Gastro-protective action of lafutidine mediated by capsaicin-sensitive afferent neurons without interaction with TRPV1 and involvement of endogenous prostaglandins.
OBJECTIVE
Lafutidine, a histamine H2 receptor antagonist, exhibits gastro-protective action mediated by capsaicin-sensitive afferent neurons (CSN). We compared the effect between lafutidine and capsaicin, with respect to the interaction with endogenous prostaglandins (PG), nitric oxide (NO) and the afferent neurons, including transient receptor potential vanilloid subtype 1 (TRPV1).


METHODS
Male SD rats and C57BL/6 mice, both wild-type and prostacyclin IP receptor knockout animals, were used after 18 h of fasting. Gastric lesions were induced by the po administration of HCl/ethanol (60% in 150 mmol/L HCl) in a volume of 1 mL for rats or 0.3 mL for mice.


RESULTS
Both lafutidine and capsaicin (1-10 mg/kg, po) afforded dose-dependent protection against HCl/ethanol in rats and mice. The effects were attenuated by both the ablation of CSN and pretreatment with N(G)-nitro-L-arginine methyl ester, yet only the effect of capsaicin was mitigated by prior administration of capsazepine, the TRPV1 antagonist, as well as indomethacin. Lafutidine protected the stomach against HCl/ethanol in IP receptor knockout mice, similar to wild-type animals, while capsaicin failed to afford protection in the animals lacking IP receptors. Neither of these agents affected the mucosal PGE2 or 6-keto PGF(1alpha) contents in rat stomachs. Capsaicin evoked an increase in [Ca2+]i in rat TRPV1-transfected HEK293 cells while lafutidine did not.


CONCLUSIONS
These results suggest that although both lafutidine and capsaicin exhibit gastro-protective action mediated by CSN, the mode of their effects differs regarding the dependency on endogenous PGs/IP receptors and TRPV1. It is assumed that lafutidine interacts with CSN at yet unidentified sites other than TRPV1.
Fukushima
Kazuhiro
K
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto 607, Japan.
Aoi
Yoko
Y
Kato
Shinichi
S
Takeuchi
Koji
K
D015121:6-Ketoprostaglandin F1 alpha / Q000032:analysis; D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000032:analysis; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology*; D015232:Dinoprostone / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000737:chemistry / Q000473:pathology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology*; D011453:Prostaglandins / Q000502:physiology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol / Q000235:genetics / Q000502:physiology; D013270:Stomach / Q000737:chemistry / Q000187:drug effects; D013272:Stomach Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000502:physiology*
D000081:Acetamides; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011453:Prostaglandins; D011725:Pyridines; D044006:Receptors, Epoprostenol; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C493922:Trpv1 protein, rat; C076948:lafutidine; D015121:6-Ketoprostaglandin F1 alpha; D015232:Dinoprostone; C071423:capsazepine; D002211:Capsaicin; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin