Proton Pump Inhibitors Inhibit Pancreatic Secretion: Role of Gastric and Non-Gastric H+/K+-ATPases

PLoS One. 2015 May 18;10(5):e0126432. doi: 10.1371/journal.pone.0126432. eCollection 2015.

Abstract

The mechanism by which pancreas secretes high HCO3- has not been fully resolved. This alkaline secretion, formed in pancreatic ducts, can be achieved by transporting HCO3- from serosa to mucosa or by moving H+ in the opposite direction. The aim of the present study was to determine whether H+/K+-ATPases are expressed and functional in human pancreatic ducts and whether proton pump inhibitors (PPIs) have effect on those. Here we show that the gastric HKα1 and HKβ subunits (ATP4A; ATP4B) and non-gastric HKα2 subunits (ATP12A) of H+/K+-ATPases are expressed in human pancreatic cells. Pumps have similar localizations in duct cell monolayers (Capan-1) and human pancreas, and notably the gastric pumps are localized on the luminal membranes. In Capan-1 cells, PPIs inhibited recovery of intracellular pH from acidosis. Furthermore, in rats treated with PPIs, pancreatic secretion was inhibited but concentrations of major ions in secretion follow similar excretory curves in control and PPI treated animals. In addition to HCO3-, pancreas also secretes K+. In conclusion, this study calls for a revision of the basic model for HCO3- secretion. We propose that proton transport is driving secretion, and that in addition it may provide a protective pH buffer zone and K+ recirculation. Furthermore, it seems relevant to re-evaluate whether PPIs should be used in treatment therapies where pancreatic functions are already compromised.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Gastric Mucosa / drug effects
  • Gastric Mucosa / enzymology
  • H(+)-K(+)-Exchanging ATPase / genetics
  • H(+)-K(+)-Exchanging ATPase / metabolism*
  • Humans
  • Imidazoles / pharmacology
  • Male
  • Omeprazole / pharmacology
  • Pancreas / drug effects*
  • Pancreas / metabolism*
  • Pancreatic Ducts / drug effects
  • Pancreatic Ducts / enzymology
  • Pancreatic Juice / metabolism
  • Proton Pump Inhibitors / pharmacology*
  • Rats
  • Rats, Wistar

Substances

  • Imidazoles
  • Proton Pump Inhibitors
  • Sch 28080
  • ATP12A protein, human
  • ATP4A protein, human
  • H(+)-K(+)-Exchanging ATPase
  • Omeprazole

Grant support

The project was supported by The Danish Council for Independent Research | Natural Sciences (FNU grant number 0602-01527B and 4002-00162), the Novo Nordisk Foundation (grant number 10723001001) and the Lundbeck Foundation (grant number R173-2014-1462). JW had a co-financed Ph.D. stipend from FNU; Department of Biology and the Lundbeck Foundation. MT was the recipient of Erasmus exchange program stipend and AG was supported by the FP7 Marie Curie Initial Training Network "IonTraC". The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.