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Physiology 57

Duodenal muscle

Pancreatic

of Vater

Sphincter

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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Mucosa

of Oddi

Figure6.1 Anatomy of the human sphincter of Oddi at the

junction of the bile and pancreatic ducts with the duodenum.

mucus- secreting glands. The mucosa is thrown into longitudinal folds likened to mucosal valvules [6]. These folds are least marked proximally and increase distally, becoming maximal in the common channel. The mucosal folds may occasionally be seen projecting through the orifice of the duodenal papilla.

Innervation

The extrahepatic biliary tract is innervated by dense networks of extrinsic and intrinsic nerves that regulate smooth muscle tone and epithelial cell function of the extrahepatic biliary tree. The celiac ganglia contribute both motor and sensory nerves made up of sympathetic fibers that originate in the T7–T10 spinal segments. The hepatic plexus is formed by nerve fibers from both vagi and supplies parasympathetic motor nerves to the extrahepatic biliary system[7].

The wall of the biliary tract is composed of three namely serosal, muscularis, and mucosal. Ganglionated nerve plexuses are located in the subserosal and the subepithelial layers. The sphincter of Oddi has a rich ganglionic plexus. It has a predominance of cholinergic ganglia and a smaller number of adrenergic ganglia. Immunohistochemical studies from our laboratory have demonstrated the presence of a wide range of peptidergic neurons in the sphincter region, including galanin- ,

Circular

Longitudinal

Papilla

Common

bile duct

duct

Pancreas

layers,

substance P-

, and somatostatin- containing nerves. In addition, the inhibitory transmitter nitric oxide has been demonstrated in nerves to the sphincter and is thought to have an important function in modulating sphincter relaxation. It has been shown that the nerves in the sphincter region communicate with the proximal biliary tract, the gallbladder, and the duodenum[8,9].

Physiology

Bile reaches the sphincter of Oddi via the common hepatic and common bile ducts. The sphincter of Oddi not only regulates the flow of bile and pancreatic juice into the duodenum, it is also the regulatory structure that prevents reflux of duodenal contents into the pancreatobiliary passages. The role of the common bile duct in the control of bile flow has been confused due to anatomic differences in species studied. Histologic studies in humans have demonstrated only thin longitudinally oriented layers of smooth muscle within the walls of the common bile duct [10]. The major tissue component appears to be elastic fibers. However, in other species such as sheep, the common bile duct is invested with circularly oriented smooth muscle that exhibits peristaltic activity.

The weight of evidence suggests that the human common bile duct does not have a primary propulsile function. However, the elastic fibers and the longitudinally oriented smooth muscle provide a tonic pressure that may help overcome the tonic resistance of the sphincter of Oddi. The diameter of the human common bile duct before and after cholecystectomy has been the subject of controversy. Part of the disagreement is due to the methodology used in determining duct size. It has become evident that duct size as determined by ultrasonography and magnetic resonance cholangiography (MRC) cannot be equated to duct size determined by endoscopic retrograde cholangiopancreatography (ERCP) or intraoperative extraluminal measurements. Ultrasound and MRC record the nondistended lumen, whereas the contrast used during ERCP produces distension. Intraoperative measurements include wall thickness. In general, the normal diameter of the common bile duct as determined by ultrasound is less than 6 than 10 mm, and by intraoperative extraluminal measurements less than 12 mm. What has become clear is that the common bile duct does not increase in diameter significantly following cholecystectomy [11,12]. The major cause of dilated common bile duct is increased intraluminal pressure, which generally is produced by either primary or secondary obstruction at the sphincter of Oddi.

mm, by ERCP, less

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

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Motility ofthe Sphincter ofOddi

The primary function of the sphincter of Oddi is to control the delivery of bile and pancreatic juice into the duodenum. This is possible because of low pressure within the bile duct. Approximately 800–1500 mL of bile flows through the human sphincter of Oddi. Various studies in animals and humans have tried to evaluate the mechanism by which the sphincter of Oddi controls the flow of bile and pancreatic secretions. These studies have shown that there is anatomic variability between species and that sphincter of Oddi motility differs from one species to another. Thus, while many commonalities exist, one needs to be circumspect in comparing animal data directly with the motility and function of the human sphincter of Oddi.

