Saudi Journal of Gastroenterology
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REVIEW ARTICLE Table of Contents   
Year : 1999  |  Volume : 5  |  Issue : 3  |  Page : 93-105
The physiology of the biliary tree. Motility of the gallbladder - Part 1


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

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

   Abstract 

An incomplete picture has emerged of the complex means by which gallbladder motility is controlled under normal and pathophysiological conditions. In the first part of this review an overall account is presented. The mechanisms of cholecystokinin release, its stimulation by dietary factors and peptides elaborated by both pancreas and small intestine are discussed. The inhibition of cholecystokinin release by bile acids and proteases is also described. In the second part attention is focussed on other peptides affecting motility. These include (a) octreotide, effective for treatment of acromegaly, (b) peptide YY, contributing to a "colonic brake', (c) motilin. associated with interdigestive contractions, analogues of which possibly correct gallbladder hypomotility, and (d) substance P and calcitonin gene-related peptide, which facilitate ganglionic transmission after release from extrinsic sensory neurones and alter gallbladder responses to vagal stimulation. The sympathetic nervous system and diabetes mellitus also influence vagal responses. The former, acting presynaptically, may provide a "brake" to prevent vagal overactivity. The latter could cause hypomotility via autonomic neuropathy, although hyperglycaemia, itself, may play a role. The role of nitric oxide, released from neurones also producing vasoactive intestinal peptide is recognized. Both lengthen muscle, the former producing responses without requiring plasma membrane receptors. Gallbladder motility also changes during pregnancy and stone formation. Progesterone and cholesterol can limit G protein actions, thus impairing contractions. Inflammation is associated with abnormal motility. The production of reactive oxygen metabolites, acting directly or releasing prokinetic prostaglandins, may be responsible. It has been proposed that the gastrointestinal tract may be normally in a state of controlled inflammation, primed to react to harmful challenges.

How to cite this article:
Ballal MA, Sanford PA. The physiology of the biliary tree. Motility of the gallbladder - Part 1. Saudi J Gastroenterol 1999;5:93-105

How to cite this URL:
Ballal MA, Sanford PA. The physiology of the biliary tree. Motility of the gallbladder - Part 1. Saudi J Gastroenterol [serial online] 1999 [cited 2019 Nov 20];5:93-105. Available from: http://www.saudijgastro.com/text.asp?1999/5/3/93/33527


Bile is a complex, variable mixture of organic and inorganic solutes elaborated by both the hepatocytes and biliary duct epithelia [1],[2],[3] .Approximately 600ml. are secreted daily. The hepatocyte produces both bile salt-dependent and independent fractions. In the former water follows the osmotically active bile salts returning from the intestines in the enterohepatic circulation. The bile salt-independent fraction reflects the secretion of solutes such as glutathione and bicarbonate that also generate a flow of water. These two fractions constitute about 75% of the total bile production. The remainder is a bicarbonate-rich fluid, produced by biliary ductules and stimulated by secretin.

Secretin is remembered as the first hormone, reported in 1902 when Bayliss and Starling were studying alimentary tract reflexes in dogs [4]. They observed that when all accessible nerve connections were severed a pancreatic secretion could still be induced by acid in the duodenal lumen. An acid extract of jejunal mucosa (filtered through cotton wool to remove lumps) injected intravenously was subsequently found to elicit a copious pancreatic secretion. The bicarbonate-rich secretion of the pancreas stimulated by secretin neutralizes acid chyme from the stomach and helps create an environment in which effective digestion within the intestinal lumen can occur. The effect of secretin on biliary ductules provides further neutralizing capacity.

Bile, produced in the liver is conducted towards, and a proportion stored and concentrated in the gallbladder. More than 75% of the hepatic bile may pass to the gallbladder in man [5] . Its appearance in the duodenum depends on its rate of secretion, the pressures generated when the gallbladder contracts, and the opening and closing of the  Sphincter of Oddi More Details. Some of the factors modifying these events are depicted in [Figure - 1]. However, the figure is deceptively simple. It provides no guide as to the mechanism(s) by which these factors exert their effects. This review intends to address some of these mechanisms focussing particularly on studies of the motility of the gallbladder over the past decade. In the first part of the review a simple overall picture is presented along with a detailed account of the central role of cholecystokinin (CCK).


   A simple picture of gallbladder motility Top


The gallbladder is a readily distensible bag with a capacity of 30-50 ml. It has tone reflecting inherent compliance of smooth muscle and fibroelastic tissue within its walls. Smooth muscle tone is continually influenced by neural and humoral factors. Motility and emptying are stimulated by food. However, gallbladder contractions can be recorded even before eating. Volunteers, after fasting for 12 hours, frequently produce contractions, when contemplating or seeing a meal, as part of a cephalic response [6] .

Following food ingestion a triphasic pattern of gallbladder motility has been described [Figure - 2]. An early net emptying phase (on average within 20 minutes of the meal) was succeeded by an early net refilling phase and then a period of slower net emptying. The whole process was completed in approximately 150 minutes. Two aspects of this response require further comment. The first are the repeated short-lived episodes of filling that occur during periods of net emptying. It has been proposed that these help to washout concentrated, viscous, stratified bile lying deep within the fundus. The other is early net refilling, surprising, perhaps, as it is followed by a further phase of emptying. One explanation is that unconjugated bile acids, sequestered in the semi-liquid contents of the large intestine are absorbed at a faster rate after eating. Food in the stomach increases colonic motility with the result that the luminal contents are better mixed and more likely to come in contact with the absorbing epithelia. Returning to the liver they stimulate bile salt-dependent bile secretion and gallbladder filling. Support for this possibility has been the discovery that serum unconjugated bile acids show a peak concentration 30-60 minutes after a meal [7]

Gallbladder contractions and emptying prior to food reaching the proximal small intestine are neurally mediated [8],[9] . The cephalic phase has been studied in humans using a sham feeding technique [10] . Fasting volunteers were given a meal of sirloin steak, french-fried potatoes and water. They were asked to chew mouthfuls of food and then spit out. Nasogastric suction was applied to some subjects to avoid possible effects of duodenal acidification. Gallbladders emptied by more than 40% within 1-2 hours. The response was eliminated by cholinergic blockade with the antimuscarinic agent atropine and could not be elicited in patients with vagotomies. Emptying as a result of sham feeding was not significantly different from that recorded after subcutaneous administration of bethanechol, a parasympathomimetic agent resistant to hydrolysis by cholinesterases. These observations indicate that intact vagus nerves and cholinergic pathways are required for the cephalic phase. A dispute has developed as to which muscarinic subtype mediates gallbladder contraction [11] . On the basis of pharmacological criteria four have been described (M 1 , M 2 , M 3 and M 4 ). From the measurement of agonist potencies and antagonist affinities in guinea pig gallbladder it has been suggested that functional M 3 receptors are involved [12]

The importance of the vagus does not mean intestinal hormones make no contribution to the cephalic phase. Indeed a role has been proposed for CCK. The effects of CCK are mediated by two types of receptor, CCK-A and CCK-B against which specific antagonists have been developed [13],[14],[15] , Administration of the highly selective and potent CCK-A antagonist loxiglumide increased basal (resting) gallbladder volumes and attenuated the decreases of this volume induced by sham feeding [16] . These findings were explained in terms of loxiglumide reducing the effectiveness of the vagal cholinergic input because of the removal of the tonic action of endogenous CCK on the gallbladder contractions (see below). While sham feeding fat- or protein-rich meals reduce gallbladder volumes carbohydrate-rich meals do not [9] . This raises the question as to how the body recognizes the composition of a meal. Do proteins or fats activate the cephalic phase or does the act of chewing induce gallbladder contractions that are inhibited by a sweet taste? Distension of the antral region of the stomach also produces gallbladder contractions. Indeed, over a 40 minute period, emptying in response to balloon inflation with 500 ml. water at 37°C was of a similar magnitude to that observed after a standard meal [8] . A vago-vagal pyloro-cholecystic reflex may provide bile for the emulsification of the first chyme reaching the duodenum.

