**3. Integrative physiology of the exocrine pancreas**

In this chapter we elucidate the mechanisms by which the exocrine pancreas secretes pancreatic ductal fluid and digestive enzymes under physiological conditions, the regulatory mechanisms that govern its function, and describe the response of pancreatic secretion to a meal. Moreover, this chapter offers some insight into the pathophysiological background of pancreatic diseases related to exocrine pancreas secretion.

#### **3.1. Composition of pancreatic fluid**

In humans, the secretion of a neutral, isotonic, Na+ , Cl− and H+ -rich fluid, active digestive proteins, as well as zymogens by the pancreatic acinar cells, and of an alkaline, isotonic and HCO3 − -rich fluid by the pancreatic ductal cell yields between 1 and 2.5 L of pancreatic fluid per day, which contains around 20 g of digestive enzymes [67–69]. More than 20 different enzymes are secreted by the acinar cells [70], and some of them are precursor enzymes, such as trypsinogen and chymotrypsinogen. The enzymes released from the acinar cells in an active form are lipases, colipases, A-amylases, collagenases, elastases, ribonucleases and phospholipases A [70, 71].

Human pancreatic fluid contains up to 150 mmol/L of HCO3 − . Its concentration increases with pancreatic fluid flow rate, and reaches its peak at 30–50% of maximal flow [72, 73]. The Cl− concentration relates inversely with the pancreatic fluid flow rate and maintains an isotonic osmolality with respect to HCO3 − . The composition of cations remains fairly constant, irrespective of pancreatic fluid flow rate, with 140 mmol/L Na+ , and 10–15 mmol/L K+ . The sum of HCO3 <sup>−</sup> and Cl− concentration closely matches the sum of Na+ and K+ concentration. Electrolytes, such as Ca2+, Mg2+, Zn2+, PO4 3− and SO4 2−, are also present, but at minimal concentrations [74–76].

#### **3.2. Regulation of acinar cell secretion**

The somata of the parasympathetic preganglionic neurons reside in the dorsal motor nucleus of vagus and the nucleus ambiguus [36, 56]. The majority of their axons join the vagus and some the splanchnic nerves and reach the neural plexuses around arteries where they intermingle with sympathetic fibres [61]. The preganglionic parasympathetic neurons finally reach intra-pancreatic ganglia together with vessels supplying them [36, 56]. The parasympathetic ganglia that reside within the inter-lobular septa, lobules and also close to islets receive input not only from parasympathetic preganglionic fibres, but also from other pancreatic ganglia, sympathetic fibres (see above), the myenteric plexus, as well as the sensory fibres (see below) [36]. Postganglionic fibres innervate acinar and ductal epithelial cells, ductal smooth muscle cells and vascular plexuses, as well as other ganglia. These fibres mediate parasympathetic stimulation of secretion from acinar and ductal cells, constriction of ducts, as well as an increase

In the pancreas, sympathetic and parasympathetic afferent fibres can also be found. They contain substance P (SP) or calcitonin gene-related product (CGRP) as neurotransmitters. Sympathetic afferents that innervate both the exocrine and the endocrine tissue join the sympathetic splanchnic nerves and transmit noci- and mechano-receptive sensory information to somata within the dorsal root ganglia and further on to preganglionic sympathetic neurons

Pancreatic sympathetic innervation is altered in chronic pancreatitis and pancreatic cancer and may contribute to the neuropathic pain and visceral neuropathy in these states [65, 66]. Dorsal root ganglion sympathetic afferent neurons send collaterals to efferent ganglia, representing a neuroanatomical substrate for intrapancreatic monosynaptic vegetative reflexes. For example, SP and CGRP released at intra-pancreatic ganglia inhibit exocrine secretion. Intra-

Somata of vagal afferent neurons reside within the nodose ganglia. They innervate the blood vessels, ducts, acini and islets. However, their centripetal pathways are not well known [36].

In this chapter we elucidate the mechanisms by which the exocrine pancreas secretes pancreatic ductal fluid and digestive enzymes under physiological conditions, the regulatory mechanisms that govern its function, and describe the response of pancreatic secretion to a meal. Moreover, this chapter offers some insight into the pathophysiological background of pancre-

proteins, as well as zymogens by the pancreatic acinar cells, and of an alkaline, isotonic and


, Cl− and H+


in the lateral horn of the spinal medulla and probably higher centres [36].

pancreatic ganglia are also contacted by vagal afferents [36].

