responses to inflammation. Hypomotility is an important factor in the development of cholesterol stones while increased incorporation of cholesterol into plasma membranes impairs both contraction and relaxation of gallbladder smooth muscle. As acute cholecystitis usually follows obstruction of the cystic duct by a stone[180] resulting in:

(a) ischaemia, because of increased pressure and distension,

(b) release of potentially harmful chemicals e.g. lysolecithin and

(c) less effective removal of bacteria, changes in gallbladder motility in response to inflammation per se are very relevant. Chronic cholecystitis is almost always associated with gallstones. Is the gallbladder epithelial barrier more leaky when inflamed? The question of gaps at cell junctions across endothelia during inflammation and our limited understanding of their opening and closing has recently been raised[181].

A recent in vitro study of human inflamed gallbladders, obtained at laparoscopic cholecystectomy, provides evidence of abnormal motility[182]. More than 70% of the fundal preparations gave no response to cholinergic stimulation with carbachol. The remainder, if compared with responses of sheep normal gallbladders, produced smaller maximal responses. One third of the inflamed fundal specimens showed early rhythmic activity (ERA) before administering carbachol, which could be abolished or reduced by indomethacin. The authors wondered whether ERA reflected a prostaglandin-mediated inflammatory response. Interestingly approximately equal forces of contractions were measured in strips taken from the fundus and outlet regions of the gallbladders. This contrasted with finding that fundal forces were approximately double those of the duct in sheep, a difference that would favour expulsion of bile from the gallbladder. If smooth muscle in the cystic duct contracts as powerfully as that in the fundus then outflow resistance will be increased. Such a mechanism has been proposed as a possible explanation of the reduced gallbladder emptying in patients with gallstone disease and healthy controls when given high doses of CCK[183]

A role for PGE 2 in controlling gallbladder functions during inflammation has been anticipated. Both the mucosa and submucosa increase their PGE 2 production[184], there being a correlation between the degree of inflammation and the level of PGE z . In animal models PGE Z can cause a dose dependent contraction of gallbladder smooth muscle and change net absorption to secretion thereby providing a cytoprotective mechanism to preserve mucosal integrity. Cyclooxygenase inhibitors have been used to relieve biliary tract pain, probably by inhibiting PGE, production. An obvious explanation is that gallbladder contractions could be decreased and intraluminal pressure would be lowered by such agents.. A more likely alternative is that a reduction of prostaglandin production prevents the increase in sensitivity of primary afferent nerves to noxious stimuli[185].

Chronic prostaglandin production may effectively denervate the gallbladder. PGE 2 has been shown to elicit a complex triphasic effect on the resting membrane potential of guinea pig gallbladder neurones with the predominant effect being a long lasting hyperpolarization[186]. Such a mechanism may decrease excitatory ganglionic output and contribute, in the long term, to gallbladder stasis. Indeed aspirin has been used to promote motility in patients who have had stones removed by non-surgical procedures and who are at risk of recurrence [187]. Another means of promoting gallbladder stasis may involve VIPergic nerves which hypertrophy around smooth muscle in chronic inflammation[188]. This contrasts with a loss of VIPergic neurones during acute inflammation.

The questions remain as to why PGE 2 production is increased and from where it is released to alter gallbladder motility in inflammatory states. A contribution from granulocytes has been recognized. Interaction of ligands e.g. formyl-methionyl-leucyl­phenylalanine and immune complexes with membrane receptors on granulocytes evokes superoxide anion and H 2 O 2 production (reactive oxygen metabolites or ROM). Activated granulocytes release myeloperoxidase which catalyses the oxidation of chloride by H 2 O 2 to form hypochlorous acid (HOCI) that may react with primary amines to yield N-chloramines e.g. monochloramine (NH 2 CI). Concentrations of H 2 0 2 , HOC1 and NH 2 C1 found in inflamed tissue increased resting tension in guinea pig gallbladder smooth muscle strips.[189] These responses were unaffected by tetrodotoxin suggesting a non-neural action. NH 2 CI is particularly interesting because it is both more stable and more potent than the other oxidants. The cyclooxygenase inhibitors indomethacin and piroxicam inhibited the response to NH 2 C1 as did the calcium channel blocker verapamil. However, verapamil had no effect on contractions induced by PGE, production. NH 2 C1 induced significant PGE 2 release from the gallbladder. It was concluded that NH 2 C1 was acting in two ways to evoke contraction:

(i) directly on smooth muscle cells through a verapamil-sensitive calcium influx and

(ii) by release of prostaglandins from fibroblasts and/or muscle cells.

Inflammatory responses have generally been assumed to be activated by pathogenic processes. However, spontaneous secretion of cytokines (interleukin-4 and interferon-y) under physiological conditions by lymphocytes present among intraepithelial cells and lamina propria of the small intestine have recently been demonstrated and discussed[190],[191] The question is being asked whether the disease free intestine is in a state of "controlled inflammation," with primed protective mechanisms ready to deal with potentially harmful challenges. We await with interest to hear whether such lymphocytes are also active and contribute towards homeostasis in the gallbladder which, like the intestine is constantly exposed to blood borne and luminal agents.

To complete this section it is worth noting that cholesterol crystals themselves have an etiological role in gallbladder inflammation. This was demonstrated by instilling crystalline cholesterol monohydrate (the form occurring in human bile) into guinea pig gallbladder for 24-72 hours after cystic duct ligation[192]. Its effects were compared with those of the inflammatory agent lysolecithin. Both caused:

(a) reductions in mucus layer thickness,

(b) conversion of a net water absorbing to a secreting epithelia,

(c) increases in gallbladder tissue levels of myeloperoxidase and interleukin-1 (a factor formed by activated macrophages in inflamed tissues), and

(d) greater release of PGE 2 to the luminal fluid.

These inflammatory changes could not be induced by mechanical irritation with inert polystyrene latex particles. Cholecystitis, resulting from cholesterol stones, therefore, may be regarded as a crystal deposition disease. These are conditions in which a chemically defined crystal is specific for the disease. Monosodium urate inducing inflammation in gout is a model.


   Pregnancy Top


Gallbladder volumes, measured by ultrasonography during fasting or 90 minutes after breakfast are increased in pregnancy. Late emptying, on the other hand is reduced[193]. A direct correlation between serum progesterone levels and gallbladder volumes has been reported. These findings suggested the possibility of a predisposition to stone formation in those situations where progesterone levels are raised. Indeed an increased incidence of gallstones during pregnancy has been reported[194],[195] and gallstone disease is associated with multiple childbirth as well as young age at menarche. One might suspect that the use of oral contraceptives containing progesterone increases the risk of gallstone formation. Any relationship, however, is not substantial[195]

How does progesterone exert its effects? Progress has been made with in vitro studies of pregnant or pseudo-pregnant (adult male progesterone-treated) guinea pigs where it was found that responses of gallbladder smooth muscle strips to CCK and acetylcholine were impaired[196],[197] Progesterone produced a shift to the right of the dose-response curve to both agonists and caused a decrease in the maximum contraction that could be elicited. A recent report confirmed poorer responses to CCK using muscle cells isolated by enzymatic digestion with collagenase from progesterone-treated animals[198] Impaired contractions were not observed in response to increased extracellular KC1 or inositol triphosphate (IP 3 ). Extracellular KC1 depolarizes the plasma membrane and induces calcium influx to produce contractions. The finding that gallbladder contractions of progesterone-treated guinea pigs induced by KCI were not different from those of control animals suggests that the contractile apparatus is not directly affected by progesterone. It has been proposed that progesterone acts at the cell membrane, limiting G proteins functions, perhaps by changing their affinity for GTP binding (or down regulating G iα3 )[198]. G proteins are the "links" between membrane receptors (sensors) and intracellular effector systems. They cycle between inactive GDP-bound and active GTP-bound forms[199], By limiting the actions of G proteins, progesterone would reduce the capacity of CCK to activate phospholipase C and generate IP 3 and diacyl glycerol (DAG). IP 3 releases intracellular calcium and produces muscle contraction. Contractile responses to IP 3 were unaffected by progesterone. This was demonstrated with gallbladder muscle cells made permeable to exogenous IP 3 with saponin. Thus the contractile apparatus can react to an intracellular effector system. In contrast impaired contractions were observed in response to aluminium fluoride (earlier described as interacting with GDP to activate G proteins by mimicking GTP) or the non­hydrolysed GTP analogue GTPyS. These findings support the concept of an action of progesterone at the level of G proteins. It is interesting that during pregnancy there is suppressed G protein coupling to phosphoinositide breakdown that may contribute to uterine relaxation[200]


   Somatostatin and its analogue Top


Repeated daily injections of octreotide, the long acting somatostatin analogue, are an effective treatment of acromegaly. However, if infused subcutaneously in large doses two to three times daily, increased fasting gallbladder volumes and decreased gallbladder emptying have been recorded and an increased prevalence of gallstones observed[201]. Postprandial gallbladder contractions are impaired for at least 4 hours after octreotide injection. Alternative strategies have, therefore, been sought whereby gallbladder emptying might be improved[202]. Two possibilities have been suggested. One involved administering octreotide continuously using an ambulatory pump, and, therefore, achieving lower plasma concentrations. The other required an adjustment of meal times so that the partial recovery of gallbladder function beyond 4 hours could be utilized.

The questions remain as to:

(a) whether the plasma level of somatostatin ever rises so that it significantly inhibits gallbladder motility and

(b) how octreotide and, perhaps, high concentrations of somatostatin exert their effects?

