{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:10:38Z","timestamp":1790485838546,"version":"4.1.0"},"reference-count":69,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,2,8]],"date-time":"2017-02-08T00:00:00Z","timestamp":1486512000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005694","name":"Hori Sciences and Arts Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005694","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23118714"],"award-info":[{"award-number":["23118714"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25293049"],"award-info":[{"award-number":["25293049"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2017,3,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> concentrations as high as 140\u00a0m<jats:sc>m<\/jats:sc> during hormonal stimulation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>A computational model has been constructed to explore the underlying ion transport mechanisms. Parameters were estimated by fitting the model to experimental data from guinea\u2010pig pancreatic ducts.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The model was readily able to secrete 140\u00a0m<jats:sc>m<\/jats:sc> HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>. Its capacity to do so was not dependent upon special properties of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels and solute carrier family 26 member A6 (SLC26A6) anion exchangers.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We conclude that the main requirement for secreting high HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> concentrations is to minimize the secretion of Cl<jats:sup>\u2212<\/jats:sup> ions.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These findings help to clarify the mechanism responsible for pancreatic HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>A computational model of guinea\u2010pig pancreatic duct epithelium was developed to determine the transport mechanism by which HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> ions are secreted at concentrations in excess of 140\u00a0m<jats:sc>m<\/jats:sc>. Parameters defining the contributions of the individual ion channels and transporters were estimated by least\u2010squares fitting of the model predictions to experimental data obtained from isolated ducts and intact pancreas under a range of experimental conditions. The effects of cAMP\u2010stimulated secretion were well replicated by increasing the activities of the basolateral Na<jats:sup>+<\/jats:sup>\u2010HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> cotransporter (NBC1) and apical Cl<jats:sup>\u2212<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> exchanger (solute carrier family 26 member A6; SLC26A6), increasing the basolateral K<jats:sup>+<\/jats:sup> permeability and apical Cl<jats:sup>\u2212<\/jats:sup> and HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> permeabilities (CFTR), and reducing the activity of the basolateral Cl<jats:sup>\u2212<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> exchanger (anion exchanger 2; AE2). Under these conditions, the model secreted \u223c140\u00a0m<jats:sc>m<\/jats:sc> HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> at a rate of \u223c3\u00a0nl\u00a0min<jats:sup>\u22121<\/jats:sup>\u00a0mm<jats:sup>\u22122<\/jats:sup>, which is consistent with experimental observations. Alternative 1:2 and 1:1 stoichiometries for Cl<jats:sup>\u2212<\/jats:sup>\/HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> exchange via SLC26A6 at the apical membrane were able to support a HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>\u2010rich secretion. Raising the HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>\/Cl<jats:sup>\u2212<\/jats:sup> permeability ratio of CFTR from 0.4 to 1.0 had little impact upon either the secreted HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> concentration or the volume flow. However, modelling showed that a reduction in basolateral AE2 activity by \u223c80% was essential in minimizing the intracellular Cl<jats:sup>\u2212<\/jats:sup> concentration following cAMP stimulation and thereby maximizing the secreted HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> concentration. The addition of a basolateral Na<jats:sup>+<\/jats:sup>\u2010K<jats:sup>+<\/jats:sup>\u20102Cl<jats:sup>\u2212<\/jats:sup> cotransporter (NKCC1), assumed to be present in rat and mouse ducts, raised intracellular Cl<jats:sup>\u2212<\/jats:sup> and resulted in a lower secreted HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup> concentration, as is characteristic of those species. We conclude therefore that minimizing the driving force for Cl<jats:sup>\u2212<\/jats:sup> secretion is the main requirement for secreting 140\u00a0m<jats:sc>m<\/jats:sc> HCO<jats:sub>3<\/jats:sub><jats:sup>\u2212<\/jats:sup>.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp273306","type":"journal-article","created":{"date-parts":[[2016,12,20]],"date-time":"2016-12-20T07:52:39Z","timestamp":1482220359000},"page":"1947-1972","source":"Crossref","is-referenced-by-count":27,"title":["Bicarbonate\u2010rich fluid secretion predicted by a computational model of guinea\u2010pig pancreatic duct epithelium"],"prefix":"10.1113","volume":"595","author":[{"given":"Makoto","family":"Yamaguchi","sequence":"first","affiliation":[{"name":"Department of Human Nutrition Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin C.","family":"Steward","sequence":"additional","affiliation":[{"name":"School of Medical Sciences"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kieran","family":"Smallbone","sequence":"additional","affiliation":[{"name":"School of Computer Science University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiro","family":"Sohma","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Human Nutrition Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru B. 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