title: Carbonic anhydrases and mucosal vanilloid receptors help mediate the hyperemic response to luminal CO2 in rat duodenum.
abstract: OBJECTIVE
  The duodenal mucosa is exposed to PCO(2) >200 mm Hg due to the luminal mixture of gastric acid with secreted bicarbonate, which augments mucosal protective mechanisms. We examined the hyperemic response to elevated luminal PCO(2) in the duodenum of anesthetized rats luminally exposed to high CO(2) saline to help elucidate luminal acid-sensing mechanisms.
  
  
  METHODS
  Blood flow was measured by laser Doppler, and intracellular pH of epithelial cells by measured by ratio microimaging. The permeant carbonic anhydrase (CA) inhibitor methazolamide, relatively impermeant CA inhibitor benzolamide, vanilloid receptor antagonist capsazepine, or sodium-hydrogen exchanger 1 (NHE-1) inhibitor dimethyl amiloride were perfused with or without the high CO(2) solution.
  
  
  RESULTS
  The high CO(2) solution increased duodenal blood flow, which was abolished by pretreatment with methazolamide or capsazepine or by dimethyl amiloride coperfusion. Sensory denervation with capsaicin also abolished the CO(2) effects. Benzolamide dose-dependently inhibited CO(2)-induced hyperemia and at 100 nmol/L inhibited CO(2)-induced intracellular acidification. The membrane-bound CA isoforms IV, IX, XII, and XIV and cytosolic CA II and the vanilloid receptor 1 (TRPV1) were expressed in duodenum and stomach. Dorsal root ganglion and nodose ganglion expressed all isoforms except for CA IX.
  
  
  CONCLUSIONS
  The duodenal hyperemic response to luminal CO(2) is dependent on cytosolic and membrane-bound CA isoforms, NHE-1, and TRPV1. CO(2)-induced intracellular acidification was inhibited by selective extracellular CA inhibition, suggesting that CO(2) diffusion across the epithelial apical membrane is mediated by extracellular CA. NHE-1 activation preceding TRPV1 stimulation suggests that luminal CO(2) is sensed as H(+) in the subepithelium.
authors.affiliation: Department of Medicine, School of Medicine, University of California Los Angeles, USA.
authors.forename: Yasutada
authors.initials: Y
authors.lastname: Akiba
authors.forename: Sara
authors.initials: S
authors.lastname: Ghayouri
authors.forename: Tetsu
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Misa
authors.initials: M
authors.lastname: Mizumori
authors.forename: Paul H
authors.initials: PH
authors.lastname: Guth
authors.forename: Eli
authors.initials: E
authors.lastname: Engel
authors.forename: Erik R
authors.initials: ER
authors.lastname: Swenson
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Kaunitz
mesh_terms: D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001574:Benzolamide / Q000494:pharmacology; D001783:Blood Flow Velocity / Q000187:drug effects; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002245:Carbon Dioxide / Q000633:toxicity; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004386:Duodenum / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006863:Hydrogen-Ion Concentration; D006940:Hyperemia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D017078:Laser-Doppler Flowmetry; D008297:Male; D008704:Methazolamide / Q000494:pharmacology; D012313:RNA / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors; D050916:TRPV Cation Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D019831:Sodium-Calcium Exchanger; D050916:TRPV Cation Channels; D002245:Carbon Dioxide; C039465:5-dimethylamiloride; D012313:RNA; D000584:Amiloride; D002256:Carbonic Anhydrases; D001574:Benzolamide; C071423:capsazepine; D002211:Capsaicin; D008704:Methazolamide