Title: New insights into neurohormonal regulation of pancreatic secretion
Abstract: The existence of high- and low-affinity cholecystokinin (CCK)-A receptors on rodent pancreatic acini is well established. Until recently, CCK was believed to act directly on pancreatic acini to stimulate pancreatic secretion in both rodents and humans. However, conclusive evidence that human pancreatic acini lack functional CCK-A receptors has been presented. Despite substantial differences in rodent and human pancreatic physiology, CCK appears to act via vagal cholinergic pathways to mediate pancreatic secretion in both species. Structural and functional evidence suggests that CCK acts on vagal afferent fibers, which may explain how CCK doses that produce physiologic plasma CCK levels act via vagal cholinergic pathways to stimulate pancreatic secretion. Although most knowledge of vagal CCK-A receptors comes from research on rodents, physiologic studies suggest that this information is applicable to humans. In contrast to its effect on satiety, which is mediated by low-affinity vagal CCK-A receptors, CCK acts through high-affinity CCK-A receptors to evoke pancreatic secretion, suggesting that different affinity states of the vagal CCK receptors mediate different digestive functions. Vagal afferent pathways also transmit sensory information about the mechanical and physiochemical state of the digestive tract, mediated in part by serotonin, which, in turn, influences pancreatic secretion. A synergistic interaction between CCK and serotonin at the level of the nodose ganglia may explain the robust postprandial pancreatic secretion despite a modest postprandial increase in plasma CCK. Important physiologically, these findings not only explain discrepancies in previous in vivo vs. in vitro studies, but they revolutionize our current concept of the mechanism of CCK on pancreatic exocrine secretion. The existence of high- and low-affinity cholecystokinin (CCK)-A receptors on rodent pancreatic acini is well established. Until recently, CCK was believed to act directly on pancreatic acini to stimulate pancreatic secretion in both rodents and humans. However, conclusive evidence that human pancreatic acini lack functional CCK-A receptors has been presented. Despite substantial differences in rodent and human pancreatic physiology, CCK appears to act via vagal cholinergic pathways to mediate pancreatic secretion in both species. Structural and functional evidence suggests that CCK acts on vagal afferent fibers, which may explain how CCK doses that produce physiologic plasma CCK levels act via vagal cholinergic pathways to stimulate pancreatic secretion. Although most knowledge of vagal CCK-A receptors comes from research on rodents, physiologic studies suggest that this information is applicable to humans. In contrast to its effect on satiety, which is mediated by low-affinity vagal CCK-A receptors, CCK acts through high-affinity CCK-A receptors to evoke pancreatic secretion, suggesting that different affinity states of the vagal CCK receptors mediate different digestive functions. Vagal afferent pathways also transmit sensory information about the mechanical and physiochemical state of the digestive tract, mediated in part by serotonin, which, in turn, influences pancreatic secretion. A synergistic interaction between CCK and serotonin at the level of the nodose ganglia may explain the robust postprandial pancreatic secretion despite a modest postprandial increase in plasma CCK. Important physiologically, these findings not only explain discrepancies in previous in vivo vs. in vitro studies, but they revolutionize our current concept of the mechanism of CCK on pancreatic exocrine secretion. The mediation of postprandial