Reviewer's report
Title:Afferent signalling from the acid-challenged rat stomach is inhibited and
gastric acid elimination is enhanced by lafutidine
Version: 1Date:16 March 2009
Reviewer: Koji Takeuchi
Reviewer's report:
The authors confirmed that the acid (0.25 M) challenge increased the expression
of c-Fos in the NTS with a minimal damage in the gastric mucosa. Lafutidine, a
histamine H2 antagonist with mucosal protective action mediated by
capsaicin-sensitive afferent neurons, reduced the acid-evoked c-Fos expression
in the NTS and elevated the luminal pH following the acid challenge. In addition,
the gastroprotective effect of lafutidine was found to be in parallel with facilitation
of gastric emptying and reduction of luminal acidity, and the effects of this drug
were only in part shared by cimetidine. They concluded that lafutidine inhibits
gastric acid-evoked vagal nociceptive signalling and that this drug protects the
gastric mucosa from acid injury independently of its ability to suppress acid
secretion due to H2 receptor blockade. The present study was well designed and
performed, and the data well supported the conclusion. However, there are
several points that should be addressed before consideration of its publication.
Major Compulsory Revisions
1. Lafutidine is known to exhibit gastroprotection mediated by capsaicin-sensitive
afferent neurons. The present study showed that lafutidine inhibited the
acid-evoked c- Fos expression in the NTS. This reviewer wonders if the
acid-evoked c-Fos expression is affected by capsaicin or ablation of
capsaicin-sensitive afferent neurons? Some comments on this point, including a
relation to the sensory neuronal activating property of lafutidine, should be made
in the text.
2. In this study, the effect of cimetidine was examined at 10 mg/kg, in comparison
with lafutidine at 30 mg/kg. The authors should give a rationale to use this dose
of cimetidine, ie., do the authors have some evidence showing that the potency
of the antisecretory action of cimetidine at 10 mg/kg is equivalent to that of
lafutidine at 30 mg/kg?
3. The authors speculated that endogenous acid plays some role in the
mechanism of the central c-Fos response to back-diffusion H+. Since lafutidine
inhibits endogenous acid secretion due to histamine H2 receptor blockade, this
action may somehow contributes to suppression of the c-Fos expression
following the acid challenge. This reviewer wonders if lafutidine inhibits the
acid-evoked c-Fos expression in the animals pretreated with omeprazole to
completely inhibit endogenous acid secretion. Does lafutidine suppress the c-Fos
response to exogenous acid challenge in the absence of endogenous acid
secretion? If it does, this action of lafutidine could be mimicked by cimetidine or
omeprazole? Such data would be helpful for further understanding of the
regulatory mechanism of c-Fos response to acid challenge.
Minor Essential Revisions
4. page 2, line 5 from the bottom and page 12, Discussion, line 3-4: The ability of
lafutidine to elevate intragastric acidity – this should be read “—to elevate
intragastric pH or to decrease intragatric acidity”
Reviewer's report
Title:Afferent signalling from the acid-challenged rat stomach is inhibited and
gastric acid elimination is enhanced by lafutidine
Version: 1Date:16 March 2009
Reviewer: Koji Takeuchi
Reviewer's report:
The authors confirmed that the acid (0.25 M) challenge increased the expression
of c-Fos in the NTS with a minimal damage in the gastric mucosa. Lafutidine, a
histamine H2 antagonist with mucosal protective action mediated by
capsaicin-sensitive afferent neurons, reduced the acid-evoked c-Fos expression
in the NTS and elevated the luminal pH following the acid challenge. In addition,
the gastroprotective effect of lafutidine was found to be in parallel with facilitation
of gastric emptying and reduction of luminal acidity, and the effects of this drug
were only in part shared by cimetidine. They concluded that lafutidine inhibits
gastric acid-evoked vagal nociceptive signalling and that this drug protects the
gastric mucosa from acid injury independently of its ability to suppress acid
secretion due to H2 receptor blockade. The present study was well designed and
performed, and the data well supported the conclusion. However, there are
several points that should be addressed before consideration of its publication.
Major Compulsory Revisions
1. Lafutidine is known to exhibit gastroprotection mediated by capsaicin-sensitive
afferent neurons. The present study showed that lafutidine inhibited the
acid-evoked c- Fos expression in the NTS. This reviewer wonders if the
acid-evoked c-Fos expression is affected by capsaicin or ablation of
capsaicin-sensitive afferent neurons? Some comments on this point, including a
relation to the sensory neuronal activating property of lafutidine, should be made
in the text.
2. In this study, the effect of cimetidine was examined at 10 mg/kg, in comparison
with lafutidine at 30 mg/kg. The authors should give a rationale to use this dose
of cimetidine, ie., do the authors have some evidence showing that the potency
of the antisecretory action of cimetidine at 10 mg/kg is equivalent to that of
lafutidine at 30 mg/kg?
3. The authors speculated that endogenous acid plays some role in the
mechanism of the central c-Fos response to back-diffusion H+. Since lafutidine
inhibits endogenous acid secretion due to histamine H2 receptor blockade, this
action may somehow contributes to suppression of the c-Fos expression
following the acid challenge. This reviewer wonders if lafutidine inhibits the
acid-evoked c-Fos expression in the animals pretreated with omeprazole to
completely inhibit endogenous acid secretion. Does lafutidine suppress the c-Fos
response to exogenous acid challenge in the absence of endogenous acid
secretion? If it does, this action of lafutidine could be mimicked by cimetidine or
omeprazole? Such data would be helpful for further understanding of the
regulatory mechanism of c-Fos response to acid challenge.
Minor Essential Revisions
4. page 2, line 5 from the bottom and page 12, Discussion, line 3-4: The ability of
lafutidine to elevate intragastric acidity – this should be read “—to elevate
intragastric pH or to decrease intragatric acidity”
Please review this paper.
user
Reviewer's report
Title:Afferent signalling from the acid-challenged rat stomach is inhibited and
gastric acid elimination is enhanced by lafutidine
Version: 1Date:16 March 2009
Reviewer: Koji Takeuchi
Reviewer's report:
The authors confirmed that the acid (0.25 M) challenge increased the expression
of c-Fos in the NTS with a minimal damage in the gastric mucosa. Lafutidine, a
histamine H2 antagonist with mucosal protective action mediated by
capsaicin-sensitive afferent neurons, reduced the acid-evoked c-Fos expression
in the NTS and elevated the luminal pH following the acid challenge. In addition,
the gastroprotective effect of lafutidine was found to be in parallel with facilitation
of gastric emptying and reduction of luminal acidity, and the effects of this drug
were only in part shared by cimetidine. They concluded that lafutidine inhibits
gastric acid-evoked vagal nociceptive signalling and that this drug protects the
gastric mucosa from acid injury independently of its ability to suppress acid
secretion due to H2 receptor blockade. The present study was well designed and
performed, and the data well supported the conclusion. However, there are
several points that should be addressed before consideration of its publication.
Major Compulsory Revisions
1. Lafutidine is known to exhibit gastroprotection mediated by capsaicin-sensitive
afferent neurons. The present study showed that lafutidine inhibited the
acid-evoked c- Fos expression in the NTS. This reviewer wonders if the
acid-evoked c-Fos expression is affected by capsaicin or ablation of
capsaicin-sensitive afferent neurons? Some comments on this point, including a
relation to the sensory neuronal activating property of lafutidine, should be made
in the text.
2. In this study, the effect of cimetidine was examined at 10 mg/kg, in comparison
with lafutidine at 30 mg/kg. The authors should give a rationale to use this dose
of cimetidine, ie., do the authors have some evidence showing that the potency
of the antisecretory action of cimetidine at 10 mg/kg is equivalent to that of
lafutidine at 30 mg/kg?
3. The authors speculated that endogenous acid plays some role in the
mechanism of the central c-Fos response to back-diffusion H+. Since lafutidine
inhibits endogenous acid secretion due to histamine H2 receptor blockade, this
action may somehow contributes to suppression of the c-Fos expression
following the acid challenge. This reviewer wonders if lafutidine inhibits the
acid-evoked c-Fos expression in the animals pretreated with omeprazole to
completely inhibit endogenous acid secretion. Does lafutidine suppress the c-Fos
response to exogenous acid challenge in the absence of endogenous acid
secretion? If it does, this action of lafutidine could be mimicked by cimetidine or
omeprazole? Such data would be helpful for further understanding of the
regulatory mechanism of c-Fos response to acid challenge.
Minor Essential Revisions
4. page 2, line 5 from the bottom and page 12, Discussion, line 3-4: The ability of
lafutidine to elevate intragastric acidity – this should be read “—to elevate
intragastric pH or to decrease intragatric acidity”
assistant