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1 First Department of Medicine, University of Szeged, Faculty of Medicine, Szeged, H-6720, Hungary; School of Cell & Molecular Biosciences, University of Newcastle, University Medical School, Newcastle, NE2 4HH, United Kingdom
2 School of Cell & Molecular Biosciences, University of Newcastle, University Medical School, Newcastle, NE2 4HH, United Kingdom; First Department of Medicine, University of Szeged, Faculty of Medicine, Szeged, H-6720, Hungary
3 Department of Pathology, University of Szeged, Faculty of Medicine, Szeged, H-6720, Hungary
4 Department of Pharmacology and Pharmacotherapy, University of Szeged, Faculty of Medicine, Szeged, H-6720, Hungary
5 Molecular Oral Biology Research Group, Department of Oral Biology, Hungarian Academy of Sciences and Semmelweis University, Budapest, H-1089, Hungary
6 School of Cell & Molecular Biosciences, University of Newcastle, University Medical School, Newcastle, NE2 4HH, United Kingdom
* To whom correspondence should be addressed. E-mail: b.e.argent{at}ncl.ac.uk.
The inhibitory control of pancreatic ductal HCO3- secretion may be physiologically important in terms of limiting the hydrostatic pressure developed within the ducts and in terms of switching off pancreatic secretion after a meal. Substance P (SP) inhibits secretin-stimulated HCO3- secretion by modulating a Cl--dependent HCO3- efflux step at the apical membrane of the duct cell (Hegyi et al. Am J Physiol Cell Physiol 285:C268-C276, 2003). Here we show that SP is present in periductal nerves within the guinea-pig pancreas; that protein kinase C (PKC) mediates the effect of SP, and that SP inhibits an anion exchanger on the luminal membrane of the duct cell. Secretin (10 nM) stimulated HCO3- secretion by sealed, non-perfused, ducts about 3 fold and this effect was totally inhibited by SP (20 nM). Phorbol 12, 13-dibutyrate (100 nM), an activator of PKC, reduced basal HCO3- secretion by about 40%, and totally blocked secretin-stimulated secretion. In addition, bisindolylmaleimide I (1 nM to 1 µM), an inhibitor of PKC, relieved the inhibitory effect of SP on secretin-stimulated HCO3- secretion and also reversed the inhibitory effect of PDBu. Western blot analysis revealed that guinea pig pancreatic ducts express the 
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and -µ isoforms of PKC. In microperfused ducts, luminal H2DIDS (0.5 mM) caused intracellular pH to alkalinise and, like SP, inhibited basal and secretin-stimulated HCO3- secretion. SP did not inhibit secretion further when H2DIDS was present in the lumen, suggesting that SP and H2DIDS both inhibit the activity of an anion exchanger on the luminal membrane of the duct cell.
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