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Abstract

Lafutidine is a new type of antiulcer drug, possessing both an antisecretory effect, exerted via a blockade of the histamine H2 receptor, and gastroprotective activity, mediated by capsaicin-sensitive afferent nerves (CSN). In the present study, we examined the effect of lafutidine on gastric mucosal blood flow (GMBF) and duodenal HCO3- secretion (DAS) under basal and acid-stimulated conditions in rats. Under urethane anesthesia, GMBF was measured using a laser Doppler flowmeter in a chambered stomach before and after exposure to 20 mM taurocholate (TC) plus 50 mM HCl, while DAS was measured in a proximal duodenal loop before and after mucosal acidification (10 mM HCl for 10 min) by titrating the perfusate at pH 7.0 using a pH-stat method and by adding 10 mM HCl. Lafutidine given intraperitoneally affected neither GMBF nor DAS under basal conditions, but augmented an increase in both GMBF and DAS induced by mucosal acidification. Although the acid-induced GMBF and DAS responses were significantly mitigated by both indomethacin and sensory deafferentation but not by ruthenium red (RT), the vanilloid receptor (VR)-1 antagonist, the responses were preserved in lafutidine-treated animals, even in the presence of indomethacin. Both GMBF and DAS were significantly increased by local application of capsaicin, the responses being attenuated by indomethacin and RT as well as sensory deafferentation. Lafutidine augmented the GMBF and DAS responses to capsaicin and preserved the responses, even in the presence of indomethacin. Capsaicin evoked an increase in [Ca2+]i in rat VR1-transfected HEK293 cells, while lafutidine had no effect by itself on [Ca2+]i in these cells and did not affect the increase in [Ca2+]i evoked by capsaicin. In conclusion, these results suggest that lafutidine mimics endogenous effects of prostaglandins to augment the GMBF and DAS responses to acid or capsaicin, probably by sensitizing CSN through an unknown site other than VR1. The luminal H+ itself is not a ligand for the RT-sensitive site of VR1 but plays a modulator role in the CSN-mediated physiological responses.

Lafutidine, a Protective H2 Receptor Antagonist, Enhances Mucosal Defense in Rat Esophagus

“…The precise mechanism by which Laf exerts its effects is unknown; nevertheless, denervation of CSAN abrogates the protective effects of Laf, suggesting involvement of the capsaicin pathway. In vitro studies have failed to document a direct interaction between Laf and TRPV1 [12, 14], whereas Laf potentiates Cap-induced CGRP release from the gastric mucosa [14], suggesting that Laf sensitizes TRPV1 or interacts at alternate components of the capsaicin pathway. Our results demonstrated that luminal Laf perfusion increased blood flow in the absence of perfused luminal acid and that Laf enhanced acid-induced hyperemia, both mediated by CSAN, supporting our hypothesis that Laf sensitizes TRPV1 or submucosal afferent nerves.…”

Lafutidine 10 mg versus Rabeprazole 20 mg in the Treatment of Patients with Heartburn-Dominant Uninvestigated Dyspepsia: A Randomized, Multicentric Trial

“…In addition to being a potent H2 receptors antagonist [12], lafutidine also activates capsaicin-sensitive afferent neurons and stimulates the release of calcitonin gene-related peptide (CGRP), which inhibits acid secretion and stimulates mucosal blood flow [13–15]. The gastro protective action of lafutidine includes increase in mucin biosynthesis via stimulation of nitric oxide production [11, 16], increasing the thickness of the surface mucus gel layer [17], and maintaining gastric mucosal blood flow and bicarbonate response [18]. Lafutidine has been elaborately studied internationally in various indications like gastritis, and gastric and peptic ulcer, while recent focus has also shifted to its use in gastroesophageal reflux disorder (GERD) [19–23].…”

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

“…Apart from this mechanism of action it is also conceivable that lafutidine facilitated gastric acid elimination by dilution with fluid and acid-neutralizing factors. The capacity of lafutidine to stimulate secretory processes other than acid secretion in the upper gut is supported by its effect to increase acid-stimulated duodenal bicarbonate secretion [7]. …”

“…In addition, there is evidence that the gastroprotective action of lafutidine involves release of neuropeptides from afferent nerve endings in the stomach [7,8]. In view of this pharmacological profile the question arose as to whether lafutidine would be able to modify vagal afferent signalling of gastric acid challenge to the brainstem.…”