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References 47

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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polarized distribution of Ca2+- sensitive Ca2+ release sites: mechanisms of unidirectional Ca

waves. J Cell Biol

2002;158:283–292.

32 Cancela JM, Van Coppenolle F, Galione A, Tepikin AV,

Petersen OH. Transformation of local Ca

transients: the combinatorial roles of multiple Ca2+

spikes to global

releasing messengers. EMBO J 2002;21:909–919.

33 Maruyama Y, Petersen OH. Delay in granular fusion

evoked by repetitive cytosolic Ca

spikes in mouse

pancreatic acinar cells. Cell Calcium 1994;16:419–430.

34 Futatsugi A, Nakamura T, Yamada MK etal. IP

receptor

types 2 and 3mediate exocrine secretion underlying energy metabolism. Science 2005;309:2232–2234.

35 Wakui M, Osipchuk YV, Petersen OH. Receptor- activated

spiking mediated by inositol trisphosphate is due to

- induced Ca2+ release. Cell 1990;63:1025–1032.

36 Cancela JM, Gerasimenko OV, Gerasimenko JV, Tepikin

AV, Petersen OH. Two different but converging messenger pathways to intracellular Ca cADPR and IP

. EMBO J 2000;19:2549–2557.

release: the roles of NAADP,

37 Petersen OH, Petersen CCH, Kasai H. Calcium and

hormone action. Annu Rev Physiol 1994;56:297–319.

38 Nicotera P, Bellomo G, Orrenius S. Calcium- mediated

mechanisms in chemically-

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Pharmacol Toxicol 1992;32:449–470.

39 Belan PV, Gerasimenko OV, Tepikin AV, Petersen OH.

Localization of Ca

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cells. J Biol Chem 1996;271:7615–7619.

40 Park MK, Ashby MC, Erdemli G, Petersen OH, Tepikin

AV. Perinuclear, perigranular and sub-

plasmalemmal mitochondria have distinct functions in the regulation of cellular calcium transport. EMBO J 2001;20:1863–1874.

41 Gerasimenko JV, Gryshchenko O, Ferdek PE etal. Ca

activated Ca

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channel blockade as a potential tool

in antipancreatitis therapy. Proc Natl Acad Sci U S A 2013;110:13186–13191.

42 Wen L, Voronina S, Javed MA etal. Inhibitors of ORAI1

prevent cytosolic calcium-

associated injury of human pancreatic acinar cells and acute pancreatitis in 3mouse models. Gastroenterology 2015;149:481–492.

43 Waldron RT, Chen Y, Pham H etal. The Orai Ca

channel inhibitor CM4620 targets both parenchymal and immune cells to reduce inflammation in experimental acute pancreatitis. J Physiol 2019;597:3085–3105.

44 Gryshchenko O, Gerasimenko JV, Petersen OH,

Gerasimenko OV. Calcium signaling in pancreatic immune cells in situ. Function 2021;2:zqaa026.

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46 Criddle DN, Murphy J, Fistetto G etal. Fatty acid ethyl

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47 Burgoyne RD, Morgan A. Secretory granule exocytosis.

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48 Park MK, Petersen OH, Tepikin AV. The endoplasmic

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49 Park MK, Lomax RB, Tepikin AV, Petersen OH. Local

uncaging of caged Ca activated Cl

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50 Petersen OH, Findlay I, Iwatsuki N etal. Human

pancreatic acinar cells: studies of stimulus–secretion coupling. Gastroenterology 1985;89:109–117.

51 Murphy JA, Criddle DN, Sherwood M etal. Direct

activation of cytosolic Ca

signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells. Gastroenterology 2008;135:632–641.

52 Voronina SG, Barrow SL, Simpson AWM etal. Dynamic

changes in cytosolic and mitochondrial ATP levels in pancreatic acinar cells. Gastroenterology 2010;138:1976–1987.

53 Petersen OH, Verkhratsky A. Calcium and adenosine

triphosphate control multiple vital functions. Phil Trans R Soc B 2016;371:20150418.

54 Huang W, Cane MC, Mukherjee R etal. Caffeine protects

against experimental acute pancreatitis by inhibition of inositol 1,4,5- trisphosphate receptor- mediated Ca

release. Gut 2017;66:301–313.

55 Mukherjee R, Mareninova OA, Odinokova IV etal.

Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP. Gut 2016;65:1333–1346.

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Physiology ofDuct Cell Secretion

Wei- Yin Lin, Paramita Sarkar, and Shmuel Muallem

Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

Introduction

The cardinal function of the pancreatic duct is fluid and

–

HCO electrolyte composition of the pancreatic juice and guards the acinar cells against damage by various stressors. Indeed, ductal fluid and electrolyte transport is compromised in diseases such as cystic fibrosis and pancreatitis, which stress the pancreas [1]. Ductal secretion is coupled to acinar secretion that provides the small volume of isotonic, plasma- like fluid. The ducts then secrete the bulk of the fluid into the pancreatic juice making economical and recirculating use of the electrolytes in primary fluid secreted by acinar cells. Thus, for a better understanding of ductal secretion and physiology, first we have to understand the mechanism of acinar secretion and its regulation. Selective transporters in acinar and duct cells mediate vectorial transport of osmotically active ions to generate and secrete fluid of defined composition. Ductal and acinar cells secretion is highly regulated at both the resting and secreting states by multiple inputs that transmit their signals through the two main second messengers Ca grated into a final response with synergized high fidelity. Other important regulators of the entire secretory process are the transported ions. This is highlighted in the regulation of ductal transporters and secretion by intracellular Cl–  [2]. This chapter discusses the principles of ductal fluid and HCO regulation and how they can be corrected in pancreatic disease states.

secretion, which determines the volume and

and cAMP. The Ca2+ and cAMP inputs are inte-

–

secretion and its

Sequential Secretion by Acinar andDuct Cells

Fluid andElectrolyte Secretion by Acinar Cell

Pancreatic fluid and electrolyte secretion is a two- step, sequential process. The acinar cells secrete a small volume of isotonic, NaCl- rich fluid. Whereas, the duct produces most of the fluid and determines the final ion composition of the pancreatic juice[3]. Understanding ductal secretion requires an understanding of acinar cells secretion. The key transporters and the mechanism of fluid secretion by acinar cells are modeled in Fig.5.1. Vectorial ion transport depends on the Na+ and K+ gradients and the membrane potential that are set by the basolateral Na+/K+ ATPase pump[4]. The Ca2+- activated K+ channel at the basolateral membrane Kcnma1 sets the membrane potential near the K+ diffusion potential of about – 60 mV [5]. About 60–70% of acinar cells salt uptake is mediated by the ubiquitous basolateral Na+/ K+/2Cl– cotransporter NKCC1[3]. The remaining salt is absorbed by the basolateral Na+/H+ exchanger NHE1 and by a Cl assumed that the ubiquitous AE2 mediates the Cl– / HCO

salivary glands, AE4, which functions as a cation- driven Cl– /HCO

–

exchange that supports fluid flux. However, in

–

exchanger[6], mediates part of the Cl– influx

necessary for fluid secretion [7]. NHE1 and AE2 also control the cytoplasmic pH (pHin) to prevent large fluctuations in pHin during the secretion[8,9]. Under resting conditions NKCC1, AE2, and AE4maintain intracellular

–

Cl– (Cl

) at 40–60 mM[10]. The importance of Cl

/HCO

–

exchange activity. It is generally

–

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Figure5.1 Mechanism of fluid and electrolyte secretion by acinar

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cells. The model shows the key transporters and the relationships between them that mediate the bulk of fluid and electrolyte secretion by acinar cells. Key regulation of acinar fluid and electrolyte secretion take place by assembly of Ca signaling complexes at the apical pole to control the function of ANO1 and K

channels.

and cAMP

discussed below in relation to regulation of the secretory process. Cl– exits across the luminal membrane through the Ca2+- activated Cl– channel TMEM16A/Ano1 [11] and water flows through the water channel AQP8[12]. The tight junction on acinar cells is the main route of paracellular Na+ flux, which may be mediated by one of the acinar claudins[13].

Acinar cells fluid and electrolyte secretion is regulated by Gq- coupled receptors that increase free cytoplasmic Ca2+ ([Ca2+]i) and is enhanced by the cAMP/PKA pathway. To prevent Ca2+ toxicity by stronger stimulation, only 1–5% of the Gq pool evoke Ca2+ oscillations under physiological stimulation. The Ca2+ oscillations initiate and remain confined to the apical pole [14], although they can propagate to the basal pole[15,16]. Acinar cell secretion starts by an increase in apical [Ca2+]i to activate Ano1[11], and K+ channels in the basal[17] and maybe apical poles[18]. This leads to Cl– efflux into the luminal space and K+ efflux into the interstitial space. Na+ transport through the tight junctions results in the net

Sequential Secretion by Acinar andDuct Cells 49

secretion of NaCl and generation of an osmotic gradient that drives water flow through the water channel Aqp8, leading to cell shrinkage. Cell shrinkage reduces [Ca

]i and activates the volume- sensitive cotransporters NKCC1[19], NHE1[20], AE2[21], and perhaps AE4 to recover cytoplasmic electrolytes and cell volume. The cycle of Ca2+- regulated water flow is repeated with each Ca2+ spike making acinar cells function as a Ca2+- driven ion and water pump.

Fluid andElectrolyte Secretion by Duct Cell

–

The main transporters mediating ductal fluid and HCO

secretion are shown in Fig.5.2. Transport is fueled by the Na+ gradient and the membrane potential set by theNa+/K+ ATPase pump[22], the K+ channels K(Ca2+)1.1[23], and an unknown basolateral K by basolateral 1Na+– 2HCO

channel. HCO

–

mediated by the electrogenic NBCe1- B isoform[26] that accumulates cytoplasmic HCO basolateral Na+/H+ exchanger NHE1[25] and Cl– /HCO exchange, likely AE2, control pHin and Cl required for stimulated secretion[27].

The bulk of HCO

–

exits across the luminal membrane

–

enters the ducts

co- transport [24,25]

–

and osmolytes. The

–

, which is

–

by the interrelated activity of the cAMP- activated Cl– channel cystic fibrosis transmembrane conductance regulator (CFTR) and the exchanger slc26a6[3]. Slc26a6, an electrogenic 1Cl– /2HCO for ductal fluid secretion because it mediates net solute transport in addition to HCO

–

exchanger[28,29], is essential

–

secretion. Fluid moves

osmotically and exits the luminal membrane through AQP1, a process essential for ductal fluid secretion[30]. CFTR has finite HCO mediated HCO

–

permeability [31] and CFTR-

flux becomes important at the distal portion of the ducts when luminal and cytoplasmic Cl– are low [3]. Other ductal transporters on the luminal membrane of note are Na+/H+ exchanger NHE3[32] and H+/K+ ATPase pump ATP12A [33]. Luminal ATP12A may inhibit H+ absorption[33], although ATP12A in the airway epithelium actually contributes to the pathology in cystic fibrosis[34], a disease that prominently affects the pancreas. Hence, the role of ATP12A in the pancreatic duct remains to be established. We have suggested that H+- secreting transporters like NHE3 and perhaps ATP12A function to salvage HCO

–

in the ductal resting

state[32] (Fig.5.2a).

Ductal secretion is stimulated by the Gs- coupled secretin receptor that transmits its signal by increasing cAMP to activate protein kinase A (PKA) [3]. PKA phosphorylates the R domain of CFTR to activate the channel. CFTR then activates the slc26a6 by interaction of CFTR R domain with the slc26a6 STAS domain[35]. In turn, this interaction further activates CFTR. At the same time, CFTR inhibits NHE3 to prevent H

secretion

Physiology ofDuct Cell Secretion

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Figure5.2 Mechanism of fluid and electrolyte secretion by duct cells. The models show the key transporters and the relationships

between them in the resting (a) and stimulated ducts (b). The resting duct can secrete H while slc26a6 is away from CFTR and not active. In the stimulated state the H are mutually activated to cause fluid and electrolyte secretion. Osmotic flow of H

into the lumen[36]. CFTR recycles the Cl– absorbed by slc26a6 to maintain HCO Net osmolyte secretion by slc26a6in the form of HCO

–

secretion through slc26a6.

–

together with paracellular Na+ flow drives osmotic water secretion to generate the final volume of the pancreatic juice.

- secreting transporters are inhibited and slc26a6 and CFTR

affect surface expression, inhibit or activate the ion transporters [40]. Another level of regulation of the WNK kinases is through interaction with kelch- like 3 (KLHL3) and cullin 3 (CUL3), which regulate WNKs level by ubiquitination and degradation[41]. The role of CaMKII in epithelial transport is not well under-

by NHE3 and perhaps ATP12A to salvage HCO

O is through the water channel AQP1.

stood, although CaMKII affects the activity of many transporters and channels, such as Ca2+ channels[42]

Regulation ofDuctal Secretion

and the regulation of NBCe1- B by Cl– [37].

