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Mucosal carbonic anhydrases and acid sensors regulate the CO2‐induced hyperemia in rat esophagus

Heartburn is usually triggered by esophageal luminal acid. We hypothesized that luminal CO2, rather than H+, permeates through the stratum epithelium, interacting with epithelial and sub‐epithelial carbonic anhydrases (CA) and acid chemosensors, producing afferent neural signals. We superfused rat lower esophageal mucosa with pH 1.0 or pH 6.4 high CO2 solution, inhibiting CA activity with methazolamide or benzolamide, TRPV1 with capsazepine, and ASIC with amiloride. We measured interstitial pH (pHint) with carboxyfluorescein iv and blood flow with laser Doppler flowmetry. Perfusion of a high CO2 solution or pH 1.0 induced hyperemia without pHint change. All inhibitors inhibited CO2‐induced hyperemia and decreased pHint. Immunofluorescence localized CA XIV and all ASICs to the prickle cells, CA XII to the basal cells, TRPV1 to the stratum granulosum, and TRPV1 and ASIC3 to the muscularis mucosa. Luminal CO2 reproduced the mucosal response to acid superfusion, suggesting that CO2 diffuses through the stratum epithelium before interacting with epithelial or submucosal acid sensors. Inhibition of the hyperemic response to CO2 by CA, TRPV1 and ASIC inhibitors implicates CA and acid sensors in the transduction of the luminal acid signal. Transepithelial CO2 permeation may explain how luminal H+ equivalents can be rapidly sensed, producing responses such as hyperemia and heartburn.