The major factor controlling postprandial gallbladder contractions in man is CCK. Its name was coined by Ivy and Oldberg to describe the factor released from the proximal small intestine in response to fat [17] . This versatile peptide has subsequently been found to have a central role in the control of digestion and absorption. Fifteen years after the Ivy and Oldberg report Harper and Raper (1943) discovered that the introduction of polypeptides into the duodenal lumen elicited a secretion of pancreatic enzymes. They named the factor mediating the response pancreozymin [18] . Subsequent purification of CCK and pancreozymin showed they were the same substance. The first name given has been retained. It has numerous other effects stimulating pancreatic growth [19] , potentiating the pancreatic bicarbonate secretion stimulated by secretin [20] , delaying gastric emptying [21],[22] and modulating satiety [23] . CCK can modify gallbladder contractions in two ways, either directly by stimulating smooth muscle membrane receptors, or indirectly, by activating intramural neurons which release acetylcholine.

Another hormone with actions on the gallbladder is pancreatic polypeptide (PP). It causes gallbladder relaxation without affecting hepatic bile secretion [24] . In addition it inhibits pancreatic enzyme secretion. Released from pancreatic islet cells, it was discovered as a major contaminant during the purification of insulin. It is released by chewing food and by signals originating in the stomach and small intestine [25] . Gastric distension is one of the factors. Perhaps the most potent stimuli for human PP secretion are intestinal intraluminal factors, particularly amino acids released from dietary proteins ` e.g. those found in ground beef and steamed cod [26],[27] . Vago-vagal reflexes account for at least some of the PP released. As atropine administration caused the virtual cessation of PP release after protein meals, although truncal vagotomy did not abolish the human response, it was suggested that PP secretion is mediated by both vagal and non-vagal cholinergically mediated mechanisms [25] . The actions of PP may seem surprising. They do not promote digestion. Furthermore, they are directly opposite those of CCK which is also released by the products of protein digestion. A clue to the possible value of PP is provided by the finding that plasma PP levels remain elevated for at least 6 hours postprandially, long after other gastrointestinal hormones have returned to their basal levels [28]. Thus the responses to PP are likely to be more important during the interdigestive period allowing gallbladder filling and conservation of pancreatic enzymes in preparation for the next meal.

Even during fasting the gastrointestinal tract is not quiescent. If the electrical activity of muscle in various parts of the stomach and small intestine of fasting conscious dogs is monitored a recurring band of intense action potential activity can be recorded [29],[30] . This band is detected initially in the stomach and duodenum before it sweeps aborally along the intestine. It has been described as the migrating myoelectric complex (MMC). When one of these bands reaches the terminal ileum another complex commences in the duodenum. In dogs the complex takes 105-135 minutes to reach the terminal ileum from the duodenum and is projected more rapidly in the proximal than in the distal intestine. Gastric distension and the passage of liquids into the small intestine are means of bringing fasting motility to an end. MMCs can also be recorded in man. An early study involved young adult volunteers induced to swallow pressure sensitive radio-pills [31] . A thread attached to the pill was tethered to the teeth or cheek after its passage beyond the duodenum allowing the device to remain at a specific location (and for it to be retrieved). Motor complexes could be detected as episodes of contraction.

Four phases of electrical activity have been recognized:­

Phase 1 - a relative absence of action potentials,

Phase 2 - persistent but random action potentials,

Phase 3 - bursts of continuous action potentials,

Phase 4 - a rapid decrease in the incidence of action potentials.

Gallbladder contractions are also observed in the interdigestive state [32],[33] . These are associated with the beginning of phase 2 of the duodenal MMC. The forces achieved by these contractions could be as high as 80% of the maximum but were already decreasing by the time greatest duodenal contractions occurred. The question remains as to the significance of gallbladder contractions during fasting. Two possibilities might be considered. One involves provision of bile to the duodenum as a part of a "housekeeper" function. Powerful, persistent contractions coordinated with secretory activity could remove undigested food particles, cell debris and bacteria from the villi and propel them distally. An alternative possibility is that gallbladder contractions cause mixing without emptying. Such an event would limit stasis during the interdigestive phase and, therefore, help to reduce the risk of cholesterol precipitation.


   Gallbladder innervation Top


The gallbladder develops as an outgrowth of the foetal gut. Its innervation, therefore, might be expected to be like that of the small intestine. Indeed intrinsic gallbladder nerves are regarded as an extension of the enteric nervous system. The ganglionated plexus of the gallbladder, found between the serosa and submucosa, is similar to the submucosal plexus of the intestine in terms of its number of neurones per ganglion and its arrangement into two irregular, anastomosing and interweaving networks [34] . It receives a direct neural input from Auerbach's but not from the submucosal plexus in the duodenum. This was established by injecting tracers (fluoro-gold and wheat germ agglutinin coupled to horseradish peroxidase) into gallbladder neurones and observing their retrograde movement exclusively to the plexus between the circular and longitudinal muscle layers.

