Effect of Lafutidine, a Histamine H2-Receptor Antagonist, on Gastric Mucosal Blood Flow and Duodenal HCO3 − Secretion in Rats: Relation to Capsaicin-Sensitive Afferent Neurons

摘要

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.