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MUCOSAL BIOLOGY

Mechanism of augmented duodenal HCO₃^– secretion after elevation of luminal CO₂

³Greater Los Angeles Veterans Affairs Healthcare System, ¹Department of Medicine, School of Medicine and ⁵Department of Biomathematics, University of California Los Angeles, Los Angeles; ⁴Division of Gastroenterology, Department of Medicine, University of California, Irvine; and ²Center for Ulcer Research and Education: Digestive Diseases Research Center, Los Angeles, California

Submitted 30 July 2004 ; accepted in final form 11 October 2004

The proximal duodenum is exposed to extreme elevations of PCO₂ because of the continuous mixture of secreted HCO₃^– 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 HCO₃^– secretion (DBS) in the rat. DBS was measured by the pH-stat method. For CO₂ challenge, the duodenum was superfused with a high PCO₂ solution. Intracellular pH (pH_i) of duodenal epithelial cells was measured by ratio microfluorometry. CO₂ challenge, but not isohydric solutions, strongly increased DBS to approximately two times basal for up to 1 h. Preperfusion of the membrane-permeant carbonic anhydrase inhibitor methazolamide, or continuous exposure with indomethacin, fully inhibited CO₂-augmented DBS. Dimethyl amiloride (0.1 mM), an inhibitor of the basolateral sodium-hydrogen exchanger 1, also inhibited CO₂-augumented DBS, although S-3226, a specific inhibitor of apical sodium-hydrogen exchanger 3, did not. DIDS, an inhibitor of basolateral sodium-HCO₃^– cotransporter, also inhibited CO₂-augemented DBS, as did the anion channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid. CO₂ decreased epithelial cell pH_i, followed by an overshoot after removal of the CO₂ solution. We conclude that luminal CO₂ diffused in 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, and submucosal prostaglandin generation and facilitated hydration of CO₂ into HCO₃^– and H⁺.

bicarbonate; duodenum; carbon dioxide; carbonic anhydrase; cyclooxygenase; epithelial cells; sodium hydrogen exchanger 1; sodium hydrogen exchanger 3; sodium bicarbonate cotransporter 1

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