| Abstract|| |
The mechanisms controlling the sphincter of Oddi (SO) have received considerable attention over the past two decades. Progress towards their elucidation has been slow, perhaps because of the sphincter's relative inaccessibility and the different responses of the human "resistor" as compared to the "pumper" observed in several animal models. The list of agents affecting the sphincter grows alarmingly. In this review, divided into two parts, substances have been classified as neurotransmitters, hormones, local factors and pharmacological agents. The first part considers the roles of neurotransmitters. These include (a) vasoactive intestinal polypeptide (VIP) and nitric oxide (NO). Both cause relaxation. A recent model of their complex interrelationships in smooth muscle is described. (b) Substance P (SP) and enkephalins. These produce contractions. The former can act directly. An indirect effect via cholinergic neurones may be the result of SP release from vagal afferents. (c) Catecholamines, which cause contraction or relaxation via activation of α- or β-adrenoreceptors, respectively. In the second part attention is focussed on cholecystokinin (CCK) which normally relaxes the SO via neuronal mechanisms. A CCK-sensitive pathway from sensory duodenal neurones to SO ganglia has been described. Reactive oxygen species are among the local factors discussed. Their description as being "the good, the bad and the ugly" seems merited. Pharmacological agents include NO donors, octreotide and botulinum toxin (BTX). Octreotide induces tachyoddia and may impair biliary flow. BTX has exciting potential in the diagnosis of SO abnormalities and as a therapeutic alternative to sphincterotomy. In both parts of the review current concepts of different aspects of smooth muscle control are presented. In several instances data regarding the SO is lacking. We discuss (a) the role of interstitial cell of Cajal in the control of slow waves, (b) different pathways contributing to tonic and phasic contractions, (c) the 4 levels of neural control, (d) interrelationships of immune and nervous systems, and (e) links between emotional states and gut functions.
|How to cite this article:|
Ballal MA, Sanford PA. Physiology of the Sphincter of Oddi - the present and the future? - part 1. Saudi J Gastroenterol 2000;6:129-46
This review, in addition to focussing on recent progress made to unravel the complex mechanisms controlling the Sphincter of Oddi More Details (SO), also projects developments in other fields of motility research which will be (are) pertinent to the sphincter. Emphasis is given to the biliary rather than the pancreatic sphincter. The pancreatic and biliary components are assumed to behave physiologically in a similar way  . However, specific regions may be exclusively involved in abnormal responses, and it has been appreciated that selective cannulation may be necessary for complete evaluation of SO disorders. Thus, for example, out of 24 patients with idiopathic recurrent pancreatitis, five had abnormal manometric measurements (elevated basal pressures) localised to the pancreatic duct  .
| Structure of the SO|| |
Less than a quarter of a century ago the question was still being debated as to whether the SO was an anatomical reality. Some regarded the SO as no more than an extension of duodenal smooth muscle even though embryologically it developed independently. Furthermore, its separate functional identity had been illustrated by its contractile responses to morphine and noradrenaline, agents that relaxed the duodenum  .
The oblique nature of the transduodenal sphincter segment raises the question as to whether duodenal contractions help to prevent duodenal contents from flowing into the biliary tree. Certainly they need to be considered along with other potential antireflux characteristics. These include (a) mucus, produced by the lining epithelia and a plethora of glands, (b) luminal folds, and (c) the oblique course of the intramural duct and its narrow opening into the intestinal lumen .
The portal for entry of bile and pancreatic juice in humans has been divided into three parts (i) choledochus, (ii) pancreaticus, and (iii) ampulla (if present). The anatomical arrangement, however, is not constant. Y, V and U configurations have been described, the first of these being by far the most common, the last relatively rare  . Anatomical arrangement is not the only sphincter variable. Attention has recently been drawn to its axial assymmetry as regards pressure measurements  . Higher pressures were recorded dorsally than ventrally. Pressure readings correlated with the greater thickness of the dorsal smooth muscle in both duodenum and SO and provided a warning of potential clinical inaccuracies. This was the first report involving the SO although vectorial assymetry had previously been recognized for the anal sphincter  .
| Physiological Characteristics of Sphincters Acting as 'Pumpers' or 'Resistors'|| |
Probably never in the history of gastroenterology has an anatomical and physiological fording been affirmed and denied by so many, and with such great decisiveness, for such a long time  . This Churchillian-like sentiment, used to describe the sphincter that has a role in:- (a) determining bile/pancreatic flow into the small intestine, (b) regulating gall bladder filling, and (c) preventing reflux of duodenal contents, seems to be merited. Progress has been slow. Indeed, in an impressive review published in 1987 of the extrinsic nervous control of the intestines and related sphincters  , the SO was conspicuous by its absence. One of the problems facing those who would investigate the activities of a structure as enigmatic as the man whose name it bears  has been that two different types of sphincter have been recognized. Those of the American opossum, Australian possum, guinea pig, prairie dog and rabbit are regarded as pumps capable of actively propelling digestive fluids into the duodenum and classified as category I sphincters. In contrast, the SO in human, cat and pig have a more passive role and are classified as resistors or category II sphincters  .
