Lafutidine, a protective H₂ receptor antagonist, enhances mucosal defense in rat esophagus.
BACKGROUND
Luminal acid or CO₂ induces a hyperemic response in the esophagus, via activation of acid sensors on capsaicin-sensitive afferent nerves (CSAN). Since disruption of the hyperemic response to luminal CO₂ acidifies the interstitium of the esophageal mucosa, the hyperemic response may maintain interstitial pH (pH(int)). We hypothesized that acid-related hyperemia maintains pH(int), preventing acid-induced injury in the esophageal mucosa.


METHODS
We examined the effects of capsaicin (Cap) or lafutidine (Laf), a mucosal protective H₂ antagonist, on the regulation of pH(int) and blood flow in rat esophagus using ratiometric microimaging and laser-Doppler measurements of the lower esophageal mucosa of living rats. The esophagus was topically superfused with pH 7.0 buffer, or a pH 1.0 or pH 1.0 + pepsin (1 mg/ml) solution with or without Laf.


RESULTS
Cap (30 or 100 µM) or Laf (0.1 or 1 mM) dose-dependently increased blood flow, accompanied by increased pH(int). The pH 1.0 solution increased blood flow without pH(int) change, whereas Laf (1 mM) increased blood flow and pH(int) during acid exposure. The effects of Laf were abolished by ablation of CSAN. Perfusion of the acidified pepsin solution gradually decreased pH(int), inhibited by Laf perfusion.


CONCLUSIONS
Activation of CSAN by Laf with or without acid, accompanied by hyperemia, increased pH(int), preventing acidified pepsin-induced interstitial acidification. Stimulation of the capsaicin pathway with compounds such as Laf enhances mucosal protection from acid-related injury in the upper gastrointestinal tract.
Akiba
Yasutada
Y
Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA 90073, USA.
Kaunitz
Jonathan D
JD
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D004947:Esophagus / Q000098:blood supply*; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D009092:Mucous Membrane / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects
D000081:Acetamides; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; C076948:lafutidine; D002211:Capsaicin
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