**3. Integrative physiology of the exocrine pancreas**

atic diseases related to exocrine pancreas secretion.

In humans, the secretion of a neutral, isotonic, Na+

**3.1. Composition of pancreatic fluid**

HCO3 −

in fluid supply by vasodilation [36, 61].

26 Challenges in Pancreatic Pathology

Secretion of digestive enzymes from acinar cells is primarily mediated by acetylcholine (ACh) release from vagal nerve endings and by the intestinal hormone, cholecystokinin (CCK). In addition to its primary role in ductal secretion (see below), the hormone secretin also influences acinar cell function, as does the vasoactive intestinal peptide (VIP) [77, 78].

The pancreas is innervated by postganglionic nerves, which receive input from the preganglionic motor neurons that stem from the dorsal motor nucleus of the vagus (DMV) [79]. ACh mediates its effects on acinar cell secretion via M1 and M3 muscarinic receptors [80], with M3 muscarinic receptors playing a predominant role [81]. The pancreas is also innervated by sensory vagal afferents, which project to the solitary nucleus, where information is integrated and relayed to the preganglionic motor neurons of the DMV, and the two together constitute the so-called dorsal vagal complex [79]. M1 and M3 muscarinic receptors are linked to the Gq/ 11 family of G-proteins and cause hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C, yielding inositol 1,4,5,-trisphosphate (1,4,5-IP3) and 1,2-diacylglycerol (DAG) [82–84]. DAG goes on to phosphorylate various proteins via protein kinase C activation, while IP3 mobilizes Ca2+ from internal stores to stimulate amylase secretion [82, 85].

Digestive elements of fats and proteins, such as fatty acids with acyl chains longer than 12 carbon atoms, and amino acids, phenylalanine and tryptophan, are prime secretagogues for CCK secretion by the intestinal I cells. Carbohydrates, on the other hand, do not exhibit particular potency. The mechanisms of CCK action on pancreatic acinar cells seem to exhibit species-specificity [86]. It was thought that the main, if not exclusive, influence of CCK on human acinar cells was mediated via interaction with cholinergic nerves by presynaptic modulation of vagal output [80]. It has been recently shown, however, that CCK can activate human pancreatic acinar cell secretion both directly [87] and indirectly through CCK-A receptors on vagal afferents [77, 79]. Mechanisms of CCK-relayed digestive enzyme secretion have not yet been fully clarified [87]. The CCK-B subtype of CCK receptors seems to be the predominant form in the human pancreas, while the presence of the CCK-A subtype has been difficult to demonstrate [88]. Similar to the M1 and M3 muscarinic receptors, CCK-B receptors are coupled to the Gq/11 family of G-proteins, and follow a similar signalling pathway to elevate intracellular calcium [83].

An alternative pathway of pancreatic acinar fluid and protein secretion is mediated by secretin and vasoactive intestinal peptide (VIP). By stimulating their respective Gα G-protein-coupled receptors an increase in cAMP is observed, which in turn increases PKA activity, leading to secretion [78, 89].

#### **3.3. Molecular mechanisms of acinar cell secretion**

In response to stimulation with ACh and CCK, acinar cells secrete an isotonic, plasma-like, protein-rich fluid containing Na+ , Cl− and H+ , which is later modified by the ductal cells to form the final fluid [69, 70, 74]. Both secretagogues stimulate mechanisms that cause Ca2+ oscillations in the cytosol of acinar cells, which is a signalling mechanism for both fluid and enzyme secretions [90–92].

The fluid secretion of acinar cells is a result of ion transport across the basolateral and apical membranes, as well as paracellular transport mechanisms [90–92]. The driving force for acinar cell fluid secretion stems from the Na+ /K+ -ATPase located on the basolateral membrane and from the trans-cellular ion gradient it creates. The Na+ /K+ /2Cl− co-transporter NKCC1 on the basal side is responsible for approximately 70% of the Cl− uptake for subsequent secretion by the pancreatic gland. The Ca2+- and voltage-activated K+ maxi-K channel on the basolateral membrane and others set the acinar cell membrane potential close to the K+ diffusion potential. The membrane potential, in turn, serves as the electromotive force for Cl− exit at the apical membrane. Along with the above-mentioned basolateral transport proteins, the Na+ /H+ exchanger NHE1 and the AE2 isoform of the Cl− /HCO3 − exchanger family also play a role in basolateral Cl uptake. Both NKCC1 and NHE1 also provide Na+ for the Na+ /K+ -ATPase and regulate intracellular pH, keeping it at about pH = 7.2 [90, 93]. Luminal secretion of Cl− occurs via a voltage- and Ca2+-activated Cl− channel TMEM16A/Ano1. As Cl− flows through the cell into the lumen of the acinus, Na+ follows via the paracellular pathway. The subsequent osmotically driven water flow is mediated by aquaporin AQP1 [70, 74, 93].