Sphincter ofOddi Motility Studies inAnimals

Invivo studies in dogs, cats, rabbits, and monkeys have demonstrated that the sphincter of Oddi exhibits muscle contractions that are independent of duodenal activity. The common bile duct and pancreatic duct proximal to the sphincter do not demonstrate spontaneous motor activity. Results from the dog studies have suggested that the sphincter of Oddi has a milking effect on bile, thus propelling small volumes of fluid from the common bile duct into the duodenum[13]. Manometric and electromyographic studies of the opossum sphincter of Oddi have demonstrated that the predominant mechanism of common bile duct emptying in the opossum is the antegrade sphincter of Oddi phasic contractions that propagate the entire length from the cephalic to the caudal end[14,15]. However, the frequency of the phasic contractions varies periodically during fasting. In cats, cholecystokinin (CCK) inhibits the sphincter phasic contractions and produces a fall in sphincter tone by stimulation of nonadrenergic noncholinergic inhibitory neurons— this effect overriding a lesser, direct smooth muscle stimulatory action of the hormone[16].

Recent studies have shown that the sphincter may act as a pump or a resistor and that bile duct pressure influences it[17]. This intrinsic activity is controlled by interstitial nerves of Cajal and is modulated by hormones[16], ATP and adenosine[18], and nitric oxide[19].

Neurohistochemical studies have demonstrated both adrenergic and cholinergic neurons within the sphincter of Oddi and experiments in animals have determined the pharmacologic effects of histaminergic, cholinergic, and adrenergic stimulation on the sphincter muscle [14].

However, the physiologic significance of these drug actions on the sphincter of Oddi requires further investigation.

The function of the vagus nerve in sphincter of Oddi physiology remains obscure. Sphincter of Oddi neurons likely receive vagal input and their activity is modulated by release of neuropeptides from sensory fibers, a significant source of excitatory synaptic input to these cells arising from the duodenum. This duodenum– sphincter of Oddi circuit is likely to play an important role in the coordination of sphincter of Oddi tone with gallbladder motility in the process of gallbladder emptying[20]. Studies in dogs have suggested that following vagal transection the resistance to flow across the sphincter of Oddi is decreased [21]. However, in theprairie dog increased resistance to flow through the sphincter of Oddi occurs after truncal vagotomy. Results from vagal stimulation studies have failed to define clearly the role of the vagus in biliary dynamics.

The Australian possum sphincter of Oddi demonstrates activity similar to that of the human sphincter. In this species, inhibition of sphincter phasic contractions promotes flow of bile. It has been shown that this inhibition is mediated by neural release of nitric oxide [16]. There is evidence that nitric oxide mediates the ceruleinand CCK octapeptide- mediated relaxation of the canine sphincter of Oddi[22]. The neuropeptide, galanin, selectively stimulates longitudinally oriented sphincter of Oddi smooth muscle via a direct mechanism, leading to a moderate reduction in trans- sphincteric flow [23]. Table6.1 illustrates the effects of various bioactive agents on the sphincter of Oddi.

Table6.1 Effects ofvarious bioactive agents onthe sphincter

ofOddi.

Stimulators

Morphine met-

Galanin

Substance P

Cholecystokinin

Neuropeptide Y

Nitric oxide

Inhibitors

Tramadol

Glucagon

Calcitonin gene-

Cholecystokinin

Peptide YY

Somatostatin

enkephalin

related peptide

Sphincter ofOddi Motility inHumans 59

mmHg

Time in seconds

Manometric procedure

Duodenal

Triple lumen catheter

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Sphincter ofOddi Motility inHumans

Cineradiographic studies of the human sphincter of Oddi exhibit rhythmic contractions that propel contrast into the duodenum [24]. Sphincter of Oddi pressure studies conducted at the time of biliary tract surgery have demonstrated variations in pressure thought to be the manometric equivalent of the cineradiographic contractions [25]. Resistance to outflow of fluid from the common bile duct into the duodenum has also been demonstrated by the intraoperative studies. This resistance was reduced after administration of CCK octapeptide or smooth muscle relaxants such as amyl nitrite[26].