In the pancreatic duct, the WNK and the SPAK/ Ductal secretion is dynamically regulated in both resting and stimulated states by kinase and phosphatase pathways and scaffolding proteins. In addition, Cl regulates the transporters that mediate ductal secretion by affecting their activity and selectivity [2]. The resting state is set by the WNK, SPAK/OSR1, and CAMKII kinases [37]. Pancreatic duct cells express CaMKII[38] and mammals have four WNKs[39], with WNK1, WNK3, and WNK4 expressed in the pancreas [3]. The WNKs regulate Na

, K+, Cl– , HCO and Ca2+ transporters in epithelia by determining their surface expression and activity[39]. SPAK and OSR1 are homologous stress- activated kinases that act downstream of the WNKs, with the WNKs serving as scaffolds to the SPAK/OSR1. The SPAK/OSR1 can

OSR1 kinases function in the same pathway with the WNKs acting as scaffolds for the SPAK/OSR1kinases.

–

The WNK/SPAK pathway regulates the ductal

NBCe1-

B [43], slc26a6 [31], and CFTR [43,44] by inhibiting surface expression and the activity of the transporters. Notably, knockdown of the WNK and of SPAK kinases enhanced stimulated ductal fluid secretion, indicating that the kinases exert tonic inhibition of the secretion [43] to set the basal non- secretory state

–

(see model in Fig. 5.3a). Similarly, by modulating

NBCe1- B inhibition by Cl

–

, CaMKII limits HCO

secretion to favor the resting state[37].

The multifunctional protein IRBIT (IP3 binding protein released with IP3) regulates the pancreatic duct stimulated, secretory state. IRBIT was discovered as a

–

Regulation ofDuctal Secretion 51

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Figure5.3 IRBIT mediates synergistic activation of the cAMP and Ca2+ signaling pathways at membrane contact sites. In the resting state

(a), the WNK/SPAK and CaMKII kinases associate with the transporters and SPAK and CaMKII phosphorylate NBCe1CFTR to sequester most of them in intracellular organelles and modulate their regulation by Cl but also aids in association of the kinases with the transporters. When the cells are stimulated (b) with physiological concentrations of IP and cAMP generating agonists, PKA phosphorylates the IP membrane contact sites. IRBIT recruits PP1 and CaN to the transporters to dephosphorylate them at the SPAK and CaMKII phosphorylation sites and target them to the plasma membrane at membrane contact sites. IRBIT remains bound to the transporters’ autoinhibitory domains and further activates the transporters and ductal secretion.

protein that binds to the IP3 receptors (IP3Rs)[45] and as an activator of NBCe1- B[46]. IRBIT has an N terminus protein phosphatase 1 (PP1) binding motif, a PEST domain, a coiled- coil domain, calcineurin (CaN) binding motif and a PDZ ligand at the end of the C- terminus[37,47]. The coiled- coil domain participates in activation of target proteins by IRBIT [48] and the PDZ ligand locates IRBIT close to the HCO ers [43] and at membrane contact sites (MCS) [49]. IRBIT activates transporters by two mechanisms, increasing their surface expression and transport activity, and perhaps by assembling them into complexes at MCS. This is best understood with NBCe1- B. The first 85 residues of NBCe1- B form an autoinhibitory domain (AID)[50]. IRBIT interacts with the AID to prevent the NBCe1- B self- inhibition[46]. In addition, IRBIT reverses the inhibition of NBCe1- B by WNK/SPAK and by CaMKII through recruiting PP1 and CaN to the transporter, which dephosphorylates the SPAK phosphorylated Ser65[37,51].

IRBIT also interacts with and potently activates CFTR [43,48] and slc26a6 [51] by interacting with a sequence similar to the NBCe1- B AID that is present in

R to facilitate release of IRBIT from the IP3R by IP3 and IRBIT localizes to

CFTR R domain and slc26a6 STAS domain[51]. Indeed, IRBIT similarly recruits the PP1 to NBCe1- B, CFTR, and slc26a6[43,51]. The key role of IRBIT in ductal secretion was established by showing that knockout of IRBIT in mice markedly inhibits ductal fluid secretion. The reduced secretion due to IRBIT knockdown was partially

–

transport-

recovered by knockdown of SPAK [43], showing the interplay between the IRBIT/PP1 and the WNK/SPAK pathways in modulating ductal secretion, as illustrated inFig.5.3b.