Digestive enzymes are stored in zymogene granules at the apical membrane of acinar cells and are released by way of exocytosis. Fusion of granules with the apical plasma membrane releases their contents into the acinar lumen and later on into the small intestine [94]. As with fluid and electrolyte secretion from pancreatic acinar cells, Ca2+ ions are the key messenger in triggering and controlling a series of events termed stimulus-secretion coupling, i.e. pathways that regulate digestive enzyme secretion from acinar cells. Upon stimulation with secretagogues, a spike in intracellular Ca2+, released from intracellular Ca2+ stores, causes fusion of zymogen granules with the plasma membrane [94, 95]. Physiological stimulants can evoke various intracellular Ca2+ patterns: (i) global Ca2+ oscillations, (ii) Ca2+ waves that flow across the cell and (iii) local calcium spikes [96]. Local apical Ca2+ spikes, which occur with lower levels of stimulation, as well as global Ca2+ spikes will increase the permeability of Ca2+ dependent Cl− channels, resulting in fluid secretion. It seems, however, that physiological stimulation yields zymogene granule fusion only when a global Ca2+ spike is observed [95].

In acute pancreatitis, a condition, which most frequently occurs due to alcohol abuse and biliary disease, the pro-enzymes stored in acinar cells become activated prematurely, causing autodigestion with inflammation and necrosis of the pancreatic tissue. Under normal conditions, intracellular Ca2+ is a key secondary messenger in pancreatic acinar cell secretion. Recently, however, a body of evidence suggests Ca2+ is a key initiator of pancreatitis. Noxious stimuli, such as alcohol, long-chain fatty acids and bile acids, provoke extensive Ca2+ release from intracellular stores, causing a prolonged and global Ca2+ elevation. This kind of abnormal calcium signalling in turn activates trypsinogen that causes pancreatic autodigestion [97–99].

#### **3.4. Regulation of ductal cell secretion**

are coupled to the Gq/11 family of G-proteins, and follow a similar signalling pathway to

An alternative pathway of pancreatic acinar fluid and protein secretion is mediated by secretin and vasoactive intestinal peptide (VIP). By stimulating their respective Gα G-protein-coupled receptors an increase in cAMP is observed, which in turn increases PKA activity, leading to

In response to stimulation with ACh and CCK, acinar cells secrete an isotonic, plasma-like,

the final fluid [69, 70, 74]. Both secretagogues stimulate mechanisms that cause Ca2+ oscillations in the cytosol of acinar cells, which is a signalling mechanism for both fluid and enzyme

The fluid secretion of acinar cells is a result of ion transport across the basolateral and apical membranes, as well as paracellular transport mechanisms [90–92]. The driving force for acinar

membrane and others set the acinar cell membrane potential close to the K+ diffusion potential. The membrane potential, in turn, serves as the electromotive force for Cl− exit at the apical membrane. Along with the above-mentioned basolateral transport proteins, the Na+

uptake. Both NKCC1 and NHE1 also provide Na+ for the Na+

via a voltage- and Ca2+-activated Cl− channel TMEM16A/Ano1. As Cl− flows through the cell

Digestive enzymes are stored in zymogene granules at the apical membrane of acinar cells and are released by way of exocytosis. Fusion of granules with the apical plasma membrane releases their contents into the acinar lumen and later on into the small intestine [94]. As with fluid and electrolyte secretion from pancreatic acinar cells, Ca2+ ions are the key messenger in triggering and controlling a series of events termed stimulus-secretion coupling, i.e. pathways that regulate digestive enzyme secretion from acinar cells. Upon stimulation with secretagogues, a spike in intracellular Ca2+, released from intracellular Ca2+ stores, causes fusion of zymogen granules with the plasma membrane [94, 95]. Physiological stimulants can evoke various intracellular Ca2+ patterns: (i) global Ca2+ oscillations, (ii) Ca2+ waves that flow across the cell and (iii) local calcium spikes [96]. Local apical Ca2+ spikes, which occur with lower levels of stimulation, as well as global Ca2+ spikes will increase the permeability of Ca2+-

stimulation yields zymogene granule fusion only when a global Ca2+ spike is observed [95].

regulate intracellular pH, keeping it at about pH = 7.2 [90, 93]. Luminal secretion of Cl−

osmotically driven water flow is mediated by aquaporin AQP1 [70, 74, 93].

