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MUCOSAL BIOLOGY

CFTR inhibition augments NHE3 activity during luminal high CO₂ exposure in rat duodenal mucosa

¹Greater Los Angeles Veterans Affairs Healthcare System; ²Department of Medicine, School of Medicine, ³Department of Biomathematics, University of California Los Angeles; ⁴Brentwood Biomedical Research Institute; and ⁵Harvard-Westlake School, Los Angeles, California

Submitted 18 January 2008 ; accepted in final form 12 April 2008

We hypothesized that the function of duodenocyte apical membrane acid-base transporters are essential for H⁺ absorption from the lumen. We thus examined the effect of inhibition of Na⁺/H⁺ exchanger-3 (NHE3), cystic fibrosis transmembrane regulator (CFTR), or apical anion exchangers on transmucosal CO₂ diffusion and HCO₃^– secretion in rat duodenum. Duodena were perfused with a pH 6.4 high CO₂ solution or pH 2.2 low CO₂ solution with the NHE3 inhibitor, S3226, the anion transport inhibitor, DIDS, or pretreatment with the potent CFTR inhibitor, CFTR_inh-172, with simultaneous measurements of luminal and portal venous (PV) pH and carbon dioxide concentration ([CO₂]). Luminal high CO₂ solution increased CO₂ absorption and HCO₃^– secretion, accompanied by PV acidification and PV PCO₂ increase. During CO₂ challenge, CFTR_inh-172 induced HCO₃^– absorption, while inhibiting PV acidification. S3226 reversed CFTR_inh-associated HCO₃^– absorption. Luminal pH 2.2 challenge increased H⁺ and CO₂ absorption and acidified the PV, inhibited by CFTR_inh-172 and DIDS, but not by S3226. CFTR inhibition and DIDS reversed HCO₃^– secretion to absorption and inhibited PV acidification during CO₂ challenge, suggesting that HCO₃^– secretion helps facilitate CO₂/H⁺ absorption. Furthermore, CFTR inhibition prevented CO₂-induced cellular acidification reversed by S3226. Reversal of increased HCO₃^– loss by NHE3 inhibition and reduced intracellular acidification during CFTR inhibition is consistent with activation or unmasking of NHE3 activity by CFTR inhibition, increasing cell surface H⁺ available to neutralize luminal HCO₃^– with consequent CO₂ absorption. NHE3, by secreting H⁺ into the luminal microclimate, facilitates net transmucosal HCO₃^– absorption with a mechanism similar to proximal tubular HCO₃^– absorption.

CO₂ absorption; bicarbonate secretion; portal venous PCO₂