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1 Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; CURE: Digestive Diseases Research Center, Los Angeles, CA, USA
2 Greater Los Angeles Veterans Affairs Healthchare System, University of California Los Angeles, Los Angeles, CA, USA; CURE: Digestive Diseases Research Center, Los Angeles, CA, USA
3 Department of Medicine, Division of Gastroenterology, University of California Irvine, Irvine, CA, USA
4 Greater Los Angeles Veterans Affairs Healthchare System, University of California Los Angeles, Los Angeles, CA, USA
5 Department of Biomathematics, University of California Los Angeles, Los Angeles, CA, USA
6 Greater Los Angeles Veterans Affairs Healthchare System, University of California Los Angeles, Los Angeles, CA, USA; Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA; CURE: Digestive Diseases Research Center, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: jake{at}ucla.edu.
Background: The proximal duodenum is exposed to extreme elevations of pCO2, due to the continuous mixture of secreted bicarbonate with gastric acid. These elevations ( up to 80 kPa) are likely to place the mucosal cells under severe acid stress. Furthermore, we hypothesized that unlike most other cells, the principal source of CO2 for duodenal epithelial cells is from the lumen. We hence examined the effect of elevated luminal pCO2 on duodenal bicarbonate secretion in the rat. Methods: Duodenal HCO3- secretion (DBS) was measured by the pH-stat method. For CO2 challenge, the duodenum was superfused with a high pCO2 solution. Intracellular pH (pHi) of duodenal epithelial cells was measured by ratio microfluorometry. Results: CO2 challenge, but not isohydric solutions, strongly increased DBS to ~2x basal, for up to 1 hr. Preperfusion of the membrane permeant carbonic anhydrase inhibitor methazolamide, or continuous exposure with indomethacin fully inhibited CO2 augmented DBS. 0.1 mM dimethyl amiloride, an inhibitor of the basolateral sodium-hydrogen exchanger 1, also inhibited CO2-augumented DBS, although S3226, a specific inhibitor of apical sodium-hydrogen exchanger 3, did not. DIDS, an inhibitor of basolateral sodium-bicarbonate cotransporter, also inhibited CO2--augemented DBS, as did the anion channel inhibitor NPPB. CO2 decreased epithelial cell pHi, followed by an overshoot after removal of the CO2 solution. Conclusions: Luminal CO2 diffused into the duodenal epithelial cells and was converted to H+ and HCO3- by carbonic anhydrase. H+ initially exited the cell, followed by secretion of HCO3-. Secretion was dependent on a functioning basolateral sodium/proton exchanger, a functioning basolateral HCO3- uptake mechanism, submucosal prostaglandin generation, and facilitated hydration of CO2 into HCO3- and H+.
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