|Year : 2001 | Volume
| Issue : 1 | Page : 6-21
|Physiology of the Sphincter of Oddi: The present and the future? - part 2
Mansour A Ballal, Paul A Sanford
Department of physiology, College of Medicine, King Khalid University, Riyadh, Saudi Arabia
Click here for correspondence address and email
|How to cite this article:|
Ballal MA, Sanford PA. Physiology of the Sphincter of Oddi: The present and the future? - part 2. Saudi J Gastroenterol 2001;7:6-21
In the first part of this review the effects on the SO of numerous substances, classified as neurotransmitters, were described. In addition, current views on the mechanisms whereby smooth muscle contracts and the role of the interstitial cells of Cajal were presented. In this part attention is directed to the effects of hormones, local factors and pharmacological agents. An attempt is also made to recognize the complexities of the relationships between the nervous system and gastrointestinal tract.
| 2. Hormones|| |
A. Cholecystokinin (and duodenal:SO relationships)
Seven years after the discovery by Ivy and Oldberg (1928)  of CCK as a factor released from the proximal small intestine in response to fat and causing gallbladder contractions it was noted that their extracts produced relaxation of the SO (canine)  . Their initial investigation was to determine whether the hormone increased or decreased intramural resistance by acting on either duodenal musculature or the SO. Flow to the duodenum was often retarded as CCK increased duodenal tone. However, when the latent period of the duodenal response to CCK was prolonged, the primary response of the sphincter to CCK was apparent. Interestingly, a combination of CCK and secretion resulted in an augmented sphincter response  illustrating yet further synergism between these two hormones in addition to their effects on gallbladder motility and pancreatic enzyme secretion  . Studies of the effects of CCK on the SO have been complicated by:(a) species differences, (b) gender differences, the amplitude of phasic contractions in response to CCK being greater in the female (prairie dog)  , and (c) the sensitivity of both sphincter neurons and smooth muscle to CCK, the former providing the dominant driving force for the response. In some animal models the direct contractile (smooth muscle) and indirect (nerve) effects are in opposite directions. Thus CCK stimulates in herbivores ("pumpers") while inhibiting the sphincter in humans ("resistors") although in both cases the flow of bile is increased. The contractions in human gallbladder but concomitant SO relaxation elicited by CCK have been attributed to "contrary" autonomic innervation  . Certainly CCK exerts effects on different autonomic neurons in the gallbladder and SO. In the gallbladder CCK acts presynaptically on cholinergic (vagal) neurons so that more acetylcholine is released every time an action potential reaches the terminal. This increases the amplitude of excitatory postsynapyic potentials, facilitating action potential generation and the stimulation of contractions  . In contrast CCK activates intramural NANC inhibitory pathways in the SO , reducing both tonic and phasic contractions and overriding a direct excitatory effect on smooth muscle. In the presence of TTX, CCK caused sphincter contraction. Some patients also respond to CCK administration with contraction rather than relaxation (paradoxical contraction). Impairment of inhibitory innervation might account for these observations  .
The questions remain as to how (a) SO inhibitory neurons are activated by CCK, and (b) neurotransmitter(s) production and release are affected by CCK. Neurons in the SO ganglia express CCK-A receptors and both tonic and phasic neurons were depolarized when these receptors were activated  . However, it was thought unlikely that circulating CCK could mediate these responses. The minimum [CCK] required to detect depolarization was in the nanomolar range whereas the peak [CCK] in serum was in the 10 pM range  . The possibility remains that such low [CCK] in the serum might facilitate responses to other stimuli e.g. from the duodenal mucosa?
Both VIP and NO are thought to contribute to neurally mediated relaxation of the SO  . How CCK might control either of these agents in the SO is not known. Progress is being made, however, in other regions of the gastrointestinal tract where CCK-A and CCK-B receptors have been found ,  . The former is thought to playa major role in mediating VIP output from the intestine (canine). In contrast, increased NO release appears exclusively to be the result of activation of CCK-B receptors. A complete picture has yet to emerge.
It is interesting that information concerning the roles of CCK receptor subtypes has been obtained using CCK-OP for CCK-A and gastrin 17 for CCKB as agonists. Gastrin has structural similarity to, and a wide range of biological effects that overlap with CCK  . CCK-like peptides are, however, much less potent than CCK and are unlikely to be physiologically important  although some abnormality in SO tone has been predicted in patients with Zollinger-Ellison syndrome.
If CCK exerts effects on both gallbladder and SO the question arises as to the relative responsiveness of these two smooth muscles to the peptide. In the guinea pig the SO was found to be the less sensitive  . Moreover the gallbladder showed increased tone at [CCK] equivalent to the peak postprandial values. It was suggested that bile flow could, therefore, be increased without altering sphincter activity although the interrelationships of gallbladder and SO (see below) might make this an unlikely possibility.
If inhibitory neurons in the sphincter ganglia are insensitive to the peak serum [CCK], how does the hormone produce relaxation? One interesting possibility is that CCK might exert its effects via neurons near to its release in the duodenal mucosa  . Close coordination between the duodenum and the SO is "intuitively likely". It would allow (a) appropriate secretion of bile ( and pancreatic juice ) and its mixing with chyme in the duodenum, (b) coordination of SO tone and duodenal motor activity both after a meal and during the interdigestive phase, and (c) prevent the propulsion of luminal contents into the biliary tree. The importance of intrinsic myoneural continuity to the SO has been shown in the opossum by translocating the papilla to the jejunum  . Subsequently measurements were made of the changes in sphincter spike activity that normally increases (a) during phases II and III of the interdigestive period and (b) after feeding. The plateau frequencies were lower after translocation. Furthermore, proximal duodenal transection, a procedure performed during conventional distal gastrectomy, has been shown to increase the basal biliary tree pressure in dogs  . It has been suggested that by altering SO motor function transection may contribute to the pathogenesis of postgastrectomy gallstone formation.
Direct neural connections between the duodenum and biliary tract have been described ,, EFS of duodenal sites 2cm oral and 2cm anal to the SO (possum) produced frequency-dependent excitatory responses in the sphincter. Tetrodotoxin pretreatment or crushing the duodenum between the site of stimulation and the SO abolished the response. Atropine and hexamethonium reduced the responses to EFS indicating the intramural pathways were primarily cholinergic. A small effect of guanethidine suggested an adrenergic component. Neurons in the duodenal submucous and myenteric plexuses (possum) were found to project to the SO from both proximal and distal sites  . Kennedy and Mawe (1998)  used retrograde labeling with small glass beads (200-300µm) coated with the dialkylcarbocyanine probe DiI to show that 92% of the labeled neuron cell bodies could be located within 5mm of the SO (guinea pig) although some were more than 12mm away. These fibers were immunoreactive for choline acetyltransferase. Approximately 20% were calbindin-IR. Calbindin is a marker of intestinal intrinsic sensory neurons with processes that pass to the mucosa , . The concept of intestinal sensory neurons contained entirely within the enteric nervous system is relatively new ,, . Until recently sensory neuron cell bodies were thought to exist in spinal and cranial sensory ganglia or within the central nervous system itself. Clearly, such intrinsic sensory neurons are in a position to detect release of compounds from mucosa and signal its release to SO ganglia. The question arises as to what might be recognized. CCK was a candidate. When this peptide was applied it elicited prolonged depolarization of labeled neurons (average 11.4mV and 68.9s)  . It was suggested, therefore, that duodenal intrinsic sensory neurons might provide an instruction to decrease sphincter resistance and facilitate bile flow into the duodenum. This is an exciting possibility as CCK levels required to evoke a detectable response on SO neurons are at least a hundred times higher than those in the serum after a meal. The possibility remains, however that circulating CCK might potentiate or modify the actions of these sensory neurons or other agents at the level of the SO ganglia.
One should not ignore the possibility that CCK can also exert effects indirectly by stimulating vagal afferent neurons. Subdiaphragmatic vagal afferents from stomach, small intestine and liver, have been found to be sensitive to CCK ,,,,, . The increased activity of these nerves could act on the vagal motor complex to increase the rate of firing of vagal preganglionic neurons.
What of other duodenal -SO neural connections? Physiological mechanisms whereby resistance can be increased have been proposed. For example, the basal pressures of the sphincter in conscious dogs were found to be raised by injecting 160 ml. air and distending the duodenum  . In a preliminary study of the human response, distension was reported to increase the frequency and amplitude of phasic contractions, not the basal pressure  . Such responses should not be ignored when measuring SO pressures. In humans, air insuflation is required to introduce endoscopes into the proximal small intestine.
In other parts of this review the importance of integration of SO tone and duodenal motor activity has been mentioned. The question has been posed as to whether reciprocal projections exist whereby such unity might be achieved  . Neural pathways to the sphincter . have been described above. The recording of antidromic responses in SO neurons (guinea pig) when the duodenum was stimulated indicated that there were pathways in the reverse direction. This finding was confirmed by retrogradely labeling SO neurons from dye application sites in the duodenum.
Both somatostatin (a family of peptides)  and the long lasting synthetic analogue octreotide (Sandostatin) have attracted the attention of those investigating the biliary tree. There are several reasons for this. (1) Although recognized, initially, as a growth hormone-inhibiting hormone released from the hypothalamus, somatostatin has been found to be more widely distributed. Numerous D cells in the gastrointestinal tract produce the peptide. Many of its actions are those of a paracrine and are inhibitory, reducing the secretions of regulatory peptides. Justifiably, somatostatin , has been given the title "the endocrine cyanide". Repeated daily injections of octreotide are 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  . (3) The plasma levels of somatostatin are not constant, even during fasting, and remarkably high concentrations have been recorded in patients with somatostatin producing tumors  These patients also have a high incidence of gallstone formation  .
The effect of somatostatin on SO motility was assessed in prairie dogs (a "pumper")  . Octreotide decreased the SO motility index of the fasting animal. This was observed with or without prior atropine treatment, leading to the view that both a cholinergic and an octreotide-sensitive noncholinergic pathway are involved in fasting motility. Furthermore octreotide prevented the increased motility associated with intraduodenal casein. This could, partly at least, be explained by the inhibition of CCK release by somatostatin  . The response of the SO to exogenous CCK-OP was not affected by octreotide. Such observations suggested a poorer pumping action of the SO and reduced transsphincteric flow. The picture, however, is confusing and species differences have been reported even with "pumping" sphincters. Thus somatostatin stimulated the SO (possum), its major action being on sphincter circular smooth muscle. The result, however, was again a reduction of transsphincteric flow. Elevated plasma levels of somatostatin during phase III of MMCs and the postprandial period might help to reduce reflux of duodenal contents and favor gallbladder filling  . The mechanism of action of somatostatin is likely to be complex. In rat aorta cultured smooth muscle processes involving both an increased intracellular calcium ion concentration and a reduction in cAMP have been suggested  .
Several reports have appeared involving human SO responses ,,, As might be expected the basal pressure increased by treatment with intravenous octreotide
Such a response would impede bile flow and complement the inhibitory effect of somatostatin on the gallbladder. This may be clinically relevant in view of increased lithiasis in acromegalic patients treated with somatostatin. Caution should be exercised in patients with stone disease or SO dysfunction and before ERCP  .
The frequencies of phasic contractions were also seen to increase with octreotide
[Figure 10]. It was concluded that acute administration of octreotide may induce tachyoddia and thus impair biliarypancreatic outflow. The length of time octreotide affects SO activity was also recognized. Studies of liver transplant patients showed that duodenal phase III activity was induced by octreotide. Phasic SO contractions, measured using percutaneous manometry, increased. However, the sphincter response continued >60min after duodenal phase III activity had finished  suggesting a persistent obstruction to bile flow with chronic supraphysiological loads.
The response of the SO to somatostatin/octreotide has also to be considered when treating patients with idiopathic recurrent pancreatitis (IRP)  .. Octreotide has been used successfully as an antisecretory drug in patients with pancreatic fistula or pseudocysts. However, by inducing tachyoddia, it was recognized that octreotide could exacerbate the situation.
| 3. Local factors|| |
A. Serotonin (5-hydroxytryptamine or 5-HT)
5-HT has been shown to alter SO motility. Its overall contribution is not easy to determine, however, as there are many subtypes of receptor in the gut and there is no reason to believe that all of them are stimulated by endogenous 5-HT  . Intravenous infusion of 5-HT, in the cat, elicited two responses  . One was excitatory in which both tonic pressures and the amplitude of phasic contractions were increased. This was partly explained by neural release of ACh. However, a direct effect of 5-HT on smooth muscle was also recognized as the contraction produced after treatment with TTX or atropine was abolished by the 5-HT analogue methysergide. The second response involved prolonged relaxation either exclusively (without) or following an earlier contraction. This relaxation was TTX-sensitive, but was not antagonized by either hexamethonium, propranolol or phentolamine suggesting that 5-HT stimulates a NANC pathway  .
The question arises as to the sources of 5-HT and the means by which it can be released. The major enteric depot is in mucosal enterochromaffin cells  . These cells are sensory transducers using 5-HT to activate both extrinsic and intrinsic primary afferent nerve fibers, thought to respond to a variety of stimuli, even light mechanical stimulation of the intestinal mucosa. It is interesting that 5-HT can also have profound effects on mucosal afferent sensitivity without playing an obligatory role in afferent signal transduction  . Other sources of 5 HT include neurons  and mast cells  . The latter increase dramatically in number (mastocytosis) with parasitic infections e.g. Nippostrongylus brasieliensis in mice  . They are activated by inflammatory mediators released after tissue injury  and by several non-immunological stimuli. Thus, for example, mast cells have been shown to release a variety of molecules when healthy volunteers were given the cold stressor test. This response could not simply be ascribed to a generalized activation of the sympathetic nervous system. Mast cell degranulation seemed to be prevented rather than promoted by sympathomimetic stimuli  . Nevertheless, the close functional, as well as anatomical association between mast cells (and other immunocompetent cells) and neurons has been recognized  and led to the suggestion that by modifying mast cell activity the central nervous system has a role in stress-related gut dysfunction  .
A recent report describes the abundance of 5-HT-immunoreactive fibers in the ganglionated plexus of the SO (guinea pig)  . Three different responses were elicited when 5-HT was applied to SO neurons. These were (a) fast depolarization via 5-HT 3 receptors, (b) prolonged depolarization mediated by 5HT,p receptors and (c) an indirect effect involving cholinergic neuron stimulation, findings that support the concept that neurally released 5-HT could play a physiological role in SO control. The sphincter may receive greater exposure to 5-HT from tumor cells of some patients with carcinoid tumors of the ampulla of Vater .