–

HCO

secretion depends on strict regulation of both

intracellular and surface membrane HCO tions that are determined by carbonic anhydrases (CA). CA are either cytoplasmic or membrane anchored with their active site at the extracellular cell surface[52]. The surface CA control the supply or the removal of HCO at the surface of the plasma membrane and the cytoplasmic CA buffer cytoplasmic HCO membrane localized CA interact with many H+ and

–

HCO

transporters[53]. We know very little about the

role and molecular identity of the CA that are important in ductal secretion. Some information became available from human disease in which mutations in CA12 causes

–

. IRBIT is sequestered by the IP3 receptors

B AID, slc26a6, and

–

concentra-

–

. The plasma

–

Physiology ofDuct Cell Secretion

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salt wasting[54,55]. CA12 is a critical activator of AE2 and ductal secretion. Deletion or mutation in CA12inhibits ductal secretion by about 50% and overexpression of CA12 markedly increases ductal secretion [27]. Hence, activation of CA12 is a potential treatment of ductal hypofunction.

Another prominent regulator of ductal function is

–

Cl HCO luminal membrane potential through CFTR and of pHin through AE2 (Fig.5.2). Sensing Cl essential for tuning the secretory process. Cl

–

. Cl

has a key role in ductal function by driving

–

secretion through slc26a6, controlling the

–

is therefore

–

regu-

lates the function of multiple channels and transporters by functioning as a signaling ion[2]. Cl– regulates the activity of at least two HCO NBCe1- B and CFTR. Cl ity of CFTR by affecting the function of WNK1[31,56]. Once Cl

–

is below 8 mM, CFTR becomes the HCO

channel to increase HCO atic juice from 120 to 140 mM[57]. A more dramatic regulation by Cl activated NBCe1- B is regulated between 5 and 20 mM

–

[58]. Ductal secretion starts when resting Cl

–

controls HCO

–

concentration of pancre-

–

is seen with NBCe1- B. IRBIT-

about 35 mM and decreases to 4 mM toward the latter phase of Cl– absorption and HCO

–

At Cl

above 20 mM, 70% of NBCe1- B activity is

inhibited, which is sufficient to support HCO tion at the proximal duct. As demand for cytoplasmic

–

HCO HCO activity of NBCe1- B threefold [58], which ensures continued HCO

increases in the face of accumulation of luminal

–

, Cl

is reduced toward 4 mM to increase the

–

supply.

–

transporters,

–

permeabil-

–

secretion [3,59].

–

secre-

–

The Ca2+ and cAMP Pathways Synergize toActivate Ductal Secretion

Synergism between signaling pathways is a fundamental concept in biology that serves to prevent cell toxicity by overstimulation. Signaling pathways function at 1–5% of capacity and synergize to generate the maximal physiological response. The Ca2+ and cAMP signaling pathways synergize in a mechanism mediated by IRBIT[51]. At the resting state IRBIT is bound to IP3 receptors. Physiological stimulation increases ductal cAMP to phosphorylate the IP3R to increase their affinity for IP3 and reduce their affinity for IRBIT[51]. A small increase in IP3 by physiological stimulation with Ca2+- mobilizing receptors releases IRBIT from the IP3R that then binds to CFTR, slc26a6, and NBCe1- B to activate them and ductal secretion [51]. This important physiological mode of synergism is illustrated in Fig.5.3.

Ductal Secretion- Associated Pancreatic Diseases

–

Ductal fluid and HCO tive enzymes to the intestine, but also protect the parenchyma from damage due to stresses to the pancreas. In addition, as a chaotropic ion, HCO tial for solubilization of macromolecules like digestive enzymes and mucins and divalent ions in biological fluids [3,60]. The duct is the first line of defense of the pancreas that must be breached before damage to acinar cells takes place. Indeed, damage to ductal secretion occurs in several diseases of the pancreas, including cystic fibrosis (CF) and pancreatitis. CF leads to destruction of the pancreas and pancreatic insufficiency[61] due to inhibition of ductal fluid and HCO secretion[3]. Moreover, several studies have identified mutations in CFTR that are associated with chronic pancreatitis [62] and specifically inhibit CFTRdependent HCO ity[56], independent of Cl– channel activity[56]. The importance of the duct in protection of the pancreas and of CFTR in ductal function[64] led to the examination of the state of CFTR in chronic autoimmune[65] and alcoholic pancreatitis[65,66], which revealed mislocalization of CFTR in these forms of pancreatitis. Notably, treatment of autoimmune pancreatitis with corticosteroids ameliorated the disease primarily by increasing ductal HCO models, induction of acute pancreatitis by cerulein stimulation, bile duct infusion, and alcohol treatment impaired ductal function[67]. Finally, the chronic pancreatitis model NOD mice and the autoimmune pancreatitis model of poly IC in MRL/Mp- Fas mice showed markedly reduced expression of CFTR. Notably, treatment with CFTR correctors restored CFTR expression, ductal function, pancreas integrity, and most notably, acinar cell functions [68]. Similarly, CFTR correctors and potentiators reduced the severity of pancreatitis in a cerulein acute pancreatitis model[69]. These findings suggest that CFTR correctors should be considered as a safe and effective treatment for pancreatitis.