/HCO3 −

channels, resulting in fluid secretion. It seems, however, that physiological

/K+ /2Cl−

, which is later modified by the ductal cells to form


follows via the paracellular pathway. The subsequent

co-transporter NKCC1 on the

/H+


occurs

uptake for subsequent secretion by

maxi-K channel on the basolateral

exchanger family also play a role in

/K+

elevate intracellular calcium [83].

28 Challenges in Pancreatic Pathology

protein-rich fluid containing Na+

cell fluid secretion stems from the Na+

into the lumen of the acinus, Na+

**3.3. Molecular mechanisms of acinar cell secretion**

from the trans-cellular ion gradient it creates. The Na+

exchanger NHE1 and the AE2 isoform of the Cl−

basal side is responsible for approximately 70% of the Cl−

the pancreatic gland. The Ca2+- and voltage-activated K+

, Cl−

and H+

/K+

secretion [78, 89].

secretions [90–92].

basolateral Cl-

dependent Cl−

Secretory control of pancreatic ductal cells exhibits great complexity as it involves a variety of receptors on both the basolateral and apical membranes. Activation of these receptors can be a stimulatory or an inhibitory factor in HCO3 − and fluid secretion [67].

The most important secretagogue for HCO3 <sup>−</sup> secretion from pancreatic ductal cells is the peptide hormone secretin [78]. The primary stimulus for secretin release from the neuroendocrine S cells in the proximal duodenum is intra-duodenal pH below 2–4.5, which occurs upon entry of acidic chyme from the stomach. Fatty acids and bile salts are also stimuli for secretin release [78, 100–102]. Upon activation of the secretin receptor on the basolateral side, which is coupled to adenylyl cyclase, increase and accumulation of cAMP are observed. cAMP activates PKA, which in turn phosphorylates the CF transmembrane conductance regulator (CFTR) in the apical membrane of ductal cells [101] and the basolateral Na+ -HCO3 <sup>−</sup> cotransporter NBCe1-B [74]. Possible alternative routes of cAMP/PKA pathway activation are the release of VIP from vagal nerve terminals, with subsequent VIP receptor VPAC1 activation and beta-adrenergic receptor activation [103]. Vagal nerve fibres release VIP together with the main neurotransmitter ACh. Ductal cells express M2 and M3 muscarinic receptors located on the basolateral membrane [104]. Stimulation with ACh and CCK causes an increase in intracellular Ca2+ concentration by stimulating G-protein coupled receptors that activate the phospholipase C pathway, which activates the calcium-activating chloride channels and possibly also the apical Cl− /HCO3 <sup>−</sup> exchanger, triggering ductal secretion [67, 105]. The effect of cholecystokinin (CCK) in humans is that of a potentiator of secretin effects on ductal HCO3 − and fluid output. The enhancing effects of secretin most likely occur by stimulation of vagal afferent fibres [68]. This indicates a synergistic relationship between the Ca2+ and cAMP pathways [74]. Ductal cells also express several types of purinergic receptors and intra-luminal application of ATP and UTP results in enhanced HCO3 − secretion [73, 106]. Luminal ATP causes stimulation of HCO3 − and pancreatic fluid which quantitatively approaches 75% of maximal secretin stimulation. In contrast, on the basolateral side, ATP inhibits both spontaneous and secretin-evoked secretion by as much as 50% [107].

Substance P, 5-HT, AVP, and the afore-mentioned basolateral ATP fall in the category of potential inhibitory factors in pancreatic HCO3 − secretion. Although molecular mechanisms of inhibition are not yet fully understood, their role is most likely curtailment of luminal hydrostatic pressure, which precludes enzyme leakage into the pancreatic parenchyma and discontinuation of secretion after a meal [67].

