Background: Acid in the esophageal lumen is often sensed as heartburn. We hypothesized that luminal CO2, a permeant gas, rather than H+, permeates through the epithelium, and is converted to H+, producing an afferent neural signal by activating chemosensors.
Methods: We superfused the rat lower esophageal mucosa with pH 7.0 buffer, and pH 1.0 or pH 6.4 high CO2 (PCO2 = 260 Torr) solutions with or without the cell-permeant carbonic anhydrase (CA) inhibitor methazolamide (MTZ, 1 mM), the cell-impermeant CA inhibitor benzolamide (BNZ, 0.1 mM), the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine (CPZ, 0.5 mM), or the acid-sensing ion channel (ASIC) inhibitor amiloride (0.1 mM). We measured interstitial pH (pHint) with 5',6'-carboxyfluorescein (5 mg/kg iv) loaded into the interstitial space and blood flow with laser-Doppler.
Results: Perfusion of a high CO2 solution induced hyperemia without changing pHint, mimicking the effect of pH 1.0 perfusion. Perfused MTZ, BNZ, CPZ and amiloride all inhibited CO2-induced hyperemia. CA XIV was expressed in the prickle cells with CA XII in the basal cells. TRPV1 was expressed in the stratum granulosum and in the muscularis mucosa, whereas all ASICs were expressed in the prickle cells with ASIC3 additionally in the muscularis mucosa.
Conclusions: The response to CO2 perfusion suggests that CO2 diffuses through the stratum epithelium, interacting with TRPV1 and ASICs in the epithelium or in the submucosa. Inhibition of the hyperemic response to luminal CO2 by CA, TRPV1 and ASIC inhibitors implicates CA and these chemosensors in transduction of the luminal acid signal. Transepithelial CO2 permeation may explain how luminal H+ equivalents can rapidly be transduced into hyperemia, and the sensation of heartburn.
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