The interior of the gallbladder plexus is avascular. Capillaries exist outside the ganglia and have no fenestrations. When compared with other capillaries their tight junctions are relatively impermeable [35] This raises the question as to how blood-borne factors modify the actions of gallbladder neurones. Are there specific mechanisms whereby agents such as CCK can penetrate the capillary walls to exert their effects?

Both the sympathetic and parasympathetic branches of the autonomic nervous system contribute a rich extrinsic supply to the gallbladder plexus. Afferent sensory and efferent motor neurones from and to the gallbladder have been demonstrated by retrograde tracing to the dorsal root (T5 to T11) and nodose ganglia, and to the coeliac ganglion and dorsal vagal nucleus. Vagal neurones liberate acetylcholine that acts on nicotinic receptors and stimulates postsynaptic parasympathetic (local network) neurones. This event can be inhibited by noradrenaline from postganglionic sympathetic fibres acting presynaptically on vagal α2 -adrenergic receptors. When stimulated the postsynaptic gallbladder neurones release acetylcholine that causes gallbladder contractions by binding to cholinergic muscarinic receptors on smooth muscle membranes. Vasoactive intestinal peptide (VIP) is also released as a result of vagal activity. This peptide can be detected in both gallbladder luminal fluid and the venous effluent following vagal stimulation [36]. VIP-like immunoreactivity is limited to ganglion cells but is not observed in association with blood vessels, suggesting that any effects of VIP on the gallbladder are unlikely to be caused by circulatory changes. There are no endocrine cells in the gallbladder that might have been a source of VIP [37] . The question as to the significance of two neurotransmitters being released from a single neurone is considered later in the review. Suffice, at this time, to recognize that VIP causes elongation of gallbladder smooth muscle and also promotes secretion of epithelial cells [38] . Thus the possibilities arise that vagal stimulation might allow the gallbladder (a) to increase in size (fill) without the intraluminal pressure rising dramatically and still be able to empty and/or (b) contents to be both diluted and mixed at the same time.


   Recent advances in CCK Top


(a) CCK release

The introduction of lipids or polypeptides into the proximal small intestine were the original means by which CCK release was elicited. How do these nutrients stimulate secretion of the hormone? The apical membrane of the CCK-releasing cell is exposed to the intestinal lumen so that luminal factors causing hormone secretion can act directly. Subsequent studies have shown that essential amino acids and long chain fatty acids are among the most potent stimulants. Certainly some digestion of lipids is a requirement for CCK release in man [39] . Thus volunteers eating a test meal 40 minutes after an intraduodenal perfusion of tetrahydrolipstatin (THL) in an oil emulsion produced no increase in plasma [CCK]. THL is a potent irreversible inhibitor of gastrointestinal lipases. In contrast, when the THL was omitted from the oil perfusion the plasma CCK levels rose and pancreatic enzyme secretions increased threefold. Furthermore, the higher plasma CCK levels associated with adaptation to high fat loads in rats has been explained by an increased efficiency of triglyceride digestion causing greater CCK release [40]

CCK release depends on adequate stimuli being able to reach CCK-secreting cells. CCK is synthesized by specific I cells scattered evenly throughout the crypts and villi of the duodenum and jejunum. A few cells can be found in the ileum. This may present a problem for those with coeliac disease [41] . In patients with flattened villi lipid products may fail to reach and stimulate their CCK releasing cells located mainly deep within the crypts. As a result lipid digestion would be poorer because of less pancreatic enzyme release. A vicious circle would be set up. Poorer gallbladder responses of coeliac patients to a fatty meal would also be expected because of the loss of the major postprandial stimulus. It is interesting that if predigested corn oil was fed to coeliac patients their plasma CCK levels were significantly higher and gallbladder emptying greater than when given in the undigested form [Figure - 3].