#### **3.5. Molecular mechanisms of ductal cell secretion**

One of the earlier models of ductal cell HCO3 − secretion proposed by Ashton, Argent and Green presupposes intracellular generation of HCO3 − from CO2, and hydration by carbonic anhydrase. The dissociated proton is transported by a Na+ /H+ exchanger, located on the basolateral membrane, and the HCO3 <sup>−</sup> ions are transported into the lumen by a HCO3 − /Cl− exchanger that is driven by the luminal Cl− availability. The luminal Cl− gradient is maintained by a cAMPactivated Cl− channel, regulated by secretin. Since the exit of HCO3 − in this model is electrogenic, it is accompanied by outflow of K+ ions through the cAMP activated maxi-K channels. This model, while providing an explanation for much of what is observed in pancreatic duct cell secretion in many species, is however, limited to a maximum luminal HCO3 <sup>−</sup> concentration of about 70 mmol/L. Human pancreatic duct cells, on the other hand, create a luminal HCO3 − concentration as high as 140 mmol/L and above [67, 68, 108, 109].

In attempts to bring the mechanisms that account for such a high HCO3 <sup>−</sup> secretion to light, several models have been proposed [110, 111]. As new information about the identity and properties of ion transporters and channels as well as cellular mechanisms of their action were discovered, a revised two-step model as described below has been suggested.

**Figure 3.** Regulation and molecular mechanisms of secretion in pancreatic acinar and ductal cells. Depiction of molecular mechanisms of pancreatic secretion in the lower half of the image and regulation of pancreatic secretion in the upper half of the image and changes in luminal Cl− ¸and HCO3 − concentrations in the lumen (see text for details).

In the proximal duct, HCO3 <sup>−</sup> is actively transported and accumulated in the cytosol of ductal cells by a 1Na+ -2HCO3 − co-transporter NBCe1-B on the basolateral membrane, which is driven by the Na+ gradient. Secretion of HCO3 <sup>−</sup> on the luminal side occurs by way of a 1Cl− /2HCO3 − exchanger SLC26A6, while the CFTR provides a recycling path for Cl− ions. HCO3 − secretion drives the translocation of Na+ ions to the lumen by a paracellular pathway. These two processes create a driving force for water efflux by AQP1 [74]. The proximal duct absorbs a part of the Cl− and secretes up to 100 mmol/L of HCO3 − and provides much of the aqueous part of the pancreatic fluid. By the time the fluid reaches the distal segments of the duct, the lumen is Cl− depleted to approximately 30 mmol/L and due to the active CFTR, the intracellular Cl− concentration drops to 10 mmol/L or less. Low concentration of Cl− activates the WNK1-OSR1/ SPAK pathway, which results in two events. First, the permeability of CFTR changes in favour of HCO3 − , making CFTR a route for HCO3 <sup>−</sup> secretion. Second, the SLC26A6 is inhibited, which favours HCO3 − accumulation in the lumen since its active state would most likely result in reabsorption, not secretion as in the proximal lumen [67, 74, 93, 112, 113] (**Figure 3**).

static pressure, which precludes enzyme leakage into the pancreatic parenchyma and discon-

−

availability. The luminal Cl−

channel, regulated by secretin. Since the exit of HCO3

cell secretion in many species, is however, limited to a maximum luminal HCO3

In attempts to bring the mechanisms that account for such a high HCO3

discovered, a revised two-step model as described below has been suggested.

concentration as high as 140 mmol/L and above [67, 68, 108, 109].

−

genic, it is accompanied by outflow of K+ ions through the cAMP activated maxi-K channels. This model, while providing an explanation for much of what is observed in pancreatic duct

of about 70 mmol/L. Human pancreatic duct cells, on the other hand, create a luminal HCO3

several models have been proposed [110, 111]. As new information about the identity and properties of ion transporters and channels as well as cellular mechanisms of their action were

**Figure 3.** Regulation and molecular mechanisms of secretion in pancreatic acinar and ductal cells. Depiction of molecular mechanisms of pancreatic secretion in the lower half of the image and regulation of pancreatic secretion in the up-

concentrations in the lumen (see text for details).