pancreatic enzyme secretion has been ascribed mainly to the peptides cholecystokinin (CCK) and serotonin (5-hydroxytryptamine; 5-HT) and to the vago-vagal reflex, which activates cholinergic postganglionic neurons in the pancreas. Knowledge of these regulatory mechanisms is considerable; however, evidence that both CCK and 5-HT act via the vagal cholinergic pathways to mediate pancreatic enzyme secretion suggests a more complex picture. Furthermore, vagal afferent signals evoked by CCK appear to be enhanced by 5-HT to stimulate pancreatic secretion. This review will discuss the current understanding of neurohormonal control of pancreatic enzyme secretion. CCK actions, both direct and neural, have been shown to mediate pancreatic secretion in rats, whereas, in humans, CCK appears to act entirely via the vagal cholinergic pathway. We will compare in vitro and in vivo actions of CCK on pancreatic secretion in rodents and humans. Conclusive evidence that human pancreatic acini lack functional CCK-A receptors will be presented, as will structural and functional evidence that CCK acts via the vagal afferent pathway to mediate pancreatic enzyme secretion. In contrast to its effect on satiety, which is mediated by low-affinity vagal CCK-A receptors, CCK acts through high-affinity CCK-A receptors to evoke pancreatic secretion. The mechanisms by which non-CCK-dependent duodenal stimuli evoke pancreatic enzyme secretion acting through intestinal 5-HT will also be reviewed. The synergistic interaction between CCK and 5-HT in the mediation of postprandial pancreatic secretion will be discussed. Important physiologic ramifications notwithstanding, these findings explain the discrepancies observed in previous in vivo vs. in vitro studies, and they revolutionize our current concept of the mechanism of action of CCK on pancreatic exocrine secretion. CCK acts directly on pancreatic acini to stimulate pancreatic secretion or so researchers have believed. Most data supporting this belief were obtained using dispersed pancreatic acini from rodents. CCK-A receptors are known to preside on pancreatic acini and exist in both high- and low-affinity states.1Sankaran H. Goldfine I.D. Bailey A. Licko V. Williams J.A. Relationship of cholecystokinin receptor binding to regulation of biological functions in pancreatic acini.Am J Physiol. 1982; 242: G250-G257PubMed Google Scholar, 2Jensen R.T. Wank S.A. Rowley W.H. Sato S. Gardner J.D. Interaction of CCK with pancreatic acinar cells.Trends Pharmacol Sci. 1989; 10: 418-423Abstract Full Text PDF PubMed Scopus (175) Google Scholar A third CCK-A receptor, also existing in a low-affinity state, has been proposed.3Yu D.H. Huang S.L. Wank S.A. Mantey S. Gardner J.D. Jensen R.T. Pancreatic receptors for cholecystokinin evidence for three receptor classes.Am J Physiol. 1990; 258: G86-G95PubMed Google Scholar In vitro studies have shown that CCK-A receptors are highly sensitive to CCK at levels as low as 1 pmol/L. Binding of CCK to CCK-A receptors on rat pancreatic acinar cells leads to an increase in the concentration of intracellular Ca2+ and an increase in digestive enzyme secretion in vitro.2Jensen R.T. Wank S.A. Rowley W.H. Sato S. Gardner J.D. Interaction of CCK with pancreatic acinar cells.Trends Pharmacol Sci. 1989; 10: 418-423Abstract Full Text PDF PubMed Scopus (175) Google Scholar These observations, together with the knowledge that atropine does not alter the enzyme response to CCK in isolated pancreatic acini4Williams J.A. Korc M. Dormer R.L. Action of secretagogues on a new preparation of functionally intact, isolated pancreatic acini.Am J Physiol. 