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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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Related in: MedlinePlus

Effect of Laf with acid-pepsin superfusion on pHint and blood flow in rat esophagus. Pepsin (1 mg/ml) with pH 1.0 acid was perfused with or without Laf (1 mM). Laf was perfused during the basal and challenge periods (0–45 min) in the Laf + pH 1.0 + pepsin group. The boxes above the graphs represent the perfusate combination for the corresponding groups. The acid-pepsin solution gradually decreased pHint (a) accompanied by biphasic hyperemia (b). Laf pre-perfusion increased pHint and blood flow, and prevented acid-pepsin-induced interstitial acidification (a). 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 + pepsin group
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Fig5: Effect of Laf with acid-pepsin superfusion on pHint and blood flow in rat esophagus. Pepsin (1 mg/ml) with pH 1.0 acid was perfused with or without Laf (1 mM). Laf was perfused during the basal and challenge periods (0–45 min) in the Laf + pH 1.0 + pepsin group. The boxes above the graphs represent the perfusate combination for the corresponding groups. The acid-pepsin solution gradually decreased pHint (a) accompanied by biphasic hyperemia (b). Laf pre-perfusion increased pHint and blood flow, and prevented acid-pepsin-induced interstitial acidification (a). 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 + pepsin group

Mentions: We further hypothesized that Laf protects the mucosa from the interstitial acidification accompanying epithelial injury or increased permeation of acid into the mucosa. We thus examined the effect of acidified pepsin on pHint and blood flow, since acidified pepsin reduces electrical resistance of rabbit esophagus in vitro and may thus also injure the rat esophagus in vivo [19]. Pepsin (1 mg/ml) was added to the pH 1.0 perfusate in order to compromise the mucosal barrier. Acidified pepsin gradually, but markedly, decreased pHint (Fig. 5a), consistent with increased H+ diffusion into the mucosa. This pHint change was reversed by Laf (1 mM) pre- and co-perfusion, consistent with mucosal protection (Fig. 5a). Perfusion of the acidified pepsin solution transiently increased blood flow as did the acid alone, followed by a second hyperemic response observed at t = 40–45 min (Fig. 5b), associated with a markedly decreased pHint (Fig. 5a). Laf increased blood flow before and after acidified pepsin superfusion, but prevented the secondary hyperemia observed in acid + pepsin group. These results suggest that Laf treatment prevents the acidified pepsin-induced mucosal injury in the esophagus by protective hyperemia and pHint increase.Fig. 5


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-pepsin superfusion on pHint and blood flow in rat esophagus. Pepsin (1 mg/ml) with pH 1.0 acid was perfused with or without Laf (1 mM). Laf was perfused during the basal and challenge periods (0–45 min) in the Laf + pH 1.0 + pepsin group. The boxes above the graphs represent the perfusate combination for the corresponding groups. The acid-pepsin solution gradually decreased pHint (a) accompanied by biphasic hyperemia (b). Laf pre-perfusion increased pHint and blood flow, and prevented acid-pepsin-induced interstitial acidification (a). 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 + pepsin group
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2958262&req=5

Fig5: Effect of Laf with acid-pepsin superfusion on pHint and blood flow in rat esophagus. Pepsin (1 mg/ml) with pH 1.0 acid was perfused with or without Laf (1 mM). Laf was perfused during the basal and challenge periods (0–45 min) in the Laf + pH 1.0 + pepsin group. The boxes above the graphs represent the perfusate combination for the corresponding groups. The acid-pepsin solution gradually decreased pHint (a) accompanied by biphasic hyperemia (b). Laf pre-perfusion increased pHint and blood flow, and prevented acid-pepsin-induced interstitial acidification (a). 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 + pepsin group
Mentions: We further hypothesized that Laf protects the mucosa from the interstitial acidification accompanying epithelial injury or increased permeation of acid into the mucosa. We thus examined the effect of acidified pepsin on pHint and blood flow, since acidified pepsin reduces electrical resistance of rabbit esophagus in vitro and may thus also injure the rat esophagus in vivo [19]. Pepsin (1 mg/ml) was added to the pH 1.0 perfusate in order to compromise the mucosal barrier. Acidified pepsin gradually, but markedly, decreased pHint (Fig. 5a), consistent with increased H+ diffusion into the mucosa. This pHint change was reversed by Laf (1 mM) pre- and co-perfusion, consistent with mucosal protection (Fig. 5a). Perfusion of the acidified pepsin solution transiently increased blood flow as did the acid alone, followed by a second hyperemic response observed at t = 40–45 min (Fig. 5b), associated with a markedly decreased pHint (Fig. 5a). Laf increased blood flow before and after acidified pepsin superfusion, but prevented the secondary hyperemia observed in acid + pepsin group. These results suggest that Laf treatment prevents the acidified pepsin-induced mucosal injury in the esophagus by protective hyperemia and pHint increase.Fig. 5

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