The opossum has been a useful animal model to study active propulsion of bile. In this species the SO measures approximately 3cm in length and is largely extraduodenal. Such anatomy provided the possibility of recording from the SO with negligible interference from duodenal motor activity. The dominant feature recorded was rhythmic peristaltic contractions that originated in the proximal SO and propagated toward the duodenum  . These occurred spontaneously at a rate of 2-8/min, had a duration of -5s and achieved pressures of up to 200 mm Hg. Each contractile wave was preceded by an electrical spike burst from the SO muscularis. Using cineradiography to follow contrast medium in the common bile duct (CBD) and electromyography of the SO it was established that peristaltic contractions stripped contrast medium from the SO into the duodenum. The terms systole and diastole (analogous to the heart) were used to describe the peristaltic contraction and subsequent relaxation phase respectively. During diastole the SO filled passively, a high pressure zone (HPZ) in the distal segment serving as a resistor to outflow. No flow was recorded when the diastolic interval was decreased and frequency of peristaltic waves were >8/min showing, as with heart, the importance of diastolic filling .
Peristaltic waves in the SO (opossum) were not abolished by tetrodotoxin (TTX, a potent neurotoxin that blocks voltage-gated Na channels in excitable tissues), implying the contractions were myogenic in origin. However, TTX decreased the frequency and amplitude of sphincter contractions indicating a role for nerves  . (Furthermore TTX blockade has been shown to increase tone both in vivo (cat)  and in vitro (rabbit)  suggesting that the sphincter is under a dominant inhibitory neural control. Perhaps such inhibition contributes to sphincter autonomy from contracting duodenal smooth muscle).
Characteristics of the pump were studied in vitro  . Preparations of the CBD and an adjacent segment of duodenum were found to propel fluid to the duodenum against a pressure gradient ranging from 10-50cm water. Interestingly, pumping stopped when the CBD pressure had been reduced to 8.5cm water. SO contractions also ceased when CBD pressures rose to values >40-50cm water  . The sphincter remained wide open and flow became passive depending on its diameter and the fluid pressure across it.
The capacity of the opossum SO to move fluid against duodenal pressure gradients was subsequently established in vivo. In contrast, choledochoduodenal flow in cats occurred only along a hydrostatic gradient, the SO never acting as a pump, only as a resistor  .
From the above discussion pumping by the SO depends on the hydrostatic pressure in the CBD. The factors controlling the development of this hydrostatic pressure are (a) the resistance offered by the SO, (b) the capacity of the biliary tree, (c) the volume of bile secreted which ceases when bile duct pressures exceed 24mm Hg  and (d) the volume of water reabsorbed by the gallbladder. Thus the resistance of the SO depends on the CBD hydrostatic pressure and vice versa. How and why might sphincter resistance be altered by changes in the CBD hydrostatic pressure? Too high a pressure could result in tissue damage and pain. One mechanism preventing such a rise was suggested by the finding that distension of the biliary tract activated inhibitory nerves and reduced flow resistance across the SO  . Such a mechanism may be regarded as equivalent to that where mechanical stimulation of the gallbladder decreases SO activity via a reflex relayed through the coeliac ganglion  . Too low a pressure, on the other hand, would limit the effectiveness of the SO in directing flow. This has led to the view that a further and major function of the SO is to maintain a positive CBD pressure and prevent marked variations of biliary duct pressure by adjusting to changes of biliary volume , .
The choledochoduodenal junction, in the guinea pig at least, is not fully developed at birth  . In guinea pig neonates up to 1 week old the sphincter (a) has fewer contractions during fasting than at 4-6 weeks, and (b) does not respond to a meal (Ensure) with increased duration of contractions as have been observed in older animals. Indeed the neonate SO may be incompetent, unlike that in the normal adult, and allow retrograde flow. In animal models reflux does not normally occur  . Reflux was never recorded in either opossum or cat even when intraduodenal pressures were as high as 100cm water  .
In humans reflux constitutes a potential problem after sphincterotomy. A 60-70% incidence of bacteriobilia has been reported at repeated endoscopic retrograde cholangiopancreatography (ERCP)  . Food debris in the CBD also points to duodenal reflux  . Both bacterial overgrowth and the presence of food debris could be major factors in the genesis of cholangitis and stone formation.
A model to explain pumping by the SO has been developed  . It required a linear array of bidirectionally coupled relaxation oscillators, each oscillator driving a more distal one. A high frequency oscillator in proximal regions of the sphincter provided pacemaker activity. Consistent with such a model was the finding that transection through the middle of the opossum SO and re-anastomosis uncouples proximal to distal SO spike bursts . Such a response was anticipated if a dominant proximal oscillator drove those distally located with progressively decreasing intrinsic frequencies.
Let us now turn to the human SO that has been classified as a resistor with alternating changes in tone. As will become clear it is a more dynamic structure than its passive nature suggests. Intraluminal pressure recordings obtained from patients with no demonstrable evidence of pancreaticobiliary disease have shown a segment of the sphincter, length 4-6mm with a basal pressure -4mm Hg higher than measured in the CBD or pancreatic duct (12.4 and 15.7 mm Hg respectively)  . The CBD pressure is approximately 10-15 mm Hg above the duodenal pressure  Superimposed on the basal, steady state pressure were pronounced phasic contractions  [Figure - 1]. Early analyses of the direction of propagation of phasic contractions suggested that the majority (60%) were antegrade towards the duodenum , although others were either simultaneous (25%) or in a retrograde direction (15%). Some investigators have recorded far fewer antegrade waves  and the variability of phasic contractions is apparent in recent published tables for normal subjects , [Table - 1].
In animal models phasic SO contractions obstruct flow from the CBD but propel small volumes of fluid to the duodenum. If antegrade phasic waves are the more frequently recorded in humans what might be their purpose? Do they keep the terminal segment free of obstruction? Do they remove small food particles, sludge and mucus that might otherwise impede bile flow? A housekeeping function in man might also expel small calculi to the duodenum.
To determine the fasting and postprandial motility patterns of the human SO prolonged manometric investigations were necessary. This was anticipated knowing that neither the small intestine nor the gallbladder is quiescent even during fasting. Intense action potential activity and episodes of contraction, detected initially in stomach and duodenum, sweep aborally along the small intestine, another complex starting when the distal ileum is reached. These waves, initially monitored in dogs and lasting 105135 min, have been described as migrating myoelectric complexes (MMCs). Human MMCs have similar but more variable periodicities  . Four phases of electrical activity have been described in the small intestine. Few action potentials were recorded during the relatively quiescent phase I, those observed in phase II being persistent but random. Phase III involved bursts of continuous activity while phase IV was characterized by a rapid decrease in the incidence of action potentials.
Extended studies of the human SO were carried out in post-cholecystectomy patients with indwelling T tubes  . Contractions were omnipresent. During fasting only two phases could be identified. The longer phase A (average 96 min) was characterized by contractions with a frequency of 3/min, a duration of ~5s and mean amplitudes of 79mm Hg. The second phase B, by contrast, lasted only 4.5 min. It was a period of rapid contraction (10.4/min) where the contraction amplitudes were greater than in phase A (101 versus 79mm Hg) although the durations were similar. A significant increase in the basal pressure was also recorded during phase B that persisted into the following early phase A. A close relationship was seen between the phasic contraction patterns of the SO and duodenum. Phase A corresponded to phase I, II and IV of the duodenal MMC. Phase B corresponded to, and usually preceded phase III [Figure - 2], raising the possibility that more resistance would be offered against reflux at a time of greater duodenal contractile activity.
After feeding a nutritionally balanced liquid meal to humans there was a fall in sphincter basal pressure and the amplitude and duration (although not frequency) of the phasic waves  . These changes facilitate the passive flow of digestive juices into the duodenum. A contribution by lipids to this response was established by the finding that the sphincter mean basal pressure fell from 23.4 to 4.4 mm Hg after intraduodenal infusions to 5 healthy volunteers  . These responses are quite different from those of the "pumping" SO (opossum) where food increases contractile activity  . Human sphincter relaxation contrasts with increased duodenal contractions on feeding. This further illustrated the autonomy of the SO, convincingly demonstrated by responses to i.v. CCK during ERCP. CCK produced violent duodenal movements, sometimes pushing the catheter out of Vater's orifice. At the same time a biliopancreatic jet issued through a wide open SO .
| Recent Advances in Smooth Muscle Control|| |
1. The role of intracellular calcium
To understand the effects of numerous agents on the SO the "murky world" of smooth muscle control has to be entered. Considerable progress has been made. Models of signal transduction have been developed e.g. for vascular smooth muscle  . As regards gastrointestinal smooth muscle it has been proposed that (a) the calmodulin pathway participates in the initial stages of phasic contractions and (b) the protein kinase C (PKC) pathway may be responsible for maintenance of tonic contractions [Figure - 3]. Both pathways appear to be involved in SO (rabbit) contractions although a final picture has yet to emerge  . Intracellular free [Ca ++ ] is clearly a major determinant activating contractile machinery. The question arises, therefore, as to how [Ca ++ ]i are regulated bearing in mind that the [Ca ++ ]i is essentially submicromolar in the face of ~1~2mM extracellular concentrations and an estimated total intracellular content of several millimolar. When smooth muscle is stimulated Ca ++ can be released from the sarcoplasmic reticulum via an inositol triphosphate (IP 3 )-regulated channel or by Cainduced Ca ++ release. The IP 3 -dependent process is influenced by the [Ca ++ ] i . If less than 300nM a +ve feedback loop occurs and more Ca ++ is released. However, a negative feedback loop operates above that concentration. Thus a "window" is created in which 1P 3 is effective  .
Little is known of the importance of mitochondria in determining [Ca ++ ]i even though they have the capacity to accumulate the divalent cation. However, a major consequence of mitochondrial uptake is upregulation of energy metabolism. This finding has led to an attractive concept in which a rise of cytoplasmic calcium for contraction (or secretion) results concurrently in increased uptake by mitochondria and modulation of oxidative phosphorylation to satisfy the greater energy demands  .
2. The role of the interstitial cells of Cajal (ICC)
A sphincter with myogenic properties has been described. Its actions, although altered, are not abolished by TTX. The question arises, therefore, as to its control in the absence of neural input. Contractions are under the control of slow waves  . These are one of the three basic types of electrical membrane potential generated by gastrointestinal smooth muscle, the others being resting membrane potentials and action potentials. Slow waves are oscillations of longer duration and smaller amplitude than action potentials. Their involvement in SO control were suggested (a) by their close correlation with contraction waves (opossum)  and (b) when the intervals between the peaks of phasic waves were found to be 3.5s or multiples thereof (dog)  . The slow waves do not trigger contractions  but increase and decrease excitability so that a contraction in response to a stimulus is more or less likely. How and where are slow waves generated? The situation in the SO is unclear. Exciting progress has been made, however, in other gastrointestinal smooth muscle where evidence is mounting that subsets of the interstitial cells of Cajal (ICC) are non-neural pacemakers of the electrical slow waves ,, . ICC are developed from mesenchymal cells, not the neural crest.
Several types of study have pointed to the ICC having a pacemaker role. Electrophysiological measurements taken from strips of smooth muscle have shown that slow waves originate from specific sites that are populated by ICC networks  . These cells make gap junctions with adjacent smooth muscle cells, structures that Thuneberg (1982)  recognized might provide a means of conduction. In humans, conduction may depend more on the apposition of cell membranes providing capacitance coupling because there is a paucity of gap junctions  . Furthermore, agents such as methylene blue and rhodamine 123, that can be selectively accumulated by ICC, have been used to cause structural damage and disrupt electrical rhythmicity  . Another approach indicating the importance of ICC has been to study gastrointestinal motility in viable, spontaneous mutant mice where the ICC are lacking (W/W v ) or absent (Sl/Sl d) . W/W v mice produce propulsive contractile activity without slow wave activity. However, propagation is irregular and not predictable and there is no mechanism to restrict propulsion to an aboral direction  . The fact that Sl/Sl d mice survive suggests that the remaining neuromuscular apparatus may be able to compensate partially for the loss of the ICC 
The exact contribution of ICC to gastrointestinal motility has been difficult to determine. There are several reasons for this. One is that the ICC form part of an electrically coupled network of cells that includes smooth muscle cells. The electrical activity of any one cell is likely to be strongly influenced by its neighbours. Similarly, the properties of ICC may be altered by intimately associated, dense neural networks. The idea has been repeatedly expressed that the ICC are intercalated between enteric smooth muscle and the enteric nervous system, acting as primitive neurones. Indeed it has been suggested that ICC might (a) facilitate active propagation of electrical events within the gastrointestinal tract and (b) mediate transmission ' as well as have a pacemaker role  . It was important, therefore, to investigate the unique, intrinsic characteristics of the ICC. Recently it has been possible to isolate and culture ICC from mouse small intestine ,, [Figure - 4] and stomach  and study their intrinsic properties. Intestinal ICC were shown to exhibit spontaneous, rhythmic inward currents and slow wave activity that had many of the characteristics of slow waves recorded in tissues. Cultured gastric smooth muscle from the antrum and corpus could not be paced by direct electrical stimulation nor could acetylcholine elicit slow waves  supporting the view that the ICC are essential for slow wave activity. While coupled and part of a syncitium ICC and smooth muscle from both intestine and stomach produce distinctly different electrical events , Furthermore, in contrast to smooth muscle cells the ICC were relatively insensitive to (a) L-type Ca ++ channel blockers and (b) hyperpolarization.
ICC develop from mesenchymal cells that express c-Kit, one of a large family of tyrosine kinase receptors, molecules involved in cellular growth and differentiation. C-Kit is a transmembrane molecule with an extracellular domain containing a receptor for stem cell factor (SCF, steel factor), its natural ligand. Neurones appear to be a major source of SCF  and whether the full functional phenotype of ICC develop in the absence of this protein ligand  is not clear. The intracellular domain has tyrosine kinase activity and sites for cytoplasmic signalling proteins. Binding of SCF activates the tyrosine kinase, resulting in autophosphorylation of tyrosine residues, binding of enzymes e.g. phospholipase C, and the initiation of a phosphorylation cascade influencing such functions as growth, differentiation and cell migration. ICC, detectable during the embryonic period, and smooth muscle cells have common precursor mesenchymal cells. Whether cells become smooth muscle or ICC depends on signalling via c-Kit. It would be interesting to know why only some precursor cells develop into ICC. The question has been raised as to what role c-Kit receptors have to play in functionally developed ICC  . An answer was sought using the anti-kit monoclonal antibody ACK2. The ICC were found almost totally to disappear although apoptosis was not detected in the regions where ICC are normally distributed. The remaining cells developed ultrastructural features similar to smooth muscle cells. These included prominent filament bundles, expression of musclespecific intermediate filament protein, desmin, and smooth muscle myosin. Kit signalling may, therefore, stabilise the ICC and be important for their long term maintenance  . An inherent plasticity between smooth muscle and ICC is suggested and raises the intriguing possibility of shifting the phenotype towards ICC in situations where the ICC are lacking.
An association between malfunctioning ICC and several motility disorders e.g. chronic idiopathic pseudoobstrucion, Hirschsprung's disease and infantile hypertrophic pyloric stenosis (IHPS) has been proposed. IHPS is a common pediatric disease and in specimens taken from 27 infants (aged 2-7 weeks) a lack of ICC was noted as compared with the numerous cells showing c-kit immunoreactivity in the normal pylorus  . It would, perhaps, be surprising if reports of a similar situation in the SO were not to appear particularly as attention is being focussed on panenteric motility disorders ,,,, . Furthermore, the concept of motor abnormalities because of damage to the ICC during inflammation is gaining acceptance  . During a Trichinella spiralis infection intestinal ICC were the first cells to undergo structural changes .
If ICC are the pacemakers of the SO, what determines whether antegrade, retrograde or simulataneous phasic contractions occur? Are there specific signals from enteric neurones or immune cells causing different parts of the ICC network to become dominant? Such a change would be analogous to the shift in dominant pacemaker cells within the s.a. node as a consequence of altered symathetic/parasympathetic input  . Or is there a relative instability of the ICC network so that different regions transiently assume pacemaker functions? Perhaps the human SO has less vectorial organisation than in those species with "pumping" sphincters.
| Chemical Control of the SO|| |
A bewildering array of substances regarded as neurotransmitters, hormones, factors produced and released locally, and pharmacological agents have been found to alter the motility of the SO [Figure - 5]. As so many agents exert effects attention has been focused on those without influence that could be used in clinical investigations of SO function e.g. diazepam  and propofol  . Some of the agents influencing SO activity do not fit conveniently into any one, single category. Some of them are produced in the body but exert effects only when administered in supraphysiological amounts. This does not necessarily reduce their clinical relevance. Thus, for example, while a physiological role for glucagon has been controversial  , the hormone has been useful in relieving SO spasm  and can exert similar effects to cholecystokinin-octapeptide (CCK-OP)  [Figure - 6]. (N.B. glucagon, given i.v. intermittently has been used to maintain duodenal ileus during ERCP  .
Neurotransmitters are derived from two principal neurone populations in the SO. One population is immunoreactive for excitatory agents e.g. acetylcholine (ACh), substance P (SP) and enkephalins, the other for agents eliciting inhibitory responses e.g. nitric oxide (NO) and vasoactive intestinal polypeptide (VIP). If excitatory cholinergic neurones were blocked by atropine the inhibitory nonadrenergic, noncholinergic (NANC) innervation was uncovered , . ACh and NO, at least, are not released by the same neurones. Coexpression of choline acetyltransferase (ChAT), necessary for acetylcholine synthesis, and nitric oxide synthase (NOS) was not observed .
A. Substance P (SP)
The tachykinin SP has several effects on smooth muscle in the gastrointestinal tract. In the gallbladder, for example, the peptide has a direct action  and modulates gallbladder neuronal activity, causing partial depolarization (slow excitatory post synaptic potentials, slow EPSPs) of postsynaptic neurones ,, . These electrical changes do not produce action potentials and gallbladder contractions but "prime" postsynaptic neurones and facilitate ganglionic transmission .
Both direct and indirect effects of SP on the SO were anticipated when SP-IR neurones were found in smooth muscle layers as well as adjacent to acetylcholinesterase-+ve ganglion cells , . Evidence consistent with this expectation has been obtained. Thus exogenous SP induced SO contraction by a mechanism resistant to atropine but sensitive to an antagonistic SP analogue. In contrast, electrical stimulation of the efferent vagus elicited a contraction that was sensitive to both agents . It was not possible to eliminate a vagal afferent source of SP in the sphincter  . Thus it is tempting to speculate that SP, released from extrinsic afferent neurones might provide a mechanism whereby local stimuli could induce rapid local responses similar to those described in the gallbladder  . Further evidence for a direct contractile effect on the SO (possum) was the fmding that close infra-arterial injection of SP elevated basal pressures and reduced transsphincteric flow, parameters unaffected by TTX  . No changes in phasic contractions were recorded (possum). This contrasted to a preliminary investigation of the porcine SO (a model with features similar to human) in which both the amplitude and frequency of phasic contractions increased in response to SP administered intravenously  .
The potent action of morphine causing spasm of the SO and substantial increases in intrabiliary pressure led to enquiries as to the effects of enkephalins. These are endogenous opioid peptides, regarded as the body's own morphines. The presence of an extensive enkephalinergic innervation in the gastrointestinal tract suggested that they might play a role in the regulation of normal gut motility  . Leucine-enkephalin (a pentapeptide with leucine at the carboxyl terminus) caused neurally-mediated initial contractions followed by more prolonged relaxation of the SO (cat)  . These effects were antagonized (a) partially by atropine and methysergide (an ergot derivative blocking 5hydroxytryptamine (5-HT, serotonin) receptors), and (b) completely by a combination of the two drugs, TTX, 5-HT depletion induced using reserpine and 5HT tachyphylaxis. Thus a dual action of opiates was exposed, both involving neural pathways. The excitatory response was best explained by enkephalins acting directly on intramural 5-HT neurones, these in turn stimulating postganglionic cholinergic neurones and, consequently, causing the contraction of sphincter smooth muscle. The inhibitory response could only be blocked by TTX and its physiological role was unknown. However, the pharmacological potential of opiate-like compounds in providing both analgesia and relaxation of the SO in patients with common duct stones or SO dyskinesia was noted.
