CO2 chemosensing in rat oesophagus.
BACKGROUND
Acid in the oesophageal lumen is often sensed as heartburn. It was hypothesised that luminal CO(2), a permeant gas, rather than H(+), permeates through the epithelium, and is converted to H(+), producing an afferent neural signal by activating chemosensors.


METHODS
The rat lower oesophageal mucosa was superfused with pH 7.0 buffer, and pH 1.0 or pH 6.4 high CO(2) (P(CO2) = 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). Interstitial pH (pH(int)) was measured with 5',6'-carboxyfluorescein (5 mg/kg intravenously) loaded into the interstitial space, and blood flow was measured with laser-Doppler.


RESULTS
Perfusion of a high CO(2) solution induced hyperaemia without changing pH(int), mimicking the effect of pH 1.0 perfusion. Perfused MTZ, BNZ, CPZ and amiloride all inhibited CO(2)-induced hyperaemia. 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 CO(2) perfusion suggests that CO(2) diffuses through the stratum epithelium, interacting with TRPV1 and ASICs in the epithelium or in the submucosa. Inhibition of the hyperaemic response to luminal CO(2) by CA, TRPV1 and ASIC inhibitors implicates CA and these chemosensors in transduction of the luminal acid signal. Transepithelial CO(2) permeation may explain how luminal H(+) equivalents can rapidly be transduced into hyperaemia, and the sensation of heartburn.
Akiba
Y
Y
Department of Medicine, School of Medicine, Los Angeles, California, USA.
Mizumori
M
M
Kuo
M
M
Ham
M
M
Guth
P H
PH
Engel
E
E
Kaunitz
J D
JD
D062565:Acid Sensing Ion Channels; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001574:Benzolamide / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors; D002245:Carbon Dioxide / Q000378:metabolism* / Q000493:pharmacokinetics; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D050782:Esophageal pH Monitoring; D004947:Esophagus / Q000098:blood supply / Q000378:metabolism*; D005764:Gastroesophageal Reflux / Q000150:complications / Q000378:metabolism*; D006940:Hyperemia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008704:Methazolamide / Q000494:pharmacology; D009092:Mucous Membrane / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D002257:Carbonic Anhydrase Inhibitors; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D002245:Carbon Dioxide; D000584:Amiloride; D001574:Benzolamide; C071423:capsazepine; D002211:Capsaicin; D008704:Methazolamide