Manometric recordings from within the sphincter of Oddi segment have been made via a pressure- sensitive catheter introduced into the sphincter of Oddi via a duodenoscope (Fig.6.2)[27].

The manometric recordings have demonstrated that the human sphincter of Oddi is characterized by prominent phasic contractions superimposed on a basal sphincter of Oddi pressure 3 bile duct and pancreatic duct (Fig.6.3). The amplitude of the phasic contractions is approximately 130 mmHg and the mean frequency is 4/min. Analysis of the direction of propagation of the phasic contractions during a continuous 3- min period demonstrated that the majority of contractions (60%) are oriented in an antegrade direction from the common bile duct toward the duodenum. A smaller number of contractions occurred either simultaneously (24%) or had a retrograde orientation (15%).

mmHg above the pressure in the common

Intravenous bolus injection of CCK octapeptide (20 ng/ kg) normally produces inhibition of the phasic contractions and a fall in the basal sphincter of Oddi pressure.

Table 6.2 shows the pressures recorded from the sphincter of Oddi of normal subjects. Studies from patients with T- tubes inserted in the common bile duct following bile duct exploration[28] have shown that the frequency of sphincter of Oddi phasic contractions

CBD

catheter

Duodenum

Figure6.2 Manometric recording from the human sphincter of

Oddi. A triple- lumen pressure- sensitive catheter is positioned in the sphincter via the biopsy channel of the duodenoscope. A separate catheter records duodenal pressure. CBD: common bile duct; PD: pancreatic duct.

Figure6.3 Manometric recording from the

human sphincter of Oddi (SO) showing prominent phasic contractions, which are inhibited after injection of cholecystokinin octapeptide (CCK-

OP).

200

100

Cephalad

200

100

Middle

200

100

Caudad

200

100

Duodenum

CCK-OP 20 ng/kg

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

SO frequency

Contractions/minute

Phase III Phase IV Phase I Phase II Phase III

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during fasting exhibits a periodicity in relation to duodenal migrating motor complexes, similar to that demonstrated in the opossum (Fig.6.4).

Following the ingestion of a meal, bile flow across the sphincter of Oddi is promoted by inhibition or reduction in the amplitude of the phasic contractions and a fall in the sphincter of Oddi basal pressure. This effect on the human sphincter of Oddi is similar to that following intravenous injection of CCK octapeptide. In humans, bile flow occurs mainly between sphincter of Oddi phasic contractions during the period of diastole. The phasic contractions do propel small volumes of bile into the duodenum, but this is not the major means by which bile flow occurs. The phasic contractions in humans may function to prevent reflux of duodenal contents into either the bile

Table6.2 Pressures recorded fromthe sphincter ofOddi

ofnormal subjects.

Normal

AbnormalMedian Range

Basal pressure (mmHg) 15 3–35 >40

Amplitude (mmHg) 135 95–195 >300

Frequency (/min) 4

Sequences

Antegrade (%) 80 12–100

Simultaneous (%) 13 0–50

Retrograde (%) 9 0–50

2–6 >7

or the pancreatic ducts, and to maintain the ducts free of small debris. In order to promote flow across the human sphincter of Oddi, inhibition or reduction of the phasic contractions and a fall in basal pressure is necessary.

Pathophysiology of the Sphincter of Oddi Dysfunction (SOD)

The terminology SOD implies motility abnormalities of the sphincter of Oddi associated with pain, elevations of liver or pancreatic enzymes, common bile duct dilatation, or episodes of pancreatitis. The most common presentations of this symptom complex include persistent or recurrent “biliary” symptoms postcholecystectomy (10–20%)[29] or features consistent with idiopathic recurrent acute pancreatitis (abnormal sphincter of Oddi manometry has been recorded in 30.5%[30]).

In 2016, the Rome IV expert consensus[31] updated the diagnostic criteria for sphincter of Oddi disorders[32]. For biliary pain, the Rome IV expert consensus[31] included the criteria listed in Table6.3, as well as the presence of elevated liver enzymes or dilated bile duct (but not both), in the absence of bile duct stones or other structural abnormalities. The consensus statement also listed supportive criteria the presence of one or more of which, in association with the pain, may help in arriving at the diagnosis. These include abnormal amylase/lipase, abnormal sphincter of Oddi manometry, and abnormal hepatobiliary scintigraphy.

The clinical diagnostic system for SOD is the Modified Milwaukee Classification described for both biliary[33]

% Interdigestive cycle

Figure6.4 Manometric recordings of the human

sphincter of Oddi showing changes in frequency of contraction in relation to the duodenal interdigestive motility pattern.

40 60 80 100

Pathophysiology of the Sphincter of Oddi Dysfunction (SOD) 61

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and pancreatic [34] disorders (Table 6.4). These have been modified f rom the original Milwaukee Classif ication proposed by Hogan and Geenen [35]. Pancreatic SOD may be considered in patients with documented acute recurrent pancreatitis, after exclusion of known etiologies for pancreatitis, and documenting elevated pancreatic sphincter of Oddi pressures on manometry[31].

An alternate classification of SOD may be based on manometric recordings. We have previously subdivided SOD into two groups [36], namely, those exhibiting a stenotic pattern (abnormally raised basal sphincter pressure >40 mmHg) and those displaying a dyskinetic pattern including paradoxical response to CCK injection, rapid contraction frequency, high percentage of retrograde contractions, or short periods of raised basal pressure[37]. These patients display an abnormal response to morphine or a fatty meal stimulus. In addition it has been postulated that SOD characterized by a manometric stenosis may contribute to the development of adult choledochal cysts[38,39].

The stenotic subtype of SOD is characterized by pathomorphological changes evident on histological

Table6.3 Rome IV diagnostic criteria for biliary- type pain

Adapted from[31].

Pain located in the epigastrium and/or right upper quadrant and all of the following:

1) Builds up to a steady level and lasting 30minutes, or longer

2) Occurring at different intervals (not daily)

3) Severe enough to interrupt daily activities or lead to an

emergency department visit

4) Not significantly (<20%) related to bowel movements

5) Not significantly (<20%) relieved by postural change or acid

suppression

Supportive criteria: Nausea and vomiting, radiation to the back and/ or right subscapular region, and waking from sleep.

examination of sphincter complexes resected at the time of transduodenal sphincteroplasty for patients with severe postcholecystectomy pain. The changes contributing to the high basal pressure include inflammation of the papilla and its transampullary septum or fibrosis with or without inflammation, papillary cholesterolosis [40], muscle hypertrophy, or mucosal edema [41]. These findings have been reported in 58% of patients undergoing transduodenal sphincteroplasty and transampullary septectomy for postcholecystectomy pain[40] and one possible cause has been postulated to be due to the chronic passage of small gallstones [40]. Another possible cause may be end- stage dyskinetic SOD. The stenotic subtype corresponds to the Modified Milwaukee type 1 and responds best to sphincterotomy (surgical or endoscopic). We have previously demonstrated that surgical sphincteroplasty and septectomy when performed for manometrically confirmed sphincter of Oddi stenosis in patients with recurrent pancreatitis resulted in a good clinical outcome in a majority of patients[42,43].

In a clinical setting, there is no need for manometry prior to ERCP and sphincterotomy for type 1 SOD of either biliary or pancreatic type presentation.