Enkephalins were thought not to contribute to basal sphincter tone (cat)  . Naloxone (a pure competitive antagonist of all opioid receptors but with no agonist activity)  was without effect. In contrast the frequencies of phasic contractions were raised by leucine-enkephalin (and ketamine, the phencyclidine derivative). Both pancreatic and biliary sphincters had the same response. The SO has the capacity to break down enkephalins. An enkephalinase has been detected and its inhibitor, acetorphan, produced a naloxone-sensitive contraction  . The picture, however, has been confused by the finding that thiorphan, an enkephalinase inhibitor not readily penetrating the blood-brain barrier, was without effect suggesting a more pronounced central effect of the peptide.
Immunoreactivities for enkephalin-endorphin (ENK-END) were subsequently demonstrated in the ganglionated plexus of the SO (guinea pig)  . Approximately half the sphincter neurones expressed immunoreactivity for both SP and ENK-END. Evidence was also forthcoming for enkephalinergic SO. control in man  . Patients with post cholecystectomy pain and symptoms suggesting SO dysfunction responded to the opiate modulator trimebutine.
C. Vasoactive intestinal polypeptide (VIP)
Non-adrenergic, non-cholinergic (NANC) neurones induce SO relaxation. VIP has been regarded as a major inhibitory neurotransmitter in NANC neurones and thought to mediate the relaxant effects of CCK , . Certainly the circular smooth muscle of the sphincter (cat) has a rich VIPergic innervation  . Futhermore administration of VIP antiserum inhibited SO responses to CCK-OP. However, the subsequent discovery of NO (see below) led to controversy as to the relative contributions of VIP and NO. The concept has now emerged of interactions of VIP and NO and both having roles to play  . A contribution of VIP, independent of NO, was suggested by the finding that inhibition of NO synthesis by L-NAME [Figure - 7] did not affect electrical field stimulation (EFS)induced relaxation in some SO preparations (possum) .
The possibility of harnessing the relaxant properties of VIP for patients with abnormalities of sphincter function has been recognized. Low frequency transcutaneous electrical nerve stimulation (TENS) in patients with biliary dyskinesia decreased SO basal pressure. This was accompanied by a rise in plasma [VIP], an increase assumed to represent "an overflow of neuronal release" from different tissues  . One might question how, and from which specific neurones, such a stimulus releases VIP (or other co-localized neurotransmitters). In healthy volunteers no significant changes to SO were recorded although VIP levels rose. One proposal considered was that VIP released under these conditions only exerted a neuromodulatory effect in tissues where VIPergic neurones were selectively damaged or where the concentrations of VIP were reduced. It is interesting that TENS also improved relaxation of the lower oesophageal sphincter in patients with achalasia where VIP-containing neurones are fewer .
D. Nitric oxide (NO)
This ubiquitous intercellular messenger has, over the past decade, been the focus of an amazing number of investigations. It has a variety of actions, one of which is to relax both vascular and gastrointestinal smooth muscle. NO is synthesized from L-arginine by a stereospecific action catalyzed by a family of nitric oxide synthases [Figure - 7]. Three isozymes, nNOS (neuronal, Type I), eNOS (endothelial, Type III) and iNOS (inducible, Type II) have been identified , . As their names suggest they were intially purified and cloned from neuronal tissue, vascular endothelia and an immunoactivated macrophage line, respectively. However, all of them are more widely distributed. 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  . The Ca ++ -independent iNOS can be induced. Numerous agents, including bacterial lipopolysaccharide and the cytokines interleukin-1 β, γ interferon and tumor necrosis factor-α, are able to increase iNOS activity. All of these enzymes could potentially contribute to NO production in the SO.
The technology has now become available whereby specific genes can be deleted from animals. It has been possible to generate "knockout" mice lacking nNOS, eNOS and iNOS and, therefore, begin:- (i) to appreciate the different roles of NO from various sources, (ii) to identify redundant and compensatory pathways, and (iii) to determine the consequences of life-long deficiency.
Thus, for example, nNOS-deficient animals were found to develop gastric dilation and stasis and those lacking iNOS were more susceptible to inflammatory damage  . This is interesting in view of the proposal that excess NO derived from iNOS promotes inflammation and tissue injury. Levels of the inducible form are raised in haemorrhagic shock. Means of removing excess NO while preserving basal beneficial levels have, therefore, been sought in the hope of overcoming the outcome of resuscitation after haemorrhage. One compound, designed to scavenge excess extracellular NO and potentially reduce toxicity, is NOX, a water-soluble dithiocarbamate. Treatment with NOX decreased liver injury (as reflected by elevated plasma ornithine carbamoyltransferase levels) in rats after haemorrhagic shock and increased their 24 hour survival  .