B. Reactive oxygen and nitrogen species
A wide variety of reactive oxygen and nitrogen species are released from tissues
[Table - 2]  Their description as being " the good, the bad and the ugly"  in a similar way to the characters of a "Western" film bearing the same title is a useful one. NO has represented the "good". Its importance as a neurotransmitter and its physiological relaxant effect on smooth muscle was the subject of an earlier section.Numerous other species, e.g.superoxide (O2) may be considered as "the bad". Normally, their concentrations are kept low even though a large flux of superoxide is produced by aerobic metabolism. Superoxide dismutase provides protection, catalyzing the reaction whereby superoxide is converted to hydrogen peroxide (H 2 0 2 ). This product, yet another reactive species, in turn forms water and oxygen under the influence of catalase. However, marked increases in superoxide levels can accompany reperfusion after ischaemia , .
Many were, perhaps, surprised when it was suggested that the bile constituent, bilirubin, should be added to the growing list of antioxidant defense systems of the body  . Previously regarded as a potentially toxic but otherwise useless waste product, it has been reported to be neuroprotective at nanomolar concentrations  .
The "ugly", as their name suggests, are likely to cause tissue damage. If NO is released in large amounts, it can compete with superoxide dismutase for superoxide and cause the accumulation of the "ugly" peroxynitrite. Peroxynitrite is remarkably stable at alkaline pH and exerts numerous effects. It (a) reacts with tyrosine residues of proteins to create nitrotyrosines, (b) damages lipids by peroxidation, and (c) causes DNA strand breakage  . These effects will clearly have major pathological consequences. Thus neurofilament and actin assembly are disrupted and superoxide dismutase is inactivated. One obvious means by which NO levels could rise and compete with SOD is when iNOS activity increases following infection.
The influence of a number of reactive species on the SO has been studied. Significant effects were anticipated as inflammation, in which the generation of free radicals is a common feature, disrupted the motility pattern of the sphincter  . Indeed a question recently attracting attention has been to what extent, even in the absence of disease, reactive species affect tissues. It has been proposed that tissues could be in a state of "controlled inflammation" and release agents ( e.g. cytokines) normally associated with inflammation i.e. they are primed and ready to deal with potentially harmful challenges , .
Responses to superoxide and/or its metabolites by the SO (opossum) have been recorded  . Superoxide, generated by the addition of xanthine with xanthine oxidase increased the contractile frequency of spontaneously contracting sphincters in vitro. Subsequent addition of SOD and catalase returned the frequency to control values. In contrast, inhibition of these scavenger enzymes with diethyldithiocarbamic acid increased the number of in vitro contractions. Immunostaining has demonstrated SOD and catalase in ganglia situated at the serosal surface of sphincter circular muscle. These observations have led to the view that superoxide alters SO motor function, but that the presence of SOD and catalase in the enteric plexi helps to clear such agents, providing an antioxidant defence mechanism.
H 2 O 2 also has a profound effect on SO motility. It increased both the tonic as well as the frequency and peak amplitude of phasic contractions. The hydroxyl radical ( . OH) was thought to be important, as ethanol, an . OH scavenger, attenuates the toxic response  . H 2 0 2 is produced by and released from neutrophils entering re-oxygenated tissues and adhering to the (vascular) endothelia.
Finally, "ugly" peroxynitrite has been found to (i) decrease the contractile frequency of spontaneously active sphincters, and (ii) increase stimulus-induced (EFS) relaxation of carbachol-precontracted sphincters (opossum)  . Pretreatment with oxyhaemoglobin prevented the latter response, suggesting that either (a) peroxynitrite generates NO, or (b) oxyhaemoglobin binds to peroxynitrite. The final picture has yet to emerge. It is interesting, however, that peroxynitrite can generate stable compounds capable of donating NO on reaction with thiol groups and molecules containing hydroxyl groups 
| 4. Pharmacological agents|| |
Botulinum toxin (BTX)
Recently interest has been focussed on a possible use of BTX to relax the SO in situations where the normal flow of bile through the sphincter is obstructed  . The toxin, protein produced by the anaerobic bacterium Clostridium botulinum, was known to exert potent skeletal neuromuscular blockade, a property exploited successfully in the treatment of several neurological and ophthalmological disorders characterized by abnormal, excessive or inappropriate muscle contractions ,, . BTX exerts its effect at neuromuscular junctions by binding to presynaptic cholinergic nerve terminals, being internalized, and then inhibiting the release of acetylcholine from synaptic vesicles. The question remains as to how? Our understanding of the precise mechanisms by which neurotransmitters are released and how bacterial toxins affect them, although incomplete, has improved considerably over the past decade ,. Exocytosis requires proteins known as SNAREs, localized on vesicle (e.g. synaptobrevin) and target plasma membranes (e.g. syntaxin and SNAP-25), that assemble to form ternary complexes. These proteins are thought to play a critical role in (a) establishing and stabilizing membrane docking and (b) membrane fusion. Clearly if SNARE structure is altered then neurotransmitter release may well be compromised. Interestingly, botulinum toxin protein acts as a zinc-dependent protease and selectively cleaves uncomplexed SNAP-25  with the result that either ternary complex formation is prevented or any complex produced is unstable.