If adequate intraluminal digestion is not taking place a decreased CCK release and its sequelae are likely. This potential problem has been recognized in patients with pancreatic insufficiency due to chronic pancreatitis. Postprandial plasma [CCK] and gallbladder emptying responses to a meal were both decreased [42] . Other groups who are at greater risk of producing biliary sludge (a viscous suspension which includes cholesterol monohydrate crystals and granules of calcium bilirubinate) and developing gallstones because of reduced release of CCK and gallbladder hypomotility include those given parenteral nutrition. In one study 12/38 patients were found to produce sludge within 10 days following gastrointestinal tract surgery [43] . Parenteral nutrition is designed to avoid irritation of the gastrointestinal tract and provide an environment for tissue recovery or clinical remission. It has, therefore, also been used in patients with inflammatory conditions e.g. Crohn's disease and ulcerative colitis. Daily injections of CCK prevented stasis. As an alternative for patients with such inflammatory conditions, continuous enteral nutrition (CEN) has been proposed in which a polymeric diet containing lipid and protein is provided nasogastrically [44],[45] . CEN is both less expensive, more physiological and leads to endogenous CCK release. Patients given CEN were found to have smaller gallbladder volumes during fasting and it was thought unlikely that CEN carried any greater risk of stone formation. Some anxiety has been expressed about the procedure because of the incidence of sludge in critically ill patients given CEN. It was noted, however, that patients also received muscle relaxants and some were treated with morphine, both probably having adverse effects on gallbladder motility [44] .

The mechanism(s) by which CCK can be released have been investigated using STC-1 cells [46],[47],[48],[49],[50],[51] , an intestinal cell line derived from an endocrine tumour developed in transgenic mice [52] . Homogeneous populations of native intestinal cells can only be isolated in small numbers. A picture has emerged illustrating the importance of raising intracellular cytosolic [Ca ++ ] via L-type channels. Calcium levels can be increased in several ways. A more direct means, by opening membrane calcium channels, has been proposed as the mechanism by which phenylalanine causes CCK secretion [48] . Free fatty acids act in a similar way, the most effective of which was dodecanoic acid [51] . In contrast basal secretions may be explained as the result of depolarision of the cell membrane by changes in the activity of ATP­ sensitive K + channels with Ca ++ channels subsequently opening [47] . The ATP-sensitive K + channels are one of several K + channel types and present in sufficient numbers to contribute significantly to the potassium permeability of the cell. They are active under basal conditions and can be inhibited by glucose increasing cytosolic ATP levels i.e. ATP has an inhibitory effect. Patch clamp studies show that STC-1 cells in which K + channels are blocked with barium chloride can increase their CCK release more than threefold. The Ba ++ -induced secretion can be inhibited with the L-type Ca ++ channel blockers diltiazem and nicardipine but not by nickel chloride, the T-type Ca ++ channel blocker. In contrast the L-type Ca ++ channel opener BAY K 8644 produces a dose-dependent stimulation of CCK release.

A recent report indicates that nitric oxide (NO) may serve as an important regulator of basal CCK secretion [49] . Thus, the NO-generating agent sodium nitroprusside decreased basal secretion of STC-1 cells, while having no effect on hormone release elicited by phenylalanine. Furthermore, inhibition of NO synthase with N-nitro-L-arginine-methyl ester (L-NAME) stimulated CCK release and reduced the activity of ATP-sensitive K + channels. It is interesting that an agent causing gallbladder relaxation and filling may also limit the release of a major hormone concerned with gallbladder contractions. A role for circulating catecholamines must not be ignored in any consideration of the control of CCK release. Certainly [3-adrenergic receptors, activated by the agonist isoproterenol, are present on STC-1 cells [50] . These are coupled to the production of cAMP, which it has been proposed, is yet another means of increasing cytosolic [Ca ++ ] and CCK secretion.

(b) Feedback inhibition of CCK release

While the secretions of bile and pancreatic juice enzymes into the duodenum are increased by CCK, evidence has accumulated to support the view that both bile acids and proteolytic enzymes suppress CCK release [53] . Three types of study suggest a physiological role for bile acids.