1978; 235: 517-524PubMed Google Scholar and that the effects of cholinergic agonists and CCK in such preparations are merely additive,4Williams J.A. Korc M. Dormer R.L. Action of secretagogues on a new preparation of functionally intact, isolated pancreatic acini.Am J Physiol. 1978; 235: 517-524PubMed Google Scholar, 5Peikin S.R. Rottman A.J. Batzri S. Gardner J.D. Kinetics of amylase release by dispersed acini prepared from guinea pig pancreas.Am J Physiol. 1978; 235: E517-E524PubMed Google Scholar suggest that the effect of CCK on pancreatic enzyme secretion is not cholinergically dependent. Hence, in rodents, at least 1 mechanism by which CCK stimulates pancreatic enzyme secretion is by direct action on CCK-A receptors that are expressed on pancreatic acinar cells. Whether this direct mechanism functions in humans has been difficult to ascertain because of the controversy regarding the presence and identity of CCK receptors on human pancreatic acinar cells. Receptor presence can be established biochemically, at the level of receptor mRNA or protein, or functionally. The expression of CCK-A receptors on rodent pancreatic acinar cells was readily established by each of these criteria. Multiple approaches, including radioligand binding to isolated acini,6Sankaran H. Goldfine I.D. Deveney C.W. Wong K.Y. Williams J.A. Binding of cholecystokinin to high affinity receptors on isolated rat pancreatic acini.J Biol Chem. 1980; 255: 1849-1853Abstract Full Text PDF PubMed Google Scholar, 7Jensen R.T. Lemp G.F. Gardner J.D. Interaction of cholecystokinin with specific membrane receptors on pancreatic acinar cells.Proc Natl Acad Sci U S A. 1980; 77: 2079-2083Crossref PubMed Scopus (223) Google Scholar receptor cross-linking,8Klueppelberg U.G. Powers S.P. Miller L.J. The efficiency of covalent labeling of the pancreatic cholecystokinin receptor using a battery of crosslinkable and photolabile probes.Receptor. 1990; 1: 1-11PubMed Google Scholar receptor autoradiography in situ,9Sakamoto C. Goldfine I.D. Roach E. Williams J.A. Localization of saturable CCK binding sites in rat pancreatic islets by light and electron microscope autoradiography.Diabetes. 1985; 34: 390-394Crossref PubMed Google Scholar Northern blot analysis,10Wank S.A. Pisegna J.R. de Weerth A. Cholecystokinin receptor family. Molecular cloning, structure, and functional expression in rat, guinea pig, and human.Ann N Y Acad Sci. 1994; 713: 49-66Crossref PubMed Scopus (151) Google Scholar, 11Monstein J.H. Nylander A.G. Salehi A. Chen D. Lundquist I. Hakanson R. Cholecystokinin-A and cholecystokinin-B/gastrin receptor mRNA expression in the gastrointestinal tract and pancreas of the rat and man. A polymerase chain reaction study.Scand J Gastroenterol. 1996; 31: 383-390Crossref PubMed Scopus (109) Google Scholar, 12Zhou W. Povoski S.P. Bell Jr, R.H. Characterization of cholecystokinin receptors and messenger RNA expression in rat pancreas evidence for expression of cholecystokinin-A receptors but not cholecystokinin-B (gastrin) receptors.J Surg Res. 1995; 58: 281-289Abstract Full Text PDF PubMed Scopus (24) Google Scholar polymerase chain reaction studies,11Monstein J.H. Nylander A.G. Salehi A. Chen D. Lundquist I. Hakanson R. Cholecystokinin-A and cholecystokinin-B/gastrin receptor mRNA expression in the gastrointestinal tract and pancreas of the rat and man. A polymerase chain reaction study.Scand J Gastroenterol. 1996; 31: 383-390Crossref PubMed Scopus (109) Google Scholar and in vitro secretion studies4Williams J.A. Korc M. Dormer R.L. Action of secretagogues on a new preparation of functionally intact, isolated pancreatic acini.Am J Physiol. 