The dyskinetic subtype, conversely, is believed to be the result of a functional or neurohormonal disturbance in the absence of any pathological reproducible abnormalities [36]. Infections such as Cryptosporidium and HIV have also been shown to lead to features of SOD[44]. This subtype corresponds to the type 2 and 3 of the Milwaukee Classification. Sphincter of Oddi manometry is essential to arrive at the diagnosis. The paradoxical response to CCK injection noted by us[41] may be the result of a defect in the enteric nervous system akin to that described for achalasia of the esophagus[45]. While sphincterotomy relieves symptoms of type 1 SOD, it is less effective in alleviating symptoms of this subtype[46]

Table6.4 Modified Milwaukee classification forbiliary andpancreatic sphincter ofOddi dysfunction.

Classification

Type 1 A) Biliary- type pain

Type 2 A) Biliary- type pain with either B or C in

Type 3 A) Biliary- type pain only without other

ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase.

Diagnostic criteria

Biliary Pancreatic

A) Pancreatic- type pain

B) Elevated ALT, AST, ALP >1.1 times the

upper limit of normal on one occasion

C) Bile duct diameter ≥9 mm

the criteria mentioned in Type 1

abnormalities

B) Serum amylase or lipase level of 1.1 times the upper limit of

normal on one occasion

C) Duct dilatation of >6 mm in the head and >5 mm in the body of

the pancreas

A) Pancreatic- type pain with either B or C in the criteria

mentioned in Type 1

A) Pancreatic- type pain only without other abnormalities

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

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and is associated with a risk of early recurrence of symptoms on follow- up[47]. Following clinical studies over the last decade there has been a change in our understanding of the SOD dyskinetic subtype.

The Rome IV consensus postulates that type 3 SOD is a disorder of “gut–brain interaction”[31]. This view was largely shaped by the findings of the clinical trial entitled “Evaluating Predictors and Interventions of SOD (EPISOD)”[48]. This multicentre randomized controlled trial conducted in seven centers involved the randomization of 214 patient with postcholecystectomy pain and without significant abnormalities on imaging or laboratory studies, with no prior sphincter of Oddi treatment or pancreatitis. Patients either had an endoscopic sphincterotomy or sham therapy irrespective of manometry findings. A significantly higher proportion of patients in the sham-

treatment group experienced relief as compared to the sphincterotomy group (37% vs. 23%; P = 0.01). These findings persisted at 5- years’ follow- up with patients who received a sphincterotomy faring worse- off based on the Patients’ Global Impression of Change (PGIC) criteria[49]. The authors recommended that ERCP be undertaken only in patients with a dilated bile duct or significantly deranged liver function tests[50]. This recommendation has been supported by the results of the ERCP for Sphincter of Oddi Disorders (RESPOnD) study[51]. The latter was a prospective longitudinal cohort study that evaluated the benefit of ERCP with sphincterotomy when performed for SOD.

Type 2 SOD is considered a “functional biliary sphincter disorder” by the Rome IV consensus[31] statement and includes those patients who have biliary pain postcholecystectomy with either dilated ducts or elevated liver enzymes. Current data supports the performance of biliary manometry in these patients [46,52] and there remains a role for sphincterotomy in those patients who had demonstrable pre- procedure abnormalities in manometry[53]. The response to sphincterotomy in patients with type 2 SOD is not uniform but demonstrates benefit in a significant number of individuals.

Management of patients with type 3 SOD and those patients with type 2 SOD who do not benefit from a sphincterotomy or in whom manometry findings remain inconclusive is a challenge. Various pharmacologic agents have been used with varying success. These include hyoscine butyl bromide, nifedipine, nitric oxide, octreotide, gabexate mesylate, ulinastatin, trimebutine, amitriptyline, and duloxetine[54–57].

The treatment of pancreatic types 2 and 3 SOD remains speculative. We have elucidated various mechanisms by which galanin may be involved in the pathogenesis of acute pancreatitis [58]. Given the action of galanin on the sphincter of Oddi [23], its contribution to SODinduced acute pancreatitis [59] is worthy of consideration. Use of galanin antagonists [60–63] may offer a potential therapy in this subgroup of patients.

The causes for pain in SOD remain conjectural. Mechanisms for production of pain may include relative obstruction of flow through the sphincter of Oddi resulting in bile duct or pancreatic duct distension, “ischemic” pain arising from spastic contractions, hypersensitivity of the papilla, and severance of nerves supplying the sphincter of Oddi during cholecystectomy. Other potential explanations may include duodenal-

specific visceral hyperalgesia (in type 3 SOD)[64], continuous visceral pain (biliary pain) caused by local inflammatory/sensitizing processes or persistent hyperexcitability of the nociceptive neurons in the central nervous system[65], or other functional gastrointestinal disorders including intestinal dysmotility[66], irritable bowel syndrome (IBS), or non- ulcer dyspepsia.

Summary

The sphincter of Oddi is a small but important complex muscle that modulates flow of bile and pancreatic juice across one of the busiest anatomic junctions of the body. Its motor activity is controlled by an interaction of neuronal and hormonal modulators. In such a complex structure it is not surprising that at times disorders in motility arise and these disorders lead to significant clinical syndromes.

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Neurohormonal andHormonal Control ofPancreatic Secretion

Chung Owyang and Matthew J. DiMagno

Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

Introduction

The pancreas, one of the most important organs in the digestive tract, has both exocrine and endocrine functions. The exocrine pancreas secretes digestive enzymes and HCO

–

to facilitate digestion and absorption of

nutrients. The endocrine pancreas releases hormones that regulate metabolism and the disposition of the breakdown products of food.

The human pancreas secretes about 1 liter of juice daily, containing mostly water, electrolytes, and digestive enzymes. Mediation of postprandial pancreatic secretion has been ascribed mainly to the hormones secretin and cholecystokinin (CCK) and to vagovagal reflexes that activate cholinergic postganglionic neurons in the pancreas. In addition to these classical pathways, other regulatory peptide hormones and neurotransmitters may be involved.

Stimulation ofPancreatic Secretion

Hormonal Mechanisms

Secretin

Secretin is the most potent and efficacious stimulant of pancreatic fluid and HCO other species tested. It is synthesized by small intestine S- type enteroendocrine cells and is released postprandially. Duodenal pH is the major regulator of secretin release. A threshold pH of 4.5 triggers secretin release and stimulates pancreatic HCO this pH, pancreatic HCO amount of titratable acid presented to the duodenum. Secretin levels in humans increase only a few picomolars postprandially because food buffers much of the gastric

–

secretion in humans and all

–

secretion[1,2]. Below

–

output is related to the total

acid and pancreaticobiliary secretion neutralizes the remaining acid entering the duodenum by [3]. The mechanism by which acid stimulates secretin release is unclear. In rodents it was shown that H

may release a secretin- releasing factor into the proximal intestinal lumen to stimulate secretin release [4]. Secretinproducing cells appear to have acid- sensing ion channels belonging to the TRP (transient receptor potential) channel family. Hence, luminal acid likely stimulates secretin release by more than one mechanism.

Nonacid factors may influence postprandial secretin release. Nutrients such as oleic acid and other digestive products of fat can increase plasma secretin levels and pancreatic HCO

–

secretion[3,5]. Bile in the upper gut

can also stimulate secretin release [6]. However, the physiological importance of these nonacid factors in postprandial secretin release is questionable, as the postprandial plasma secretin level does not increase in achlorhydria or in health if meal- induced acid secretion is neutralized with NaHCO

–

The pancreas appears highly sensitive to the small amounts of secretin released into the circulation postprandially[3,6]. Invitro animal models show that secretin stimulates HCO fragments [7,8].

–

secretion by isolated ducts or duct

125

I- labeled secretin and autoradiography revealed a secretin- binding site on pancreatic acini and duct cells[3], suggesting that secretin acts directly on the pancreas to stimulate pancreatic secretion. Conversely, invivo studies have shown that the effect of secretin at physiological doses is highly sensitive to atropine[3]. Receptor autoradiography, immunocytochemistry, and electrophysiology demonstrate the presence of secretin receptors in vagal afferent fibers[3,9,10]. Vagal nodose ganglia also contain high- affinity CCK

recep-

tors [3]. Injection of a subthreshold dose of CCK- 8 (5 pM) significantly enhances the neural response to

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

Neurohormonal andHormonal Control ofPancreatic Secretion

Acetylcholine

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5 pM secretin. This synergistic interaction helps to explain the robust postprandial pancreatic HCO

–

and enzyme secretion despite a modest postprandial increase in plasma CCK and secretin.