1. Nutrient-stimulated biliary secretions are inhibited by exogenous bile/bile acids. When trypsin and bilirubin outputs (as indices of pancreatic secretion and gallbladder contractions respectively) were measured in humans during continuous intraduodenal perfusion of essential amino acids or monooleate, it was found that both were strongly inhibited by intraduodenal taurocholate [54],[55] . These responses were achieved with bile acid concentrations (10mM) similar to those found in the proximal small intestine following a meal. The effects of taurocholate were local. Jejunal perfusion of the bile acid did not prevent the release of CCK activity by essential amino acids. Furthermore, duodenal bile acid perfusion did not affect exogenous CCK-induced gallbladder contractions. indicating that the bile acid was not exerting a systemic inhibitory influence on the CCK target organ.

2. Biliary and pancreatic secretions stimulated by luminal nutrients are augmented by cholestyramine [56] . Cholestyramine is an anion exchange resin that adsorbs bile acids in the intestinal lumen [57] . The agent is neither digested nor absorbed and because it also binds to cholesterol has been used in attempts to prevent dietary cholesterol absorption. Both basal and meal-stimulated plasma CCK levels are elevated when endogenous bile is unable to exert its normal effects within the duodenum [58] . This was demonstrated by comparing patients with obstructive jaundice who either had bile diverted internally into the duodenum or were under external bile drainage. Furthermore, when external was changed to the more physiological internal bile drainage plasma CCK levels were normalized.

3. An exaggerated CCK release in response to luminal nutrients is observed when volunteers are treated with the CCK receptor antagonist MK­329 [59] . This observation has been interpreted as due to the removal of an inhibitory effect of bile acids on CCK release and not to the loss of pancreatic enzymes. The CCK antagonist caused a marked inhibition of bile acid output but only a small and insignificant reduction of trypsin secretion.

How might bile acids reduce nutrient-stimulated CCK release? One explanation might be that by accelerating the absorption of fatty acids bile acids promote the removal of a stimulus for CCK release. Initially when chyme enters the duodenum gastric and pancreatic lipases release fatty acids. These fatty acids are mixed with low concentrations of bile acids. However, the bile acid concentrations are inadequate for micelle formation. Thus fatty acids are "free" to stimulate CCK release which in turn causes gallbladder contractions and further bile secretion. The bile acid concentrations in the lumen rise and favour micelle formation, the absorption of fatty acids and the loss of a signal for CCK release.

A contribution by pancreatic proteases to the control of CCK release has been established in rats. Trypsin inhibitors introduced into rat upper small intestine or the diversion of pancreatic juice and bile resulted in greater pancreatic exocrine secretions. A negative feedback system was suspected. Proteins were found to be more potent secretagogues than amino acids or hydrolysed protein suggesting that the capacity of dietary protein to stimulate the pancreas is related to its ability to serve as a digestible substrate. This raised the question as to what sort of mechanism might exist whereby "taking the attention of intraluminal proteases" enhances pancreatic secretion. It was proposed that a trypsin­ sensitive substrate may act to release CCK [60] . If trypsin (and other proteases) are not "otherwise occupied" they would degrade and inactivate the releasing factor. Subsequently, evidence of a trypsin-sensitive, heat stable factor, removed by rapid perfusion of the intestine with saline has been reported [61],[62] . The partial structure of what is called the luminal CCK-releasing factor (LCRF) has recently been determined. It is a peptide composed of 70-75 residues with a mass of 8136 kDa, found throughout the gut but with highest levels in the small intestine [63],[64] . The N-terminal fragment (LCRF1-35) is biologically active [65] . The existence and importance of LCRF in humans is more controversial [53],[66] . Thus the trypsin inhibitor from soybeans (the Bowman-Birk inhibitor) stimulated pancreatic secretion in the presence of intraluminal amino acids [67] . However, the synthetic inhibitor camostat had no effect on plasma CCK levels in the absence of nutrient stimulation [68] . Green (1994) has tried to explain these findings by suggesting that LCRF release in rats is tonic or spontaneous but in humans requires intraluminal nutrients [53]

Another factor releasing CCK has been purified from pancreatic juice. It has been called monitor peptide as it "monitors" the intraduodenal environment [69] . If undigested it stimulates further pancreatic secretion. Small amounts of trypsin under fasting conditions are expected to degrade both LCRF and monitor peptide and prevent stimulation of CCK release. However, with chyme providing a "competing substrate" for pancreatic proteases, LCRF can stimulate CCK release and, subsequently, monitor peptide secretion in pancreatic juice. The latter may exert a positive feedback effect on CCK secretion. Monitor peptide can also act as a trypsin inbitor [70] so that part of its action maybe due to inhibition of proteases in addition to direct effects on CCK-releasing cells.

