6-ketoprostaglandin-f1-alpha and lafutidine

Sensory neuron activation reduces water-immersion restraint stress (WIR)-induced gastric mucosal injury by inhibiting neutrophil activation through increase in endothelial production of prostacyclin. This study was designed to examine whether lafutidine, which is an H(2)-receptor antagonist and activates sensory neurons, inhibits neutrophil activation, thereby reducing WIR-induced gastric mucosal injury. Lafutidine enhanced WIR-induced increases in gastric tissue levels of calcitonin gene-related peptide (CGRP) and 6-keto-PGF(1alpha), a stable metabolite of prostacyclin, whereas famotidine, another H(2)-receptor antagonist, did not. Such lafutidine-induced increases in gastric tissue levels of 6-keto-PGF(1alpha) were reversed by pretreatment with capsazepine, an inhibitor of sensory neuron activation, CGRP(8-37), a CGRP antagonist, and indomethacin. Lafutidine inhibited acid-induced exacerbation of gastric mucosal injury in animals subjected to WIR by inhibiting neutrophil activation, whereas famotidine did not. Lafutidine synergistically increased CGRP release from isolated rat dorsal root ganglion neurons in the presence of anandamide, but famotidine did not. These observations suggest that lafutidine might reduce WIR-induced gastric mucosal injury not only by inhibiting acid secretion but also by inhibiting neutrophil activation through enhancement of sensory neuron activation.

Topics: 6-Ketoprostaglandin F1 alpha; Acetamides; Animals; Anti-Ulcer Agents; Arachidonic Acids; Calcitonin Gene-Related Peptide; Capsaicin; Cells, Cultured; Cyclooxygenase Inhibitors; Disease Models, Animal; Endocannabinoids; Famotidine; Ganglia, Spinal; Gastric Acid; Gastric Mucosa; Histamine H2 Antagonists; Indomethacin; Male; Neurons, Afferent; Neutrophil Activation; Peptide Fragments; Piperidines; Polyunsaturated Alkamides; Pyridines; Rats; Rats, Wistar; Restraint, Physical; Stomach Ulcer; Stress, Psychological

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).. 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.. 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.. 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.

Topics: 6-Ketoprostaglandin F1 alpha; Acetamides; Animals; Calcium; Capsaicin; Dinoprostone; Dose-Response Relationship, Drug; Gastric Mucosa; Histamine H2 Antagonists; Humans; Indomethacin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons, Afferent; NG-Nitroarginine Methyl Ester; Piperidines; Prostaglandins; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Epoprostenol; Stomach; Stomach Diseases; TRPV Cation Channels