1978; 235: 517-524PubMed Google Scholar identified the CCK receptor on rat pancreatic acinar cells to be the CCK-A subtype. In contrast, the presence, let alone the type, of CCK receptors in the human pancreas has been difficult to verify using any criterion. Early attempts using Northern blot analysis10Wank S.A. Pisegna J.R. de Weerth A. Cholecystokinin receptor family. Molecular cloning, structure, and functional expression in rat, guinea pig, and human.Ann N Y Acad Sci. 1994; 713: 49-66Crossref PubMed Scopus (151) Google Scholar and the sensitive method of reverse-transcriptase polymerase chain reaction13Weinberg D.S. Ruggeri B. Barber M.T. Biswas S. Miknyocki S. Waldman S.A. Cholecystokinin A and B receptors are differentially expressed in normal pancreas and pancreatic adenocarcinoma.J Clin Invest. 1997; 100: 597-603Crossref PubMed Scopus (103) Google Scholar failed to detect CCK-A receptor mRNA in the human pancreas. Researchers eventually succeeded in detecting CCK receptors using reverse-transcriptase polymerase chain reaction,11Monstein J.H. Nylander A.G. Salehi A. Chen D. Lundquist I. Hakanson R. Cholecystokinin-A and cholecystokinin-B/gastrin receptor mRNA expression in the gastrointestinal tract and pancreas of the rat and man. A polymerase chain reaction study.Scand J Gastroenterol. 1996; 31: 383-390Crossref PubMed Scopus (109) Google Scholar, 14Ji B. Bi Y. Simeone D. Mortensen R.M. Logsdon C.D. Human pancreatic acinar cells lack functional responses to cholecystokinin and gastrin.Gastroenterology. 2001; 121: 1380-1390Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 15Nishimori I. Kamakura M. Fujikawa-Adachi K. Nojima M. Onishi S. Hollingsworth M.A. Harris A. Cholecystokinin A and B receptor mRNA expression in human pancreas.Pancreas. 1999; 19: 109-113Crossref PubMed Scopus (29) Google Scholar but, unlike the rodent pancreas, CCK-B rather than CCK-A receptor mRNA was found to bepredominant (Figure 1). In this regard, humans resemble several other species, including calves,16Le Meuth V. Philouze-Rome V. Le Huerou-Luron I. Formal M. Vaysse N. Gespach C. Guilloteau P. Fourmy D. Differential expression of A- and B-subtypes of cholecystokinin/gastrin receptors in the developing calf pancreas.Endocrinology. 1993; 133: 1182-1191Crossref PubMed Scopus (53) Google Scholar pigs,17Morisset J. Levenez F. Corring T. Benrezzak O. Pelletier G. Calvo E. Pig pancreatic acinar cells possess predominantly the CCK-B receptor subtype.Am J Physiol. 1996; 271: E397-E402PubMed Google Scholar and dogs.18Kopin A.S. Lee Y.M. McBride E.W. Miller L.J. Lu M. Lin H.Y. Kolakowski L.F.J. Beinborn M. Expression cloning and characterization of the canine parietal cell gastrin receptor.Proc Natl Acad Sci U S A. 1992; 89: 3605-3609Crossref PubMed Scopus (478) Google Scholar, 19Fourmy D. Zahidi A. Pradayrol L. Vayssette J. Ribet A. Relationship of CCK/gastrin receptor binding to amylase release in dog pancreatic acini.Regul Pept. 1984; 10: 57-68Crossref PubMed Scopus (20) Google Scholar Receptor autoradiography confirmed this finding; CCK-B receptors but not CCK-A receptors were detected in sections of human pancreas.20Tang C. Biemond I. Lamers C.B. Cholecystokinin receptors in human pancreas and gallbladder muscle a comparative study.Gastroenterology. 1996; 111: 1621-1626Abstract Full Text PDF PubMed Scopus (64) Google Scholar Quantitative polymerase chain reaction methods have since explained the difficulties encountered in detecting CCK-A receptor messenger RNA (mRNA) in human samples. Low levels of mRNA for both CCK receptor subtypes were measured in human pancreas.21Higuchi R. Fockler C. Dollinger G. Watson R. Kinetic PCR analysis real-time monitoring of DNA amplification reactions.Bio/Technology. 