The intimate involvement of the duct in the health of the pancreas and pancreatic diseases suggests that the duct should be a prime target for therapy. There are several potential targets. One could be activators of IRBIT together with inhibitors of the WNK/SPAK/ OSR1kinases. Because of their involvement in renal salt homeostasis and hypertension [41], such drugs may became available in the future. Another potential target is CA12 that affects ductal function[27] and is modified in several cancers[70]. Drugs affecting CA12 activity are being developed in the cancer field and

secretion not only wash diges-

–

is essen-

–

transport [56,63] and permeabil-

–

secretion [65]. In animal

–

References 53

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may become useful for the treatment of pancreatitis. A very promising option is the use of CFTR potentiators and correctors that are approved for the treatment of CF[71]. These drugs repair CFTR localization and increase ductal secretion to slow progress of the disease in animal models and further improve the function of acinar cells. These drugs are effective in humans and in CF patients by increasing pancreatic and acinar cells function, although they increased

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Physiology andPathophysiology ofFunction ofSphincter ofOddi

Savio George Barreto

Division of Surgery and Perioperative Medicine, Flinders Medical Centre, Adelaide, South Australia, Australia

College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia

1,2

and James Toouli

Introduction

The presence of gallbladder and biliary tract was described in some of the earliest recorded observations of humans[1], but their role in digestion was not appreciated until much later. In the sixteenth century, a membrane near the distal end of the common bile duct thought to impede reflux of duodenal contents into the bile duct was described but it was not until 1887 that this structure was described as a sphincter and named after Rugero Oddi, who published a detailed description of its anatomy as a result of dissections undertaken while studying medicine[2]. The physiological role of the sphincter of Oddi was further appreciated after the hormone cholecystokinin (CCK) was shown to contract the gallbladder and reduce sphincter of Oddi resistance. These and subsequent studies firmly established that an intimate relationship existed between gallbladder contraction, sphincter of Oddi function, and the flow of bile and pancreatic juice into the duodenum.

Anatomy andMorphology

The terminal parts of the common bile duct and pancreatic duct, the common channel, and major duodenal papilla of Vater are invested by varying thickness of smooth muscle that together form the sphincter of Oddi segment (Fig.6.1). The major part of the human sphincter of Oddi lies within the duodenal wall, and is anatomically and functionally independent of the duodenal muscle.

Distinct sphincters have been described at the terminal end of the common bile duct (sphincter choledochus), pancreatic duct (sphincter pancreaticus), and

common channel (sphincter ampullae) [3]. However, studies using a combination of radiologic, duct cast techniques, and histologic sectioning methods did not distinguish separate sphincters[4], and human autopsy studies have concluded that the common bile duct and pancreatic duct become fused in a common connective tissue sheath outside the duodenal wall and pass together through a slit in the duodenal muscle known as the “choledochal window.” However, the lumina do not join at this level but are separated by a thick muscular septum. In most subjects, fusion of the two lumina occurs in the submucosal layer of the duodenum to form a common channel that varies in length between 2 and 17 mm. Before entering the duodenum, each duct becomes completely surrounded by circular muscle, some of which forms a figure- of- eight pattern around the two ducts. The point at which the smooth muscle starts on each duct is readily identified radiologically as a notch. Distal to the notch each lumen becomes narrow as it traverses the duodenal wall, this narrowing being associated with a thickening of the duct wall due to smooth muscle, connective tissue, and mucous glands. As the ducts pass through the duodenal wall longitudinal muscle, fibers interdigitate between the circular ductular muscle fibers and the duodenal muscle. The ducts emerge from the duodenal muscle layers and pass through the duodenal submucosa for a variable distance before opening onto the papilla of Vater; throughout this submucosal course, the ducts are ensheathed by circularly oriented smooth muscle. Manometric studies in humans support Hand’s description of the sphincter of Oddi in that separate sphincteric zones have not been identified[5].

The mucosa of the human sphincter of Oddi segment

is lined by columnar epithelium and contains numerous

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