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Lafutidine, a protective H₂ receptor antagonist, enhances mucosal defense in rat esophagus.

Akiba Y, Kaunitz JD - Dig. Dis. Sci. (2010)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA 90073, USA.

ABSTRACT

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.

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Effect of Laf with acid on pHint and blood flow in rat esophagus. A pH 1.0 solution was perfused with or without Laf (1 mM). Laf was perfused during the basal and challenge periods (0–20 min) in the pH 1.0 + Laf and in the Cap-t (capsaicin pretreated) + pH 1.0 + Laf groups. The boxes above the graphs represent the perfusate combination for the corresponding groups. Pretreatment with Laf increased pHint (a) and blood flow (b), and enhanced acid-induced hyperemia. Cap-t abolished the effects of Laf perfusion and further decreased pHint. Data are expressed as mean ± SEM (n = 6). * p < 0.05 versus pH 7.0 Krebs group, † p < 0.05 versus pH 1.0 group, ‡ p < 0.05 versus pH 1.0 + Laf group
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Fig4: Effect of Laf with acid on pHint and blood flow in rat esophagus. A pH 1.0 solution was perfused with or without Laf (1 mM). Laf was perfused during the basal and challenge periods (0–20 min) in the pH 1.0 + Laf and in the Cap-t (capsaicin pretreated) + pH 1.0 + Laf groups. The boxes above the graphs represent the perfusate combination for the corresponding groups. Pretreatment with Laf increased pHint (a) and blood flow (b), and enhanced acid-induced hyperemia. Cap-t abolished the effects of Laf perfusion and further decreased pHint. Data are expressed as mean ± SEM (n = 6). * p < 0.05 versus pH 7.0 Krebs group, † p < 0.05 versus pH 1.0 group, ‡ p < 0.05 versus pH 1.0 + Laf group

Mentions: Since Laf increased pHint and blood flow via the activation of CSAN, we hypothesized that Laf enhances mucosal protection during acid exposure in the esophagus. We perfused Laf during the basal and also during the challenge periods in order to maximize its effects on mucosal defenses. A pH 1.0 solution had no effect on pHint, but increased blood flow as previously reported [5, 6] (Fig. 4a, b). Laf (1 mM) pretreatment increased pHint during coperfusion with a neutral solution. Subsequent coperfusion of Laf with a pH 1.0 solution increased pHint more than the pHint in the pH 1.0 group during the acid challenge period (Fig. 4a). In the Laf group, increased pHint was accompanied by increased blood flow during the basal period, followed by an enhanced hyperemic response to acid perfusion compared to the pH 1.0 group (Fig. 4b). Cap-t abolished the Laf-induced pHint increase during the basal and acid challenge periods, and further acidified pHint during the acid challenge period (Fig. 4a). This result is consistent with a previous report showing that Cap-t irreversibly lowers pHint during luminal perfusion of a high CO2 solution, consistent with mucosal injury [6]. Furthermore, Cap-t abolished the hyperemic response to acid + Laf (Fig. 4b). Cap-t also abolished the acid-induced hyperemia associated with interstitial acidification (data not shown). These results suggest that luminal acid stimulates CSAN, and that Laf enhances the hyperemic response to acid via CSAN activation or modulation, with a resultant increase of pHint.Fig. 4


Lafutidine, a protective H₂ receptor antagonist, enhances mucosal defense in rat esophagus.

Akiba Y, Kaunitz JD - Dig. Dis. Sci. (2010)

Effect of Laf with acid on pHint and blood flow in rat esophagus. A pH 1.0 solution was perfused with or without Laf (1 mM). Laf was perfused during the basal and challenge periods (0–20 min) in the pH 1.0 + Laf and in the Cap-t (capsaicin pretreated) + pH 1.0 + Laf groups. The boxes above the graphs represent the perfusate combination for the corresponding groups. Pretreatment with Laf increased pHint (a) and blood flow (b), and enhanced acid-induced hyperemia. Cap-t abolished the effects of Laf perfusion and further decreased pHint. Data are expressed as mean ± SEM (n = 6). * p < 0.05 versus pH 7.0 Krebs group, † p < 0.05 versus pH 1.0 group, ‡ p < 0.05 versus pH 1.0 + Laf group
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Related In: Results  -  Collection

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Fig4: Effect of Laf with acid on pHint and blood flow in rat esophagus. A pH 1.0 solution was perfused with or without Laf (1 mM). Laf was perfused during the basal and challenge periods (0–20 min) in the pH 1.0 + Laf and in the Cap-t (capsaicin pretreated) + pH 1.0 + Laf groups. The boxes above the graphs represent the perfusate combination for the corresponding groups. Pretreatment with Laf increased pHint (a) and blood flow (b), and enhanced acid-induced hyperemia. Cap-t abolished the effects of Laf perfusion and further decreased pHint. Data are expressed as mean ± SEM (n = 6). * p < 0.05 versus pH 7.0 Krebs group, † p < 0.05 versus pH 1.0 group, ‡ p < 0.05 versus pH 1.0 + Laf group
Mentions: Since Laf increased pHint and blood flow via the activation of CSAN, we hypothesized that Laf enhances mucosal protection during acid exposure in the esophagus. We perfused Laf during the basal and also during the challenge periods in order to maximize its effects on mucosal defenses. A pH 1.0 solution had no effect on pHint, but increased blood flow as previously reported [5, 6] (Fig. 4a, b). Laf (1 mM) pretreatment increased pHint during coperfusion with a neutral solution. Subsequent coperfusion of Laf with a pH 1.0 solution increased pHint more than the pHint in the pH 1.0 group during the acid challenge period (Fig. 4a). In the Laf group, increased pHint was accompanied by increased blood flow during the basal period, followed by an enhanced hyperemic response to acid perfusion compared to the pH 1.0 group (Fig. 4b). Cap-t abolished the Laf-induced pHint increase during the basal and acid challenge periods, and further acidified pHint during the acid challenge period (Fig. 4a). This result is consistent with a previous report showing that Cap-t irreversibly lowers pHint during luminal perfusion of a high CO2 solution, consistent with mucosal injury [6]. Furthermore, Cap-t abolished the hyperemic response to acid + Laf (Fig. 4b). Cap-t also abolished the acid-induced hyperemia associated with interstitial acidification (data not shown). These results suggest that luminal acid stimulates CSAN, and that Laf enhances the hyperemic response to acid via CSAN activation or modulation, with a resultant increase of pHint.Fig. 4

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA 90073, USA.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus