CFTR inhibition augments NHE3 activity during luminal high CO 2 exposure in rat duodenal mucosa

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 CO 2 diffusion and HCO 3 − secretion in rat duodenum. Duodena were perfused with a pH 6.4 high CO 2 solution or pH 2.2 low CO 2 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 ([CO 2 ]). Luminal high CO 2 solution increased CO 2 absorption and HCO 3 − secretion, accompanied by PV acidification and PV Pco 2 increase. During CO 2 challenge, CFTR inh -172 induced HCO 3 − absorption, while inhibiting PV acidification. S3226 reversed CFTR inh -associated HCO 3 − absorption. Luminal pH 2.2 challenge increased H + and CO 2 absorption and acidified the PV, inhibited by CFTR inh -172 and DIDS, but not by S3226. CFTR inhibition and DIDS reversed HCO 3 − secretion to absorption and inhibited PV acidification during CO 2 challenge, suggesting that HCO 3 − secretion helps facilitate CO 2 /H + absorption. Furthermore, CFTR inhibition prevented CO 2 -induced cellular acidification reversed by S3226. Reversal of increased HCO 3 − 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 HCO 3 − with consequent CO 2 absorption. NHE3, by secreting H + into the luminal microclimate, facilitates net transmucosal HCO 3 − absorption with a mechanism similar to proximal tubular HCO 3 − absorption.