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Afferent signalling from the acid-challenged rat stomach is inhibited and gastric acid elimination is enhanced by lafutidine.

Edelsbrunner ME, Nakano M, Holzer P - BMC Gastroenterol (2009)

Bottom Line: Lafutidine reduced the HCl-evoked expression of c-Fos in the NTS and elevated the intragastric pH following intragastric administration of excess HCl.Further analysis showed that the gastroprotective effect of lafutidine against excess acid was delayed and went in parallel with facilitation of gastric emptying, measured indirectly via gastric volume changes, and a reduction of gastric acidity.The H2 receptor antagonist cimetidine had similar but weaker effects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria. ma.edelsbrunner@medunigraz.at

ABSTRACT

Background: Lafutidine is a histamine H2 receptor antagonist, the gastroprotective effect of which is related to its antisecretory activity and its ability to activate a sensory neuron-dependent mechanism of defence. The present study investigated whether intragastric administration of lafutidine (10 and 30 mg/kg) modifies vagal afferent signalling, mucosal injury, intragastric acidity and gastric emptying after gastric acid challenge.

Methods: Adult rats were treated with vehicle, lafutidine (10 - 30 mg/kg) or cimetidine (10 mg/kg), and 30 min later their stomachs were exposed to exogenous HCl (0.25 M). During the period of 2 h post-HCl, intragastric pH, gastric volume, gastric acidity and extent of macroscopic gastric mucosal injury were determined and the activation of neurons in the brainstem was visualized by c-Fos immunocytochemistry.

Results: Gastric acid challenge enhanced the expression of c-Fos in the nucleus tractus solitarii but caused only minimal damage to the gastric mucosa. Lafutidine reduced the HCl-evoked expression of c-Fos in the NTS and elevated the intragastric pH following intragastric administration of excess HCl. Further analysis showed that the gastroprotective effect of lafutidine against excess acid was delayed and went in parallel with facilitation of gastric emptying, measured indirectly via gastric volume changes, and a reduction of gastric acidity. The H2 receptor antagonist cimetidine had similar but weaker effects.

Conclusion: These observations indicate that lafutidine inhibits the vagal afferent signalling of a gastric acid insult, which may reflect an inhibitory action on acid-induced gastric pain. The ability of lafutidine to decrease intragastric acidity following exposure to excess HCl cannot be explained by its antisecretory activity but appears to reflect dilution and/or emptying of the acid load into the duodenum. This profile of actions emphasizes the notion that H2 receptor antagonists can protect the gastric mucosa from acid injury independently of their ability to suppress gastric acid secretion.

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Effect of lafutidine (30 mg/kg) and cimetidine (10 mg/kg), relative to vehicle, on (A) intragastric acidity and (B) weight of gastric content measured 60 and 120 min after exposure of the stomach to HCl (0.25 M) and expressed as a percentage of the respective values measured immediately after gastric acid loading (0 min). Lafutidine, cimetidine or vehicle was administered by gastric gavage 30 min before administration of HCl. The values represent means + SEM, n = 8. ** P ≤ 0.05 versus time 0 min under the same treatment, + P ≤ 0.1, ++ P ≤ 0.05 versus time 60 min under the same treatment, °P ≤ 0.1, °°P ≤ 0.05 versus vehicle at the same time point post-HCl.
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Figure 4: Effect of lafutidine (30 mg/kg) and cimetidine (10 mg/kg), relative to vehicle, on (A) intragastric acidity and (B) weight of gastric content measured 60 and 120 min after exposure of the stomach to HCl (0.25 M) and expressed as a percentage of the respective values measured immediately after gastric acid loading (0 min). Lafutidine, cimetidine or vehicle was administered by gastric gavage 30 min before administration of HCl. The values represent means + SEM, n = 8. ** P ≤ 0.05 versus time 0 min under the same treatment, + P ≤ 0.1, ++ P ≤ 0.05 versus time 60 min under the same treatment, °P ≤ 0.1, °°P ≤ 0.05 versus vehicle at the same time point post-HCl.

Mentions: The amount of acid equivalents present in the gastric lumen fell significantly over the 2 h interval post-HCl in all treatment groups (Figure 3B). Most of the drop in gastric acidity occurred within 60 min post-HCl, and there was no significant difference in the gastric acidity levels 0 and 60 min post-HCl between the three treatment groups. In lafutidine-treated rats there was a further significant drop of gastric acidity during the period 60 – 120 min post-HCl, a change that was not seen in vehicle- and cimetidine-treated rats (Figure 3B). The decrease in gastric acidity 120 min post-HCl in lafutidine-treated rats was significantly more marked than in vehicle-treated animals (Figure 3B). When gastric acidity measured 60 and 120 min post-HCl was expressed relative to the acidity measured immediately (0 min) after gastric acid loading, it was found that the drop of gastric acidity 120 min post-HCl seen in lafutidine-treated rats was most pronounced, compared with that seen in vehicle- and cimetidine-treated rats (Figure 4A).