1993; 11: 1026-1030Crossref PubMed Scopus (1697) Google Scholar CCK-B receptor mRNA levels were at least 10-fold lower than mRNA levels for m3 muscarinic cholinergic receptors in human pancreas. In rats, by comparison, CCK-A receptor RNA levels were similar to m3 muscarinic cholinergic receptor mRNA levels. Furthermore, in human samples, mRNA levels for CCK-A receptors were much lower than those for CCK-B receptors and in fact were estimated to be less than 1 copy per acinar cell. Therefore, studies of human acinar cells at the level of mRNA did not support the expression of CCK-A receptors in any significant amount but suggested rather the presence, albeit at low levels, of CCK-B receptors. The expression of CCK-B receptors on human pancreatic acinar cells has been difficult to corroborate. Immunohistochemical studies failed to detect significant CCK-B expression on human pancreatic acinar cells; those receptors observed appeared to be localized to cells within the pancreatic islets of Langerhans.22Saillan-Barreau C. Dufresne M. Clerc P. Sanchez D. Corominola H. Moriscot C. Guy-Crotte O. Escrieut C. Vaysse N. Gomis R. Tarasova N. Fourmy D. Evidence for a functional role of the cholecystokinin-B/gastrin receptor in the human fetal and adult pancreas.Diabetes. 1999; 48: 2015-2021Crossref PubMed Scopus (77) Google Scholar, 23Morisset J. Laine J. Courassa J. Lessard M. Rome V. Guilloteau P. Presence and localization of CCK receptor subtypes in calf pancreas.Regul Pept. 2003; 111: 103-109Crossref PubMed Scopus (15) Google Scholar, 24Morisset J. Wong H. Walsh J.H. Laine J. Bourassa J. Pancreatic CCK(B) receptors their potential roles in somatostatin release and δ-cell proliferation.Am J Physiol Gastrointest Liver Physiol. 2000; 279: G148-G156PubMed Google Scholar Specifically, CCK-B receptors were reported to exist on the somatostatin-secreting D cells,23Morisset J. Laine J. Courassa J. Lessard M. Rome V. Guilloteau P. Presence and localization of CCK receptor subtypes in calf pancreas.Regul Pept. 2003; 111: 103-109Crossref PubMed Scopus (15) Google Scholar, 24Morisset J. Wong H. Walsh J.H. Laine J. Bourassa J. Pancreatic CCK(B) receptors their potential roles in somatostatin release and δ-cell proliferation.Am J Physiol Gastrointest Liver Physiol. 2000; 279: G148-G156PubMed Google Scholar and CCK-A receptors were observed on insulin-secreting β cells in fetal human pancreas.22Saillan-Barreau C. Dufresne M. Clerc P. Sanchez D. Corominola H. Moriscot C. Guy-Crotte O. Escrieut C. Vaysse N. Gomis R. Tarasova N. Fourmy D. Evidence for a functional role of the cholecystokinin-B/gastrin receptor in the human fetal and adult pancreas.Diabetes. 1999; 48: 2015-2021Crossref PubMed Scopus (77) Google Scholar Conclusive evidence for the presence of either CCK-A or CCK-B receptors on human acinar cells could not be found. The most compelling evidence that human pancreatic acinar cells lack CCK receptors has come from functional studies. Early attempts to isolate human acini resulted in preparations that showed low levels of response to stimulation; the isolated acini appeared to respond only to pharmacologically high concentrations of either CCK or the acetylcholine agonist carbachol.25Susini C. Estival A. Scemama J.L. Ruellan C. Vaysse N. Clemente F. Esteve J.P. Fourmy D. Ribet A. Studies on human pancreatic acini action of secretagogues on amylase release and cellular cyclic AMP accumulation.Pancreas. 1986; 1: 124-129Crossref PubMed Scopus (37) Google Scholar The difficulties of obtaining viable samples of normal human pancreas combined with the formidable challenge of isolating functional preparations of acini were thought to explain this apparent lack of responsiveness. Subsequently, preparations of normal human acini were produced that showed robust secretory responses to activation of muscarinic cholinergic receptors and no response to stimulation with CCK.14Ji B. Bi Y. Simeone D. Mortensen R.M. Logsdon C.D. Human pancreatic acinar cells lack functional responses to cholecystokinin and gastrin.Gastroenterology. 