NO from its various sources acts locally. It cannot be transported in blood because it reacts with oxyhaemoglobin to form nitrate. Furthermore, it is far less reactive and less toxic than in vitro studies would have us believe because in vitro there is no drain to remove  . However, toxicity is greatly increased if NO combines with superoxide to produce peroxinitrite (ONOO") (see below).
A contribution from NO in SO control was anticipated. Certainly NO-producing nerves have been demonstrated throughout the biliary tree and are more abundant in the SO than the gallbladder  . Most of the neuronal cell bodies in the SO (cat) were positive for NADPH diaphorase, an enzyme that colocalizes with NOS and is an accurate marker for NOS immunoreactivity , . Indeed a third of the myenteric plexus neuronal population in children was NADPH diaphorase +ve  .
A number of in vitro studies suggested a role for NO , . Relaxation of the possum or guinea pig SO induced by EFS and blocked by TTX could be reduced by L-NAME. NO released from neurones, rather than produced within sphincter muscle cells, appeared more likely as oxyhaemoglobin, which is, unlikely to penetrate smooth muscle cells, reduced the EFS response of the possum sphincter  .
Support was also gained from in vivo investigations. Thus:- (a) L-NAME increased SO resting tone (rabbit, guinea pig, opossum) , , (b) L-NAME increased the sphincter motility index (prairie dogs), a parameter calculated from the product of phasic wave amplitude and frequency  , (c) in the opossum model the frequency of contractions decreased after i.v. administration of recombinant human haemoglobin (rHbl.1)  and (d) a dose-dependent increase in sphincter resistance caused by the NOS inhibitor N G -nitro-L-arginine in anaethetized cats was recorded, an effect reversed stereospecifically by L-arginine  .
Although many have favoured the concept of NO as a final inhibitory transmitter  others were careful not to ignore the possibility that VIP, released from motor neurones, caused in turn the release of NO from smooth muscle cells  . A recent mode1  showing the complex interrelationships of VIP and NO in producing smooth muscle relaxation is presented in [Figure - 8]. Indeed, this picture is probably an oversimplification. Inhibitory transmission in the gastric fundus (guinea pig) is thought to represent the combined actions of VIP, NO and the recently discovered pituitary adenylate cyclase-activating polypeptide (PACAP)  . PACAP, generated in 2 biologically ' active forms (PACAP38 and PACAP27), has substantial similarities to VIP and also exerts potent relaxant effects on smooth muscle  . It activates 3 receptor subtypes that have different affinities for VIP and is, therefore, not likely to produce identical responses.
Nitric oxide donors
For many years before the physiological importance of NO was appreciated, agents now regarded as NO donors had clinically been valuable. They have some effect on almost all smooth muscle. Some had maintained a dominant position among vasodilators for over a hundred years  . In the biliary tree (a) amyl nitrite was a useful agent to distinguish between SO stenosis (narrowing) and spasm  , and (b) glyceryl trinitrate (GTN, nitroglycerin) rapidly reduced both basal and phasic sphincter pressures.
In 1983 Bar-Meir et a1  reported the case of a 64 year old female patient who 5 years postcholecystectomy presented with recurrent right upper quadrant abdominal pain. ERCP revealed elevated SO basal pressures (43 mm Hg) and phasic pressures at the upper limit of normal (158 mm Hg). She responded rapidly to sublingual GTN. Pain disappeared and both basal and phasic pressures fell. Subsequent long-acting nitrate therapy with isosorbide dinitrate enabled the patient to be free of symptoms for a year.
Organic nitrites and nitrates were subsequently found to release NO. However:- (a) nitrites and nitrates are not pharmacologically identical  , (b) the form of NO released is important in determining its effects (NO+, NO. and NO- are redox forms)  , (c) NO donors may elicit effects more complex than can be explained by the production of NO  , and (d) the pathways leading to NO formation and the kinetics of its release differ greatly among individual compound classes. The importance of the cytochrome P450 system in NO formation from isosorbide dinitrate  and xanthine oxidoreductase in NO production under hypoxic conditions  has been reported.
Animal studies established that amyl nitrite, isosorbide dinitrate and sodium nitroprusside (an unstable agent releasing NO on exposure to light or alkaline conditions) decreased both (a) the initial rapid rise and (b) the frequency and amplitude of the tachyrhythmia (>9 waves/min) produced by ACh administration to guinea pig isolated SO. In contrast methylene blue, a soluble guanylate cyclase inhibitor preventing cGMP production, increased the frequency and amplitude of the peristaltic waves  .
