Bicarbonate-rich fluid secretion predicted by a computational model of guinea-pig pancreatic duct epithelium

Makoto Yamaguchi, Martin C. Steward, Kieran Smallbone, Yoshiro Sohma, Akiko Yamamoto, Shigeru B.H. Ko, Takaharu Kondo, Hiroshi Ishiguro

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Abstract

Key points: The ductal system of the pancreas secretes large volumes of alkaline fluid containing HCO3 concentrations as high as 140 mm during hormonal stimulation. 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-pig pancreatic ducts. The model was readily able to secrete 140 mm HCO3 . 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. We conclude that the main requirement for secreting high HCO3 concentrations is to minimize the secretion of Cl ions. These findings help to clarify the mechanism responsible for pancreatic HCO3 secretion, a vital process that prevents the formation of protein plugs and viscous mucus in the ducts, which could otherwise lead to pancreatic disease. Abstract: A computational model of guinea-pig pancreatic duct epithelium was developed to determine the transport mechanism by which HCO3 ions are secreted at concentrations in excess of 140 mm. Parameters defining the contributions of the individual ion channels and transporters were estimated by least-squares 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-stimulated secretion were well replicated by increasing the activities of the basolateral Na+-HCO3 cotransporter (NBC1) and apical Cl/HCO3 exchanger (solute carrier family 26 member A6; SLC26A6), increasing the basolateral K+ permeability and apical Cl and HCO3 permeabilities (CFTR), and reducing the activity of the basolateral Cl/HCO3 exchanger (anion exchanger 2; AE2). Under these conditions, the model secreted ∼140 mm HCO3 at a rate of ∼3 nl min−1 mm−2, which is consistent with experimental observations. Alternative 1:2 and 1:1 stoichiometries for Cl/HCO3 exchange via SLC26A6 at the apical membrane were able to support a HCO3 -rich secretion. Raising the HCO3 /Cl permeability ratio of CFTR from 0.4 to 1.0 had little impact upon either the secreted HCO3 concentration or the volume flow. However, modelling showed that a reduction in basolateral AE2 activity by ∼80% was essential in minimizing the intracellular Cl concentration following cAMP stimulation and thereby maximizing the secreted HCO3 concentration. The addition of a basolateral Na+-K+-2Cl cotransporter (NKCC1), assumed to be present in rat and mouse ducts, raised intracellular Cl and resulted in a lower secreted HCO3 concentration, as is characteristic of those species. We conclude therefore that minimizing the driving force for Cl secretion is the main requirement for secreting 140 mm HCO3 .

Original languageEnglish
Pages (from-to)1947-1972
Number of pages26
JournalJournal of Physiology
Volume595
Issue number6
DOIs
Publication statusPublished - 2017 Mar 15

Keywords

  • bicarbonate secretion
  • computational model
  • pancreatic duct

ASJC Scopus subject areas

  • Physiology

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    Yamaguchi, M., Steward, M. C., Smallbone, K., Sohma, Y., Yamamoto, A., Ko, S. B. H., Kondo, T., & Ishiguro, H. (2017). Bicarbonate-rich fluid secretion predicted by a computational model of guinea-pig pancreatic duct epithelium. Journal of Physiology, 595(6), 1947-1972. https://doi.org/10.1113/JP273306