¸and HCO3 −

<sup>−</sup> ions are transported into the lumen by a HCO3

/H+

secretion proposed by Ashton, Argent and Green

−

from CO2, and hydration by carbonic anhy-

exchanger, located on the basolateral

gradient is maintained by a cAMP-

exchanger that

<sup>−</sup> concentration

<sup>−</sup> secretion to light,

−

in this model is electro-

− /Cl−

tinuation of secretion after a meal [67].

membrane, and the HCO3

30 Challenges in Pancreatic Pathology

activated Cl−

is driven by the luminal Cl−

per half of the image and changes in luminal Cl−

One of the earlier models of ductal cell HCO3

presupposes intracellular generation of HCO3

**3.5. Molecular mechanisms of ductal cell secretion**

drase. The dissociated proton is transported by a Na+

A mutation in the CFTR encoding gene that codes for the chloride and bicarbonate channel involved in pancreatic ductal cell fluid secretion results in a disease called cystic fibrosis, where anomalous fluid secretion results in dysfunction in several organ systems such as the lung, gastrointestinal tract, liver, male reproductive tract and pancreas. Reduced or even absent CFTR function causes a change in ductal fluid composition – decreased pH and fluid volume, and hyper-concentration of fluid components – that is thought to lead to obstruction. As the disease progresses, acinus plugging and dilation provoke epithelial injury and destruction, with inflammation, calcium deposits and fibrosis. These pathological processes lead to indigestion and malnutrition [114, 115].

#### **3.6. Meal-response of pancreatic secretion and the inter-digestive phase**

The basal pancreatic exocrine secretion rate reaches approximately 20% of the maximum capacity for enzyme secretion in humans. This basal secretion could be explained by an intrinsic characteristic of the pancreas, stimulation of the gland by low levels of CCK or secretin, or by ACh release [88]. Inhibition of ACh and CCK input reduces pancreatic enzyme secretion by about 50% [116].

The basal pancreatic duct HCO3 − secretion amounts to only 1–2% in comparison with secretion stimulated with exogenous secretin. Since secretin is the primary regulator of HCO3 <sup>−</sup> secretion, basal HCO3 − mainly parallels plasma secretin levels, along with cholinergic input [88].

In the long term, this is, however, not the full extent of regulation. Inter-digestive pancreatic exocrine function is cyclically coupled with fasting motility phases termed the inter-digestive migratory motor complex (MMC), although they do follow different trends for overall daytime and night time secretory and motor activity [117, 118]. Upon ingestion of a meal, this behaviour is interrupted within minutes. Postprandial enzyme secretion reaches peak levels within the first hour and decreases followed by a stable phase of secretion, only to return to inter-digestive levels in 3–4 h [119].

The meal response of pancreatic secretion can be divided into four phases, i.e. cephalic, gastric, intestinal and inter-digestive phases. The names correspond to the origin of the predominant form of pancreatic secretion control. There is however significant overlap and integration between these regulatory mechanisms in response to a meal. Average pancreatic secretion stimulated by a meal amounts to about 50–60% of the maximum output of the gland [120–122].

The cephalic phase contributes approximately 25% of the meal-response secretion. It is caused by input of visual, olfactory, gustatory and tactile (mastication) sensory modalities. Sham feeding (a process, in which people are allowed to see, smell, taste but not swallow the food) causes pancreatic secretion that is rich in enzymes but low in concentration and volume of HCO3 <sup>−</sup> [88]. It amounts to a response that is up to 50% of maximum secretory capacity. The main mediator of the cephalic phase is the vagus nerve with ACh as the dominant neurotransmitter [123].

The gastric phase accounts for about 10% of the meal-response secretion and starts with arrival of food into the stomach. It is regulated by enteropancreatic, vagovagal reflexes, which are stimulated by gastric distension [121].

The majority of the meal-response pancreatic secretion occurs in the intestinal phase. The secretory output amounts to 50–60% of maximal capacity [120]. It starts as the acidic chyme from the stomach, passes into the intestine, where components of the chyme, HCl, bile and bile salts elicit hormonal and neural responses. Hormonal influence on pancreatic secretion in the intestinal phase is mainly the result of CCK and secretin and the amplification of the secretory response by neural influences of the enteropancreatic reflex [121]. Passing of stomach contents into the intestine lowers the luminal pH, which is a signal for the duodenal S cells to release secretin. It, in turn, functions as the main secretagogue for HCO3 <sup>−</sup> secretion from the ductal cells and also as an enhancer of enzyme secretion from the acinar cells [77, 102].