NO donors have been put to several uses clinically although their benefits when administered sublingually are limited because of their potential side effects (headache and hypotension). Their topical administration decreases SO motility during endoscopy , . Common bile duct stones between 5-12mm diameter have been removed from intact papillae after SO relaxation with GTN without resort to sphincterotomy  . GTN can even overcome the drastic contractile effects of morphine . After cholecystectomy approximately 5% of patients experience recurrent biliary pain. This is episodic in nature and may reflect a SO dyskinesia not revealed during ERCP. Special provocation tests e.g. the prostigmine-morphine (Nardi) test, were introduced to mimic the pathophysiological condition occurring postprandially in those with SO dyskinesia. Nine female patients responded to prostigmine-morphine with marked spasm visualized by quantitative hepatobiliary scintigraphy (QHBS) and the appearance of typical biliary pain. Infusion of GTN overcame the morphine response.
Recently attempts have been made to stimulate endogenous NO production by the SO with the view to relieving spasm or permitting easier catheter introduction. In animal models (cat and rabbit) somatothermal stimulation resulted in sphincter relaxation, a response that was blocked by pretreatment with a NOS inhibitor . Different SO types (a - "pumper" and a "resistor") were, therefore, affected by a heat-sensitive neural release of NO. Chiu (1998)  reports that a similar mechanism may occur in humans. Application of local heat by pads to the right subcostal region produced obvious inhibitory responses. Thus, a simple procedure may be available to augment NO production using a protocol reminiscent of the old approach for the treatment of visceral pain. (N.B. Somatic electrical nerve stimulation (SENS) in the 6 th and 7 th intercostal spaces (right midclavicular line) was also found to induce inhibitory SO responses (cat)  and potentially provide an easily applicable method of regulating motility of patients who have hyperactive SO function).
The beneficial effects of nitrates in supplying NO (or nitrosothiol)  to the vascular wall in cardiovascular disease have to be tempered with the rapid development of nitrate tolerance. The mechanisms underlying this tolerance are not well defined. One suggestion that has gained support is that cellular events initiated by the increased circulating levels of angiotensin II, produced during prolonged nitrate treatment, attenuate vasodilator effects  . A recent report raises the question as to whether nitrates might similarly affect the capacity of the SO to relax  . In vitro, at least, tolerance to GTN was found to impair NANC relaxation of the sphincter (rabbit).
E. Acetylcholine and catecholamines
The concept has already been introduced of sphincter smooth muscle with myogenic properties being modified by 2 neurone populations, one excitatory (cholinergic, coexpressing tachykinin and opiate peptides) the other inhibitory (expressing NOS but not ChAT)  .
Neurones within the sphincter have been further classified as either tonic or phasic. The tonic cells were the most frequently encountered and similar to S/Dogiel type I cells of the small intestine. Might these cells contribute to the maintenance of a persistent contractile state?  The phasic neurones could be either excitatory or inhibitory.
These neurones/muscles (directly or indirectly) receive input from intrinsic circuits but also from extrinsic sympathetic and vagal efferent nerves. One must ask what influence these extrinsic nerves may exert and their significance. Electrical stimulation of efferent vagal fibres elicited contractile responses . The vagus, however, appeared to make little contribution to fasting motility as vagotomy had no effect , . The vagal contractile responses were blocked by atropine of an antagonistic SP analogue. One explanation of these results was that postganglionic cholinergic neurones were activated via SP neurons  . An afferent mechanism could not be excluded for the SP response. Release of SP from vagal afferents !night result in activation of intrinsic cholinergic neurones providing a response analogous to that described in gallbladder, urinary bladder and stomach  .
The contribution of catecholamines to SO control has also been studied. Sympathomimetic drugs can dilate  . Non-selective stimulation of β-receptors (isoprenaline) or selective β2 -adrenoceptor activation (terbutaline) caused a relaxation that could be antagonized by propranolol. The effect of adrenergic agents, however, on a molar basis was 40-50 times less potent than that of VIP  . An increased basal tone in the presence of β-adrenoceptor antagonists suggested some tonic inhibition exerted via β-adrenoceptors.
More emphasis has recently been put on discovering the role of α-adrenergic receptors. The areas of densest catecholaminergic innervation are within the sphincter intrinsic ganglionated plexus (although the musculature contains some fibres)  . Their activation appeared to increase tone  . Neurones immunoreactive . for tyrosine hydroxylase and dopamine β hydroxylase, two of the enzymes involved in noradrenalme production have been detected  . Furthermore, (a) exogenous noradrenaline inhibited EPSPs and caused generation of IPSPs in SO ganglia, responses that were mimicked by an adrenergic agonist (UK14304) but inhibited by an α2-adrenoreceptor antagonist (idazoxan), (b) release of endogenous catecholamines by tyramine produced similar responses to those recorded with exogenous noradrenaline, and (c) blockade of catecholamine reuptake, using desipramine, enhanced IPSPs. These findings supported the view that noradrenaline released from nerve terminals in the SO acts in two ways, presynaptically on a 2 -adrenoreceptors to block acetylcholine release and postsynaptically, again on α2-adrenoreceptors, to mediate IPSPs [Figure - 9]. A presynaptic action has been well established in other regions of the gastrointestinal tract e.g. stomach, gallbladder and small intestine , . It has been speculated that effects postsynaptically might suppress ongoing inhibitory motor output from SO ganglia and increase tone  .
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Paul A Sanford
Department of Physiology, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8], [Figure - 9]
[Table - 1]