2001; 121: 1380-1390Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 26Miyasaka K. Shinozaki H. Jimi A. Funakoshi A. Amylase secretion from dispersed human pancreatic acini neither cholecystokinin A nor cholecystokinin B receptors mediate amylase secretion in vitro.Pancreas. 2002; 25: 161-165Crossref PubMed Scopus (34) Google Scholar Additional evidence of the functionality of the isolated human acinar cells came from experiments indicating that adenoviral-mediated transfer of CCK-A receptor cDNA resulted in full secretory responses to CCK stimulation (Figure 2).14Ji B. Bi Y. Simeone D. Mortensen R.M. Logsdon C.D. Human pancreatic acinar cells lack functional responses to cholecystokinin and gastrin.Gastroenterology. 2001; 121: 1380-1390Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Furthermore, an increase in the concentration of intracellular Ca2+ was measured in isolated human acini treated with CCK, after, but not before, CCK receptor gene transfer (Figure 3).14Ji B. Bi Y. Simeone D. Mortensen R.M. Logsdon C.D. Human pancreatic acinar cells lack functional responses to cholecystokinin and gastrin.Gastroenterology. 2001; 121: 1380-1390Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Because changes in intracellular Ca2+ are a sensitive biologic indicator of CCK receptor activation, these data strongly indicate the lack of direct functional responses to CCK in human pancreatic acinar cells.Figure 3Intracellular Ca2+ levels increase in human pancreatic acini in response to carbachol but not to CCK-8. An estimate of intracellular Ca2+ was obtained by measuring emitted fluorescence from fura-2-loaded acini using an Attofluor digital imaging system. CCK-8 (100 nmol/L) or carbachol (1 mmol/L) was introduced at the times indicated. (A) Freshly prepared acini were treated with CCK-8 and then carbachol. Acini infected for 4 hours with an adenovirus encoded with either human CCK-B receptor (B) or rat CCK-A receptor (C) were treated with CCK-8 (100 nmol/L). Data shown are typical and are representative of 4 separate experiments. Reprinted with permission from Ji et al.14Ji B. Bi Y. Simeone D. Mortensen R.M. Logsdon C.D. Human pancreatic acinar cells lack functional responses to cholecystokinin and gastrin.Gastroenterology. 2001; 121: 1380-1390Abstract Full Text Full Text PDF PubMed Scopus (121) Google ScholarView Large Image Figure ViewerDownload Hi-res image Download (PPT) Experimental evidence suggests that cholinergic pathways play a major role in mediating pancreatic secretion under physiologic conditions. Konturek et al.27Konturek S.J. Tasler J. Ottulowicz W. Effect of atropine on pancreatic responses to endogenous and exogenous cholecystokinin.Dig Dis Sci. 1972; 17: 911-917Crossref Scopus (53) Google Scholar demonstrated that blockade of the cholinergic nervous system suppressed basal pancreatic secretion in dogs. Furthermore, atropine inhibited 80% of the pancreatic protein output evoked by intraduodenal perfusion of an amino acid mixture. Others confirmed inhibition of amino acid- and oleate-evoked enzyme output.28Singer M.V. Soloman T.E. Grossman M.L. Effect of atropine on secretion from intact and transplanted pancreas in dog.Am J Physiol. 1980; 238: G18-G22PubMed Google Scholar, 29Thomas J.E. Mechanism of action of pancreatic stimuli studied by means of atropine-like drugs.Am J Physiol. 1964; 206: 124-128PubMed Google Scholar, 30Thomas J.E. Crider J.O. The secretion of pancreatic juice in the presence of atropine and hyoscamine in chronic fistula dogs.J Pharmacol Exp Ther. 1946; 87: 81-89PubMed Google Scholar, 31Valenzuela J.E. Lamers C.B. Modlin I.M. Walsh J.H. Cholinergic component in the human pancreatic secretory response to intra-intestinal oleate.Gut. 1983; 24: 807-811Crossref PubMed Scopus (50) Google Scholar Numerous investigators, however, failed to demonstrate atropine inhibition of CCK- or CCK-like peptide-evoked pancreatic enzyme secretion in the dog.29Thomas J.E. Mechanism of action of pancreatic stimuli studied by means of atropine-like drugs.Am J Physiol. 1964; 206: 124-128PubMed Google Scholar, 32Henriksen F.W. Effect of vagotomy or atropine on the canine pancreatic response to secretin and pancreozymin.Scand J Gastroenterol. 1969; 4: 137-144Crossref PubMed Scopus (52) Google Scholar None of these studies assessed whether the high doses of CCK typically used reproduced physiologic conditions. Konturek et al.27Konturek S.J. Tasler J. Ottulowicz W. Effect of atropine on pancreatic responses to endogenous and exogenous cholecystokinin.Dig Dis Sci. 1972; 17: 911-917Crossref Scopus (53) Google Scholar reported that atropine inhibited pancreatic enzyme secretion induced by low doses of exogenous CCK in dogs, whereas enzyme output in response to high doses of CCK was relatively insensitive to atropine. Soudah et al.33Soudah H. Lu Y. Hasler W.L. Owyang C. Cholecystokinin at physiological levels evokes pancreatic enzyme secretion via a cholinergic pathway.Am J Physiol. 1992; 263: G102-G107PubMed Google Scholar and others34Guido A. Beglinger C. Braun U. Reinshagen M. Arnold R. Interaction of the cholinergic system and cholecystokinin in the regulation of endogenous and exogenous stimulation of pancreatic secretion in humans.Gastroenterology. 1991; 100: 537-543PubMed Google Scholar, 35Bozkurt T. Adler G. Koop I. Arnold R. Effect of atropine on intestinal phase of pancreatic secretion in man.Digestion. 1988; 41: 108-115Crossref PubMed Scopus (33) Google Scholar reported similar observations in humans; in healthy subjects, CCK infusion that produces plasma CCK levels similar to those seen postprandially stimulates pancreatic secretion by an atropine-sensitive pathway (Figure 4). Considered together, these observations suggest that, in experimental animals and in humans, cholinergic neural pathways rather than pancreatic acini represent the primary targets in which CCK acts to stimulate pancreatic enzyme secretion. Atropine and hexamethonium completely abolish pancreatic enzyme responses to physiologic doses of CCK in rats, which suggests that CCK acts on a presynaptic site along the cholinergic pathway.36Li Y. Owyang C. Vagal afferent pathway mediates physiological action of cholecystokinin on pancreatic enzyme secretion.J Clin Invest. 1993; 982: 418-424Crossref Scopus (190) Google Scholar Vagotomy also completely abolishes pancreatic responses to CCK stimulation but has little effect on the pancreatic response to supraphysiologic doses of CCK.36Li Y. Owyang C. Vagal afferent pathway mediates physiological action of cholecystokinin on pancreatic enzyme secretion.J Clin Invest. 1993; 982: 418-424Crossref Scopus (190) Google Scholar The proposal that direct stimulation of pancreatic acinar secretion by CCK requires a basal vagal cholinergic tone was ruled out by the demonstration that, after vagotomy, CCK did not evoke an additional increase in pancreatic secretion stimulated by bethanechol.36Li Y. Owyang C. Vagal afferent pathway mediates physiological action of cholecystokinin on pancreatic enzyme secretion.J Clin Invest. 1993; 982: 418-424Crossref Scopus (190) Google Scholar This result suggests rather that CCK stimulates pancreatic secretion via vagal pathways, a premise supported by previous reports that truncal vagotomy leads to reduced basal and nutrient-stimulated pancreatic secretion.34Guido A. Beglinger C. Braun U. Reinshagen M. Arnold R. Interaction of the cholinergic system and cholecystokinin in the regulation of endogenous and exogenous stimulation of pancreatic secretion in humans.Gastroenterology. 1991; 100: 537-543PubMed Google Scholar, 37Soloman T.E. Control of exocrine pancreatic secretion.in: Johnson L.R. Physiology of the gastrointestinal tract. Volume 1. Raven Press, New York1994: 1499-1529Google Scholar These findings must be contrasted with earlier reports that vagotomy did not significantly reduce pancreatic enzyme secretion in response to exogenous CCK.38Chariot J. Nagain C. Hugonet F. Tsocas A. Roze C. Control of interdigestive and intraduodenal meal-stimulated pancreatic secretion in rats.Am J Physiol. 1990; 259: G198-G204PubMed Google Scholar, 39O'Rourke M.F. Reidelberger K.D. Soloman T.E. Effects of atropine on pancreatic response to bethanechol, cholecystokinin and food intake in rats.Am J Physiol. 1991; 261: G735-G741PubMed Google Scholar, 40Soloman T.I. Grossman M.I. Effect of atropine and vagotomy on response of transplanted pancreas.Am J Physiol. 1979; 236: E180-E190PubMed Google Scholar Contradictory findings such as these may be the result of different lengths of time postvagotomy prior to taking experimental measurements and, in the earlier studies, the use of supraphysiologic doses of CCK. The pancreas quickly regains function when challenged with vagal injury.41Li Y. Owyang C. Musings on the wanderer: what's new in our understanding of vago-vagal reflexes? V. Remodeling of vagus and enteric neural circuitry after vagal injury.Am J Physiol Gastrointest Liver Physiol. 2003; 285: G461-G469Crossref PubMed Scopus (42) Google Scholar This extraordinary plasticity may explain both the profound effect36Li Y. Owyang C. Vagal afferent pathway mediates physiological action of cholecystokinin on pancreatic enzyme secretion.J Clin Invest. 1993; 982: 418-424Crossref Scopus (190) Google Scholar, 37Soloman T.E. Control of exocrine pancreatic secretion.in: Johnson L.R. Physiology of the gastrointestinal tract. Volume 1. Raven Press, New York1994: 1499-1529Google Scholar and the absence of effect of vagotomy on pancreatic secretion.38Chariot J. Nagain C. Hugonet F. Tsocas A. Roze C. Control of interdigestive and intraduodenal meal-stimulated pancreatic secretion in rats.Am J Physiol. 1990; 259: G198-G204PubMed Google Scholar, 40Soloman T.I. Grossman M.I. Effect of atropine and vagotomy on response of transplanted pancreas.Am J Physiol. 1979; 236: E180-E190PubMed Google Scholar, 42Konturek S.J. Radecki T. Biernat J. Thor P. Effect of vagotomy on pancreatic secretion evoked by endogenous and exogenous cholecystokinin and caerulein.Gastroenterology. 1972; 63: 273-278PubMed Google Scholar After chronic vagotomy, pancreatic protein secretion in response to CCK-8 stimulation is fully restored by day 20 in both anesthetized and conscious rat models.43Li Y. Owyang C. Mechanism underlying pancreatic adaptation following vagotomy mediation by recruitment of CCK-sensitive intrapancreatic neurons.Gastroenterology. 1993; 104 (abstr): A318Google Scholar, 44Owyang C. Physiological mechanisms of cholecystokinin action on pancreatic secretion.Am J Physiol. 1996; 271: G1-G7PubMed Google Scholar In contrast to its effect in vagally intact rats, atropine fails to inhibit pancreatic secretion stimulated by CCK in chronically vagotomized rats.43Li Y. Owyang C. Mechanism underlying pancreatic adaptation following vagotomy mediation by recruitment of CCK-sensitive intrapancreatic neurons.Gastroent
Publication Year: 2004
Publication Date: 2004-09-01
Language: en
Type: review
Indexed In: ['crossref', 'pubmed']
Access and Citation
Cited By Count: 150
AI Researcher Chatbot
Get quick answers to your questions about the article from our AI researcher chatbot