Certainly remarkably high concentrations have been recorded in patients with somatostatin producing tumours[203]. These patients are known to have a high incidence of gallstone formation[204] Somatostatin has, justifiably, been assigned the title "endocrine cyanide" because it powerfully inhibits the secretion of many regulatory peptides[205]. Therefore an obvious target for somatostatin might be CCK, the major gastointestinal peptide stimulating gallbladder contractions. Hardly surprisingly, somatostatin has been found to decrease CCK release. However, its mechanism of action is not direct but involves inhibition of both the secretion and action of luminal CCK-releasing factor (LCRF)[206]. Even under physiological conditions plasma somatostatin concentrations are not constant. During fasting somatostatin-like immunoreactivity in the peripheral plasma can be measured (50-300 pg/ml.)[207]. After a standard meal plasma somatostatin concentrations rise in a biphasic manner. Peaks were recorded at 25 and 120 minutes postprandially even though the hormone is secreted by gastrointestinal mucosal cells and exerts its effects locally as a paracrine. This raises the interesting possibility that the postprandial increases in somatostatin levels provide a "brake" to prevent the overstimulation of normal digestive processes.


   Diabetes mellitus Top


Individuals with diabetes mellitus have a 2- to 3­fold increase in the incidence of cholesterol gallstones. Reduced gallbladder motility has been proposed as the most important factor. Gallbladder volumes, both while fasting and after a fatty meal, were significantly greater in a group of diabetic patients than in age- and weight-matched control subjects[208]. Gallbladder hypomotility in diabetes mellitus could be the result of autonomic neuropathy. When diabetic patients are divided according to the presence or absence of autonomic neuropathy, those classified as the former had the lower gallbladder ejection fractions after a fatty meal. However, hyperglycaemia per se may also have a role to play, perhaps by decreasing vagal cholinergic tone. Glucose infusions suppressed the activity of the vagus nerve[209]. Reductions of gastric acid secretion, gastric emptying and pancreatic secretion have been observed in healthy subjects when given intravenous infusions of glucose. Gastric contractions were also markedly reduced during the interdigestive phase if serum glucose levels were maintained at 8 mM[210]. It was further noted that normalization of serum glucose in hyperglycaemic diabetics could restore antral phase III activity in some patients.

A reduction of gallbladder contractile activity during hyperglycaemia was suspected when it was shown that bile salt output into the jejunum in response to a test meal was decreased by intravenous glucose infusions[211] )Direct observations of gallbladder have been made more recently[212] . The effects of acute hyperglycaemia (8 and 15 mM) on gallbladder responses of healthy volunteers to increasing CCK levels were measured by ultrasonography. CCK was infused in stepwise increasing doses producing concentrations equivalent to those achieved after a light, normal and fatty meal. Glucose concentrations were stabilized using a glucose clamp technique. Gallbladder responsiveness to CCK was decreased. A subsequent report provides evidence that the gallbladder responses to CCK of patients with diabetes mellitus are also reduced by elevated serum glucose concentrations[213].


   Stress Top


In an earlier section an inhibitory role for sympathetic adrenergic neurones in the control of gallbladder motility was mentioned. Presynaptic inhibition of a 2 -adrenoreceptors on cholinergic neurones (vagal, interganglionic or projections from duodenal myenteric) was suggested on the basis of responses to the specific agonist clonidone and antagonist yohimbine[214]. One might ask the question as to the role of the sympathetic nervous system both under normal resting conditions and in situations when increased discharge from such nerves occur. In the former the sympathetic may be acting as a "brake" to prevent overactivity of the vagus. Decreased fasting volumes and ejection fractions have been reported in patients with spinal cord injuries above T10 and were thought to reflect a deranged sympathetic tone[215]. It is interesting that excessive distension of the colon activates sensory nerves that increase the activity of postganglionic sympathetic neuronas supplying the colon from the inferior mesenteric ganglion. This response serves to relax the colon and limits any increase in intraluminal pressure which could produce pain[216]. Might such a mechanism exist in the gallbladder?

Since increased sympathetic activity is regarded as a characteristic of stress, is gallbladder hypomotility predisposing to gallstone formation a feature of those with stressful life styles? No convincing answer is currently available. Responses of the gastrointestinal tract to stress have been suspected but often not satisfactorily established. Wolf's classic account of studies with Tom are, perhaps, an exception[217]. Biliary and other functional gastrointestinal disorders have been described as a common occurrence in patients with post traumatic stress syndrome[218]. An association with abuse during childhood was recognised although it was unclear as to why traumatic experiences led to specific visceral changes in some but not in others.

 
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Correspondence Address:
Paul Anthony Sanford
Department of Physiology, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461
Saudi Arabia
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PMID: 19864723

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