Mechanism of augmented duodenal HCO(3)(-) secretion after elevation of luminal CO(2).
The proximal duodenum is exposed to extreme elevations of P(CO(2)) because of the continuous mixture of secreted HCO(3)(-) 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 CO(2) for duodenal epithelial cells is from the lumen. We hence examined the effect of elevated luminal P(CO(2)) on duodenal HCO(3)(-) secretion (DBS) in the rat. DBS was measured by the pH-stat method. For CO(2) challenge, the duodenum was superfused with a high Pco(2) solution. Intracellular pH (pH(i)) of duodenal epithelial cells was measured by ratio microfluorometry. CO(2) 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 CO(2)-augmented DBS. Dimethyl amiloride (0.1 mM), an inhibitor of the basolateral sodium-hydrogen exchanger 1, also inhibited CO(2)-augumented DBS, although S-3226, a specific inhibitor of apical sodium-hydrogen exchanger 3, did not. DIDS, an inhibitor of basolateral sodium-HCO(3)(-) cotransporter, also inhibited CO(2)-augemented DBS, as did the anion channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid. CO(2) decreased epithelial cell pH(i), followed by an overshoot after removal of the CO(2) solution. We conclude that luminal CO(2) diffused in the duodenal epithelial cells and was converted to H(+) and HCO(3)(-) by carbonic anhydrase. H(+) initially exited the cell, followed by secretion of HCO(3)(-). Secretion was dependent on a functioning basolateral sodium/proton exchanger, a functioning basolateral HCO(3)(-) uptake mechanism, and submucosal prostaglandin generation and facilitated hydration of CO(2) into HCO(3)(-) and H(+).
Furukawa
Osamu
O
Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Hirokawa
Masahiko
M
Zhang
Lening
L
Takeuchi
Tetsu
T
Bi
Luke C
LC
Guth
Paul H
PH
Engel
Eli
E
Akiba
Yasutada
Y
Kaunitz
Jonathan D
JD
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D027321:Anion Transport Proteins / Q000378:metabolism; D001639:Bicarbonates / Q000378:metabolism*; D002245:Carbon Dioxide / Q000378:metabolism*; D002256:Carbonic Anhydrases / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004386:Duodenum / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007091:Image Processing, Computer-Assisted; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009579:Nitrobenzoates / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
D027321:Anion Transport Proteins; D001639:Bicarbonates; D016861:Cyclooxygenase Inhibitors; D009579:Nitrobenzoates; D017923:Sodium-Hydrogen Exchangers; D002245:Carbon Dioxide; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D011451:Prostaglandin-Endoperoxide Synthases; D002256:Carbonic Anhydrases; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D007213:Indomethacin