Gastro-protective action of lafutidine mediated by capsaicin-sensitive afferent neurons without interaction with TRPV1 and involvement of endogenous prostaglandins

Figure 1 Effects of lafutidine (A) and capsaicin (B) on HCl/ethanol-induced gastric lesions in rats. The animals were given 1 mL of HCl/ethanol (60% ethanol in 150 mmol/L HCl) po and killed 1 h later. Lafutidine (1-10 mg/kg) and capsaicin (1-10 mg/kg) were administered po 30 min before HCl/ethanol. Ablation of capsaicin-sensitive afferent neurons was achieved by consecutive s.c. injections of capsaicin (total dose of 100 mg/kg) once daily for 3 d 2 wk before the experiment. Data are presented as the mean ± SE from 4-7 rats. ^aP < 0.05, ^cP < 0.05 vs control.

Figure 2 Effect of capsazepine on the protective action of lafutidine or capsaicin against HCl/ethanol-induced gastric lesions in rats. The animals were given 1 mL of HCl/ethanol (60% ethanol in 150 mmol/L HCl) po and killed 1 h later. Lafutidine or capsaicin was given po 30 min before HCl/ethanol. Capsazepine (12.5 mg/kg) was administered po 30 min before lafutidine or capsaicin. Data are presented as the mean ± SE from 4-7 rats. ^aP < 0.05 vs control, ^cP < 0.05 vs vehicle.

Figure 3 Effects of indomethacin and L-NAME on the protective action of lafutidine or capsaicin against HCl/ethanol-induced gastric lesions in rats. The animals were given 1 mL of HCl/ ethanol (60% ethanol in 150 mmol/L HCl) po and killed 1 h later. Lafutidine (10 mg/kg) or capsaicin (10 mg/kg) was given po 30 min before HCl/ethanol. Indomethacin (5 mg/kg) or L-NAME (20 mg/kg) was administered sc 1 h before HCl/ethanol. Data are presented as the mean ± SE from 6-9 rats. ^aP < 0.05 vs control, ^cP < 0.05 vs saline.

Figure 4 Effects of lafutidine and capsaicin on mucosal PGE₂ contents in rat stomachs. The animals were given lafutidine (10 mg/kg) or capsaicin (10 mg/kg) po and killed 1 h later. Indomethacin (5 mg/kg) was administered sc 30 min before capsaicin or lafutidine. Gastric mucosal PGE₂ content was determined by EIA. Data are presented as the mean ± SE from 5 rats. ^aP < 0.05 vs control.

Figure 5 Effects of lafutidine and capsaicin on HCl/ethanol-induced gastric lesions in wild-type and IP-receptor knockout mice. The animals were given 1 mL of HCl/ethanol (60% ethanol in 150 mmol/L HCl) po and killed 1 h later. Lafutidine (10-30 mg/kg) or capsaicin (10 mg/kg) was given po 30 min before HCl/ethanol. Data are presented as the mean ± SE from 5-7 rats. ^aP < 0.05 vs control.

Figure 6 Effects of lafutidine and capsaicin on gastric mucosal 6-keto-PGF_1α levels in mice. The animals were given capsaicin (10 mg/kg) po and killed 1 h later. Indomethacin (5 mg/kg) was administered sc 30 min before capsaicin. Gastric mucosal 6-keto-PGF_1α levels were determined by EIA. Data are presented as the mean ± SE from 4-5 rats. ^aP < 0.05 vs control.

Figure 7 Changes in the intracellular concentration of Ca²⁺ in response to capsaicin and lafutidine in HEK293 cells transfected with VR1. Rat VR1 was introduced into HEK293 cells. Capsaicin (10^-8-10^-6 mol/L) or lafutidine (10^-4 mol/L) was added to the medium. Data are presented as the mean ± SE from 3 experiments. ^aP < 0.05 vs control.