Afferent signalling from the acid-challenged rat stomach is inhibited and gastric acid elimination is enhanced by lafutidine.

Edelsbrunner ME, Nakano M, Holzer P - BMC Gastroenterol (2009)

Effect of lafutidine (30 mg/kg) and cimetidine (10 mg/kg), relative to vehicle, on (A) intragastric acidity and (B) weight of gastric content measured 60 and 120 min after exposure of the stomach to HCl (0.25 M) and expressed as a percentage of the respective values measured immediately after gastric acid loading (0 min). Lafutidine, cimetidine or vehicle was administered by gastric gavage 30 min before administration of HCl. The values represent means + SEM, n = 8. ** P ≤ 0.05 versus time 0 min under the same treatment, + P ≤ 0.1, ++ P ≤ 0.05 versus time 60 min under the same treatment, °P ≤ 0.1, °°P ≤ 0.05 versus vehicle at the same time point post-HCl.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2698872&req=5

Figure 4: Effect of lafutidine (30 mg/kg) and cimetidine (10 mg/kg), relative to vehicle, on (A) intragastric acidity and (B) weight of gastric content measured 60 and 120 min after exposure of the stomach to HCl (0.25 M) and expressed as a percentage of the respective values measured immediately after gastric acid loading (0 min). Lafutidine, cimetidine or vehicle was administered by gastric gavage 30 min before administration of HCl. The values represent means + SEM, n = 8. ** P ≤ 0.05 versus time 0 min under the same treatment, + P ≤ 0.1, ++ P ≤ 0.05 versus time 60 min under the same treatment, °P ≤ 0.1, °°P ≤ 0.05 versus vehicle at the same time point post-HCl.
Mentions: The amount of acid equivalents present in the gastric lumen fell significantly over the 2 h interval post-HCl in all treatment groups (Figure 3B). Most of the drop in gastric acidity occurred within 60 min post-HCl, and there was no significant difference in the gastric acidity levels 0 and 60 min post-HCl between the three treatment groups. In lafutidine-treated rats there was a further significant drop of gastric acidity during the period 60 – 120 min post-HCl, a change that was not seen in vehicle- and cimetidine-treated rats (Figure 3B). The decrease in gastric acidity 120 min post-HCl in lafutidine-treated rats was significantly more marked than in vehicle-treated animals (Figure 3B). When gastric acidity measured 60 and 120 min post-HCl was expressed relative to the acidity measured immediately (0 min) after gastric acid loading, it was found that the drop of gastric acidity 120 min post-HCl seen in lafutidine-treated rats was most pronounced, compared with that seen in vehicle- and cimetidine-treated rats (Figure 4A).

Bottom Line: Lafutidine reduced the HCl-evoked expression of c-Fos in the NTS and elevated the intragastric pH following intragastric administration of excess HCl.Further analysis showed that the gastroprotective effect of lafutidine against excess acid was delayed and went in parallel with facilitation of gastric emptying, measured indirectly via gastric volume changes, and a reduction of gastric acidity.The H2 receptor antagonist cimetidine had similar but weaker effects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria. ma.edelsbrunner@medunigraz.at

ABSTRACT

Background: Lafutidine is a histamine H2 receptor antagonist, the gastroprotective effect of which is related to its antisecretory activity and its ability to activate a sensory neuron-dependent mechanism of defence. The present study investigated whether intragastric administration of lafutidine (10 and 30 mg/kg) modifies vagal afferent signalling, mucosal injury, intragastric acidity and gastric emptying after gastric acid challenge.

Methods: Adult rats were treated with vehicle, lafutidine (10 - 30 mg/kg) or cimetidine (10 mg/kg), and 30 min later their stomachs were exposed to exogenous HCl (0.25 M). During the period of 2 h post-HCl, intragastric pH, gastric volume, gastric acidity and extent of macroscopic gastric mucosal injury were determined and the activation of neurons in the brainstem was visualized by c-Fos immunocytochemistry.

Results: Gastric acid challenge enhanced the expression of c-Fos in the nucleus tractus solitarii but caused only minimal damage to the gastric mucosa. Lafutidine reduced the HCl-evoked expression of c-Fos in the NTS and elevated the intragastric pH following intragastric administration of excess HCl. Further analysis showed that the gastroprotective effect of lafutidine against excess acid was delayed and went in parallel with facilitation of gastric emptying, measured indirectly via gastric volume changes, and a reduction of gastric acidity. The H2 receptor antagonist cimetidine had similar but weaker effects.

Conclusion: These observations indicate that lafutidine inhibits the vagal afferent signalling of a gastric acid insult, which may reflect an inhibitory action on acid-induced gastric pain. The ability of lafutidine to decrease intragastric acidity following exposure to excess HCl cannot be explained by its antisecretory activity but appears to reflect dilution and/or emptying of the acid load into the duodenum. This profile of actions emphasizes the notion that H2 receptor antagonists can protect the gastric mucosa from acid injury independently of their ability to suppress gastric acid secretion.

Show MeSH
Related in: MedlinePlus