Smooth muscle activity has also been found to be inhibited by botulinum toxin. In the gastrointestinal tract the toxin again interferes with cholinergic signaling. As the control of smooth muscle activity is often dependent on a balance between excitatory cholinergic and inhibitory nerve inputs, the absence of the latter could result in unopposed excitation and abnormal, maintained contractions. Such a mechanism has been proposed as an explanation of the failure of the lower esophageal sphincter to relax with resultant dysphagia in achalasia. It was proposed that botulinum toxin might be beneficial to patients with this condition. Adults with achalasia had botulinum toxin injected with a 5mm sclerotherapy needle into the different quadrants of their lower esophageal sphincters. Good short term results were achieved (90%), although a number relapsed and needed further injections , . Two recent papers have stressed the value of BTX for patients with achalasia. In one it was noted that because of its transient effects, BTX provides a useful and safe means of guiding therapy in atypical or complex achalasia e.g. where it is unclear whether more invasive techniques, such as pneumatic dilation, or surgical myotomy are the correct therapy  . In the other it was reported that BTX injections, repeated as needed, can approximate the benefits of a single pneumatic dilation for up to two years. Furthermore the potential value of this therapy in patients who would tolerate poorly a perforation from pneumatic dilation or complications of surgical oesophagomyotomy was recognized  .
Ano-rectal motility disorders have also been recognized as potentially treatable with BTX. Indeed, its use has resulted in significant improvement for patients with anismus, where inappropriate contraction of the anal sphincters upon straining hinders defecation  . Furthermore, by relieving pain and sphincter spasm, the healing of anal fissures has been facilitated ,, .
The SO was, perhaps an obvious target for studies with BTX. Recurrent upper abdominal pain after cholecystectomy is not uncommon and thought frequently to be due to SO dysfunction resulting in elevated sphincter pressures. In a preliminary report involving two women a single injection of BTX into the SO was found to reduce basal pressures (by 50%) and improve bile flow  . It was recognized that BTX might be clinically useful in two ways. First of all, it could provide a means of selecting patients whose pain is caused by Sphincter of Oddi More Details dysfunction. A simple procedure can be performed at the initial diagnostic ERCP. Sphincterotomy could be avoided in those whose pain does not respond to botulinum toxin  . Secondly, if BTX can be shown to be effective in the long term as well as for the short term relief of symptoms then it may provide a viable and potentially safer therapeutic alternative to sphincterotomy.
A presynaptic action of BTX on the SO, similar to that described in skeletal muscle, has recently been demonstrated using a porcine model  . Contractions induced in vitro by direct stimulation of sphincter smooth muscle with KCl were not affected by either BTX or atropine. In contrast, (a) exogenous acetylcholine-induced contractions were completely inhibited by atropine but not by BTX, and (b) electrical field stimulation caused contractions that were inhibited by both agents
[Figure 11]. As BTX has no postsynaptic anticholinergic effect the toxin must have interfered with the release of endogenous acetylcholine.
A canine model has provided evidence of the prolonged effects of botulinum toxin on the SO  . Reduced basal pressures, phasic wave amplitudes and motility indices were recorded in vivo after toxin injection.
These effects took place within 4-7 days, reaching a maximum in 7-10 days. The amplitudes and motility indices remained low over a period of 28 weeks, although the basal pressure recovered.
Recent advances on neural control of gastrointestinal smooth muscle
The preceding sections of this review have given emphasis to the importance of chemical agents, many of them neurotransmitters, in the control of the SO. We would like to complete this review by considering several aspects of neural control. Four levels for neural control of gastrointestinal function have been recognized i.e. the gut wall itself, prevertebral ganglia, spinal cord, and the brain
[Figure 12]  .
The ganglia of the enteric nervous system (ENS) cannot be regarded simply as relay stations. They form neural networks like those found in the central nervous system (CNS) and are capable of integrating and processing information. The interneurons of the ENS form "logic" circuits that transform sensory information into motor functions.
Control independent of the CNS was implied in an earlier section where CCK was reported to stimulate duodenal afferent neurons projecting to the SO  . Are there other possibilities? A relationship between the sphincter and the gallbladder is an attractive concept. Indeed, it has been suggested that the SO might even "perceive" a full gallbladder and "deliver" bile directly to the duodenum. The increase in sphincter phasic wave frequency recorded with gallbladder filling in the prairie dog (a "pumper")  was consistent with such a view. If emptied, the gallbladder might be filled as a result of the SO offering greater resistance to bile flow.
Mechanical or electrical stimulation of the gallbladder has been shown to produce inhibition of the SO (dog). The former was achieved upon excision of the fundus to introduce a catheter. Passive changes in gallbladder pressure were not effective  . The reflex elicited relayed through the prevertebral coeliac ganglion. Ganglionectomy or section of nerves travelling with the coeliac artery towards the biliary tree abolished the sphincter response. In contrast splanchnic nerve division or vagotomy were without effect. It was not possible to say how great a contribution this CNSindependent reflex played to normal function. The reflex might only be a response to abnormal stimuli. It was, however, tempting to speculate that the reflex might be initiated by contraction of gallbladder smooth muscle and that it was the basis of a physiological response.