(c) Dietary constituents (lectins) and CCK release

Rats fed raw soybean flour (RSF) have been found to develop pancreatic hypertrophy, a response attributed to soybean trypsin inhibitor increasing CCK release [71],[72] . Trypsin inhibitors are not the only means, however, by which soybeans might promote growth. Soybeans also contain a heat labile lectin, a 120 kDa glycoprotein which binds to D-galactose and N-acetyl D-galactose. As lectins have been found to stimulate the intestinal cell line HT29 [73] , increasing thymidine incorporation, a study has recently been made of the effects of soybean lectin on CCK and pancreatic protein release [74] . Selective removal of the lectin from flour containing both lectin and soybean trypsin inhibitor indicated that the lectin makes a major contribution to pancreatic protein output. Replacement of the lectin restored the response. Lectin alone or with cooked soy flour was ineffective. These observations suggested that a lack of intestinal proteolytic activity is necessary for lectin to exert its effects, a view supported by the finding that lectin alone stimulated the rat pancreas providing pancreatic juice was diverted from the intestine. The effect on the pancreas was accompanied by a rise in plasma [CCK] and abolished by CCK-A receptor blockade. How soybean lectin releases CCK is not known although its capacity to specifically bind to D-galactose and N-acetyl D-galactose residues found in cell surface molecules, including receptors, is creating interest. What is recognized, however, is that lectins are plentiful in the normal diet and often escape digestion and so may exert numerous previously

(d) Effects of CCK on the gallbladder and bile ducts

How CCK produces gallbladder contractions and emptying has been a subject of considerable debate [75] . An involvement of CCK-A receptors is illustrated by the finding that the specific antagonist, loxiglumide, causes dilatation of the gallbladder and exaggerated plasma CCK levels in response to intraduodenal fat in healthy volunteers [76] . In contrast, multiple oral doses of a non- peptide antagonist for type B receptors (L365,260) to normal humans failed to inhibit gallbladder contractions [77] . Certainly the hormone exerts direct effects on gallbladder smooth muscle cells where CCK-A receptors can be detected autoradiographically [75] . When CCK is applied to gallbladder muscle strips a concentration-dependent increase in tension is recorded that is not affected by muscarinic antagonists or the sodium channel blocker tetrodotoxin. Nevertheless a neurally mediated process requiring CCK-A receptors has also been recognized [78],[79],[80] . Reduced gallbladder emptying after a meal or in response to CCK has been observed following vagotomy [78] . Muscarinic antagonists attenuated both food and CCK-induced contractions suggesting that CCK was increasing the release of acetylcholine. Furthermore, in experiments with dogs, ligation of the abdominal vagus resulted in the accumulation of CCK receptors in the vagus nerve immediately proximal to the ligature and in the smooth muscle layer [79] .

Two questions need to be addressed. 1. How might CCK modify the activity of cholinergic (vagal) nerves? 2. Which, physiologically, is the more important process, the direct action on gallbladder smooth muscle or the indirect stimulation via nerve pathways? Data has accumulated from studies of guinea pig and opossum [81],[82],[83] to show that CCK can act presynaptically in gallbladder ganglia to increase the release of acetylcholine each time an action potential reaches the terminal. The resultant increase in amplitude of excitatory postsynaptic potentials (fast EPSPs) facilitates the achievement of threshold potentials, the generation of action potentials and greater neurotransmitter release to stimulate gallbladder smooth muscle. Another possible site of action of CCK is the vagal afferent neurone.

Subdiaphragmatic vagal afferents e.g. from stomach, small intestine and liver, have been found to be sensitive to CCK [84],[85],[86],[87],[88],[89] . The increased activity of these nerves could act on the vagal motor complex to increase the rate of firing of vagal preganglionic neurones. In his current working model Mawe (1998) incorporates an effect of CCK on both gallbladder ganglia and vagal afferent fibres [75].

Over the past few years support has grown for the view that the major physiological effect of CCK on the gallbladder is via a neural mechanism [75],[90]. Nerves have been found to be more sensitive than smooth muscle [Figure - 4], the former responding to CCK concentrations of the order found postprandially (serum [CCK] ~ 10 pM). Using voltage clamp techniques, it has been possible to measure increases in synaptic currents with such low concentrations [82] . In contrast, the threshold at which increased tension can be recorded with gallbladder strips is in the 1-5 nM range with maximum changes at 50-100 nM [91] .