Cholecystokinin

CCK is the other gut hormone that plays an important role in pancreatic secretion. It is synthesized in specific enteroendocrine I cells in the proximal intestine and released by hydrolytic products of digestion such as amino acids and fatty acids[11]. Undigested fat is ineffective, but products of lipolysis such as fatty acids are the most potent stimulants of CCK release [12]. The CCK response to fatty acids is influenced by chain length, saturation, concentration, and total load[13].

Fasting plasma CCK levels are low, averaging about

pM in humans [14–16]. Postprandially, plasma CCK

1 concentration increases to 6–8 pM within 10–30 min, then gradually declines to basal levels during the ensuing 3 h[15,16]. Several molecular forms of CCK appear to be released into the circulation postprandially, including CCK- 58, CCK- 33, CCK- 22, CCK- 12, and CCK- 8 [17]; CCK- 58 being predominant in dogs and humans and the only form detected in rats[16–19].

Nutrients may stimulate CCK secretion by a number of mechanisms. In species such as the rat, in which feedback inhibition of pancreatic enzyme secretion occurs, CCK release is mediated by a trypsin- sensitive CCKreleasing peptide [20]. Duodenal peptone stimulates serotonin (5- HT) release from intestinal enterochromaffin cells, which in turn activates submucosal sensory substance P neurons. Signals are then transmitted to

cholinergic interneurons and to epithelial CCK- releasing peptide- containing cells by way of cholinergic secretomotor neurons[20]. CCK release may be controlled by the level of active intraluminal proteases [16]. Protein, the major food stimulant of CCK secretion in rats, may bind or inhibit intraluminal endopeptidases, which would otherwise inactivate the CCK- releasing peptide[21] (Fig. 7.1). The mechanisms responsible for the actions of CCK- releasing peptide in humans are unclear, but may be similar to rats as feedback regulation of CCK release by proteases also occurs in humans. Study of CCK secretion from purified CCK- producing cells shows that amino acids stimulate CCK release by binding to the

- sensing receptor [22], whereas fatty acids bind to specific G- protein–coupled fatty acid receptors [23]. Thus CCK secretion may be mediated by more than one mechanism.

CCK plays an important role in the stimulation of postprandial pancreatic enzyme secretion. The infusion of physiological doses of CCK produces the same level of pancreatic enzyme secretion as during the postprandial state [24]. Furthermore, administration of the potent CCK antagonist lorglumide or MK- 329 produces a 50–60% inhibition of meal- stimulated pancreatic secretion in dogs[25] and humans[26]. CCK can also stimulate fluid and HCO HCO

–

secretion is weak but physiologically relevant

–

secretion [27]. The effect on

because CCK potentiates the action of secretin on the pancreas [28]. In intact dogs and humans, CCKstimulated pancreatic enzyme secretion is not potentiated by secretin [24,29,30]. The mechanisms by which CCK stimulates pancreatic enzyme secretion remain

Atropine

Protein

Trypsin-protein

Duodenum

CCK-RP

Trypsin

complex

CCK

Pancreas

CCK-RP cell

CCK cell

Enterocytes

Figure7.1 Cholecystokinin (CCK)- releasing peptide

(CCK- RP) stimulation of postprandial secretion. CCK- RP is secreted into the proximal small intestine under the influence of cholinergic pathway and inactivated by trypsin. When food enters the duodenum postprandially, protein binds to trypsin and prevents the inactivation of CCK- RP. CCK- RP stimulates CCK cells in the duodenum to release CCK into the bloodstream. CCK, in turn, stimulates pancreatic enzyme secretion.

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