Subsequent studies in humans demonstrated that distension of the gallbladder decreased basal pressure and the frequency of SO phasic contractions . After aspirating bile, gallbladders were distended by introducing saline. Overdistension was avoided, the gallbladder pressures recorded being similar to those in animals following a meal. Whether the mechanisms in humans were the same as those in animal mvulcls was not known. However, the rapidity of the response suggested a reflex. Furthermore it was appreciated that damage to neurons integrating the functions of gallbladder and SO could lead to permanently raised basal pressures and SO dysfunction. An earlier report had described relaxation of the SO (feline) when the biliary tree hydrostatic pressure rose from 0-20 cm water in control but not cholecystectomized animals  . The absence of inhibitory effects from the gallbladder could contribute to the pathophysiology of post-cholecystectomy sphincter abnormalities seen in some patients, unmasking defects normally compensated for. The importance of preserving pericholedochal nerves during biliary tract surgery has been stressed.
What are the consequences of gallbladder removal? About 500,000 cholecystectomies in the USA alone are performed annually, the procedure removing the "factory making gallstones"  . With a loss of the bile acid reservoir (a) oro-caecal transit was found to slow, but (b) passage through the colon accelerated  . How might these observations be explained? It was speculated that increased bile acid concentrations in the small intestine might contribute to an ileal brake to minimize their "spilling" into the colon. In contrast, an increased bile acid output and a shift to more diarrheogenic secondary bile acids, affecting both secretory and motor events, might account for more rapid movement in the large bowel. A compensatory increase in common bile duct diameter has also been observed . This was not age-related although increases of 3mm or more in older patients were thought to reflect a weakening of the duct wall.
The effect of cholecystectomy on SO motility was recently investigated in 5 female patients before and 6 months after laparoscopic cholecystectomy for uncomplicated cholelithiasis  . Motility was normal before removal. The most striking finding after cholecystectomy was that pharmacological doses of CCK no longer inhibited phasic activity of the sphincter. The variability of human responses, however, was again exposed in a subsequent study. 10 patients underwent cholecystectomy and subsequently responded to I.V. CCK-OP with decreased frequencies and amplitudes of phasic contraction .
An explanation for the insensitivity to CCK was not easy to provide  . One possibility was that in addition to the loss of gallbladder-induced sphincter responses, the common bile duct was no longer subjected to distension from the enormous flow of bile normally associated with gallbladder contractions. A reflex resulting from increased bile duct pressure causing total inhibition of sphincter phasic contractions has been observed in subjects with gallbladders and 4/7 post-cholecystectomy patients , . It is interesting that such inhibition failed to occur in the others. Altered motility, therefore, occurs in only a fraction of patients (3/7) and could contribute to the pain experienced by some, the susceptible group, post-cholecystectomy. The persistent abdominal pain reported in 25-30% of patients following cholecystectomy may not originate exclusively from the biliary tree. Patients with SO dysfunction type III  undergoing duodenal barostat studies were found to have similar duodenal compliance to control subjects but exhibited duodenal (though not rectal) hyperalgesia  . Such patients were also shown to exhibit increased psychological distress , .
If, eventually, a complete picture of the interrelationships of the gut, specifically the SO, and the nervous system is to be produced several questions need to be addressed. Currently many of them are, at best, only partially answerable, with no data available as regards the sphincter. The questions, some of them clearly overlapping, include:
1. How does the CNS connect to the gut?
2. What parts of the CNS are involved?
3. What informations is sent to the CNS from the gut (are neurons projecting to the CNS separate from those to ENS or do fibers
4. Are there communications between the CNS and immunocompetent cells? Is information from the CNS modified by immunocompetent
cells? How are the functions of the immunocompetent cells altered by input from the CNS?
5. What is the role of stress on CNS output?
Efferent discharges from the brain are via the vagus and descending pathways in the spinal cord to preganglionic sympathetic neurons. The former provides the major pathway. Previously, vagal efferent fibers were thought to synapse directly with enteric motor neurons. Current concepts, however, regard vagal fibers as providing command signals to expanded blocks of integrated circuits within the gut wall. With such organization the ENS can be thought of as a microcomputer having its own independent software, with the CNS providing a larger mainframe
[Figure 13]  .
Noradrenaline, released from postganglionic sympathetic neurons modifies intestinal motility by blocking transmission at cholinergic synapses. However sympathetic axons have also been observed in smooth muscle coats (chiefly circular), suggesting actions at both nervous and muscular levels  . The contribution of each has not been defined.
Vagal pathways to the biliary tree have been studied in dogs. Contractile responses of both SO and gallbladder induced by thoracic vagal stimulation were greatly reduced by ligation of the pyloric sphincter, as were the relaxations recorded after treatment with atropine and sympathetic blockers  .
Extragastric vagal routes were thought, therefore, to play only a minor role. An attempt has been made to determine the central areas involved with vagal control of SO function. Microinjections were made of L-glutamate into the dorsal motor nucleus of the vagus (DMN) of spinal cord-transected animals. It was concluded that inhibitory areas were in caudal portions of the DMN, while those concerned with excitatory events were more widely distributed and included the rostral DMN  .
Vagal efferent discharge is influenced by input from regions other than the gut. Projections from the frontal cortex, the paraventricular nucleus of the hypothalamus, the central nucleus of the amygdala and the bed nucleus of the stria terminals have been described  . The recognition of links with areas processing emotional stimuli (i.e. the limbic system) makes it hardly surprising that an association between some gastrointestinal disorders and emotional states have been found, or that subtle malfunctions in brain circuits could result in functional gastrointestinal disorders (FGID). Indeed antidepressant medication. has been found to relieve some FGID symptoms.
With 4 levels of neural control involved in gastrointestinal activity there are potentially many different ways by which abnormal motility (or sensations) can be generated. These include (a) exaggerated signals from sensitized receptors, (b) malfunctioning brain circuits misinterpreting accurate information, and (c) abnormal reactions of the ENS to commands from higher centers. The concept of silent, as distinct from high or low threshold receptors  , provides a model of how exaggerated signals might be produced. Low threshold receptors respond to innocuous levels of stimulation (distension). In contrast silent receptors no not respond even to the strongest stimulus, but are sensitized by inflammatory mediators so that subsequently even innocuous stimuli produce responses.
A link between emotional states and gut function has been referred to. Certainly psychological factors have a role not only in illness behavior but also in alterations of gut function
[Figure 14] ,, Their possible contribution to the chronic gastrointestinal symptoms of Gulf War veterans, who obviously survived in a highly stressful environment, has been recognized  .
However, not only does stress affect physiological responses, it upregulates (rekindles) a host's reactions to later stress. This has been observed in rats that, after recovery from colitis induced experimentally with trinitrobenzene sulphonic acid, were physically restrained. Such a stress resulted in a considerably increased inflammatory response .
Once inflammation has been established in the gut, a subsequent challenge may induce hypermotility even after inflammation has subsided .
Indeed preexistent life stress and hypochondriasis have been taken to predict which patients, three months after acute gastroenteritis, would fulfil criteria for irritable bowel syndrome (IBS) .
The accuracy of these predictions leads to the question as to whether psychologically susceptible Individuals might be provided with early psychophamacological or psychological treatment to limit their later visceral sensitivity and inflammatory responses. Read (1999)  has discussed how several psychotherapies (e.g. relaxation therapy, hypnosis, biofeedback, cognitive behavioral therapy and analytical psychotherapy) have been/are being used in the treatment of IBS. He observed that while patients do not respond identically such techniques need not be "the last resort of the pharmacologically destitute".
Although neurons affecting (a) smooth muscle activity, both vascular and gastrointestinal and (b) transport across epithelial cells are easy to appreciate, the concept of interrelationships of nerves and the immune system is more difficult to assimilate. Do they exist? One has to consider the possibilities that cells of the immune system alter neuronal function and vice versa. The former requires specialized sensing for specific antigens and the capacity of the ENS "minibrain" to interpret intelligently the signals generated  . Activation of specific programs, needed for coordinated secretion and propulsion to clear an antigenic threat (foodstuffs, toxins and invading organisms), provides an example. The latter would appear to need neurotransmitters affecting specific immune cells. Which cells of the immune system might be involved? Several have been proposed including lymphocytes, polymorphonucleocytes (PMNs) and mast cells  . Interestingly the structural foundation for communication has been established , . Three to four times greater numbers of contacts between enteric nerves and plasma cells were revealed by light microscopy in the mucosa and submucosa of mouse small intestine than would have been expected by chance  . Magnification, using electron microscopy, showed close synaptic contacts between axonal varicosity's and B immunoblasts or plasma cells.
Neurons making contact with intestinal mast cells include vagal afferent fibers. Their intimate contacts with mast cells were demonstrated by injecting DiI into the nodose ganglion to label them, and observing the subsequent appearance of the marker in jejunal villi tips  . A trophic effect of the vagus on mast cells (and plasma cells) has also been suggested  . Three weeks after vagotomy or three months after neonatal capsaicin treatment fewer intestinal mucosal mast cells could be detected.
Mast cells are regarded as the "best understood" of the inflammatory cells  . These cells can be activated in more than one way. Antigens evoke degranulation and the release of a variety of messengers e.g. 5-HT, histamine, prostaglandins, leukotrienes, and platelet activating factor (PAF), cytokines and tryptase (an abundant specific neutral protease serving as a useful marker of mast cell activation  ). In addition, the CNS may activate mast cells. Santos (1998)  has recently provided evidence that intestinal mast cells are activated by stress and suggested that these cells may have a role in stress-related gut dysfunction. The intraluminal release of tryptase and histamine increased in both healthy volunteers and inpatients with food allergy when subjected to a cold presser test.