Gallbladder emptying in man is normally enhanced as the dosage of CCK is increased from 0.5ng/Kg/min to 3.3ng/Kg/min. At higher doses, however, the ejection fraction decreases [92] . An explanation for these findings is that normally the gallbladder body and fundus are more sensitive to CCK than the cystic duct, i.e. the latter has a higher threshold. One can only speculate as to the significance of these responses. Might such a system help to (a) limit the flow of bile in the face of increasing plasma [CCK] or (b) protect and maintain the shape of biliary ducts, perhaps fulfilling a function similar to that carried out by salivary myoepithelial cells? Whatever the physiological responses of the biliary tree smooth muscle, it is clear that abnormal sensitivity to CCK in different regions is likely to produce marked changes in gallbladder function. This is seen when the cystic duct contracts in response to physiological doses of CCK, causing an increased resistance to bile flow. The condition, described as the cystic duct syndrome, represents a form of biliary dyskinesia. This is distinguishable from that occurring because of abnormalities of the sphincter of Oddi. Normally CCK produces relaxation of the sphincter of Oddi. However, hyposensitivity of the sphincter, spasm of the sphincter, or hypersensitivity of the gallbladder to CCK results in contractions of the gallbladder against a closed sphincter and pain [93]

How CCK directly causes the contraction of gallbladder muscle is a further problem to be answered. CCK acts by releasing calcium from intracellular stores [94] . Thus contractions are unaffected in a calcium-free medium, but blocked when strontium is substituted. Strontium is taken into the endoplasmic reticulum and displaces calcium from its high affinity binding sites but cannot readily be released. Calcium release from the endoplasmic reticulum is thought to be mediated by inositol-1, 4, 5-triphosphate (1P 3 ), one of the products of hydrolysis of phosphatidylinositol by phospholipase C [95],[96] The other product is diacylglycerol (DAG). Heparin, which competes specifically for IP 3 binding sites, inhibits contractions produced by either IP 3 or CCK [94],[97] Once released calcium could activate calmodulin, or protein kinase C (PKC), the latter directly or by its synergistic action with DAG. Activation of either calmodulin or PKC could result in muscle contraction [98],[99] . It appears that the pathway stimulated in human single gallbladder muscle cells depends on the [CCK]. At low concentrations CCK activates only the more calcium-sensitive PKC pathway. At higher concentrations contractions are mediated through the calcium- calmodulin pathway with calmodulin inhibiting PKC [100]

(e) The CCK provocation test (CCKPT)

The importance of CCK in controlling the normal contractions of the gallbladder has long been recognized. Its possible value in determining gallbladder dyskinesia as a cause of biliary pain in acalculous patients has led to the development of the CCKPT. The rationale behind the test has been that patients whose pain was reproduced or whose gallbladder emptying was delayed by CCK infusion, had abnormal gallbladder motility. The neck was thought to have contracted asynchronously with the body, producing a functional obstruction, a buildup of pressure in the gallbladder lumen and resulting in pain. The test provided a simple, cheap, bedside or out-patient procedure. Symptoms should be relieved by cholecystectomy [101] . The results recorded of patients undergoing the operation after a positive CCKPT have been surprisingly successful, the cynical pondering the powerful placebo effect of the surgery [102] . In one series of 103 CCKPT positive patients 67% had complete and 24% had partial symptom relief following cholecystectomy [103] Recently, however, doubt has been cast on the value of the test [104] . Cholecystectomy was found to reduce symptoms in some patients who preoperatively had given a negative CCKPT. In their editorial Al­Musawi and Williamson (1998) concluded that a case can still be made for performing the CCKPT for patients with recurrent biliary pain but a normal gallbladder on conventional imaging [102] . Many of the CCKPT positive patients will be helped by cholecystectomy. They recognize that the pragmatist might respond that any fit patient should be advised to undergo the cholecystectomy, whether positive or negative, particularly as minimal access techniques have reduced the metabolic insult of the procedure.

 
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Correspondence Address:
Paul Anthony Sanford
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Saudi Arabia
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