Lafutidine, a Protective H(2) Receptor Antagonist, Enhances Mucosal Defense in Rat Esophagus

BACKGROUND: Luminal acid or CO(2) 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 CO(2) 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 H(2) 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.