When mucosal mast cells release inflammatory mediators and elicit hypersensitivity responses (characterized by hypersecretion and strong muscular contractions) their actions on enteric neurons have to be considered. Prostanoids  appear to have a role to play. PGE 2 has recently been shown to have a direct and excitatory action on neurons (AH and S) in the myenteric plexus  providing strong support for the view that PGE 2 functions as a neuromodulator. Functional changes of myenteric neurons during inflammation have also been reported in nematode-infected guinea pigs  . Recordings taken from jejunal neurons, 3-10 days postinfection with Trichinella spiralis, had: - (a) lower resting potentials, (b) increased membrane resistances, (c) decreased thresholds for action potentials, (d) decreased durations and amplitudes of post-spike hyperpolarization, and (e) increased fast EPSP amplitudes and durations, than uninfected controls. This upregulation towards a state of increased excitability occurred concurrently with increased cytochrome oxidase and c-Fos immunoreactivity, indicators of neuronal metabolic and transcriptional-translational activity respectively. These findings indicated a reorganization of intrinsic neurons, possibly for adaptive or host defense purposes.
A final agent, demanding attention when attempting to understand the complex relationships between the immune system, neurons and smooth muscle, is interleukin-4 (IL-4)  . This cytokine, produced by mast cells, T cells and basophils, increased the contractile response of intestinal smooth muscle to cholinergic stimulation. Neuronal sensitivity was enhanced, not muscle sensitivity to acetylcholine. IL-4, therefore, has a role in the expulsion of gastrointestinal parasites. It has been reported that IL-4 also induces mastocytosis and amplifies cholinergic excitation. Leukotriene D4, released from mast cells, contributes to this change in motility. Enhanced contractions were prevented by leukotriene D4 receptor antagonism and were not observed in 5-lipoxygenase knock-out mice.
Reviewing progress made in understanding the mechanisms whereby the SO is controlled has been both an interesting and frustrating task. An ever increasing number of substances have been shown to have effects on the sphincter. For convenience these have been classified as neurotransmitters, hormones, local factors and pharmacological agents although several fit into more than one group. The list is sufficiently large to merit comments as to the clinical value of drugs without effects! In this review attention has been focussed on VIP, NO, CCK and BTX. The first two named are both neurotransmitters inducing relaxation of smooth muscle. After years of heated debate as to the relative importance of each, complex interrelationships of VIP and NO have been described and the concept proposed that both have roles to play. Interestingly, agents now recognized as NO donors were known to be of clinical significance well before the physiological importance of NO was appreciated. Although CCK can directly contract SO smooth muscle, its physiological effect on the sphincter is inhibitory so that bile flow to the duodenum is increased. The physiological response has been explained in terms of the greater sensitivity of the inhibitory neurons to the sphincter than of smooth muscle to CCK. The recent discovery of duodenal sensory neurons, sensitive to CCK and projecting to the SO, provides a possible means of activating sphincter inhibitory neurons apparently unresponsive to the serum [CCK] recorded after a meal. Of the pharmacological agents exerting effects BTX has been the subject of numerous reports. Used successfully to treat several disorders characterized by excessive or inappropriate skeletal muscle contractions, its value in relaxing SO smooth muscle has been investigated. Over the short term it has been proposed that it could be used to identify those patients with pain due to SO dysfunction and, perhaps over longer periods, to provide a safer alternative to sphincterotomy.
Finally, incomplete but hopefully provocative sections of the review have been devoted to smooth muscle contractions and their control. Frustratingly, it was necessary to look at smooth muscle in regions of the gastrointestinal tract other than the SO where information is lacking. It will be interesting to discover how many of the mechanisms currently proposed are applicable to the SO. Models have been described with different mechanisms for tonic and phasic contractions, and explanations given as to how smooth muscle can be controlled in the absence of input from the autonomic nervous system by nonneural pacemakers. The importance of the ICC in this control has recently been stressed with the advent of techniques whereby (i) the ICC were cultured and studied in isolation and (ii) spontaneously mutant mice were produced with absent or deficient ICC networks. To simplify neural control of smooth muscle function four distinct but interrelated levels have been described. These are via the enteric nervous system, prevertebral ganglia, the spinal cord and the brain, none of which can now be regarded as simple relay stations. Indeed, the enteric nervous system has been likened to a microcomputer with its own independent software. Each level is considered able to exert specific effects on smooth muscle. However, because of the relationships between each level, any alteration of activity in one may change the overall effects of the nervous system on motility. Exciting progress is being made, for example, describing how neural activity can be modified by, and can modify the immune system, with the result that gastrointestinal smooth muscle function is altered in response to various challenges. Perhaps, at a different level, the time is approaching when a clearer picture will become available of the influence of "life's stresses" on gastrointestinal motility. Prominent and respected investigators in the field will not then be forced to report that there is very little worthwhile to say.
The excellent artwork of Mr. James R Chu is gratefully appreciated.
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Paul A Sanford
Department of Physiology, College of Medicine, King Saud University, P. 0. Box 2925, Riyadh 11461
[Figure - 10],
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