Impairment by 5-fluorouracil of the healing of gastric lesions in rats: effect of lafutidine, a histamine H2 receptor antagonist, mediated by capsaicin-sensitive afferent neurons.
We investigated the influence of 5-fluorouracil (5-FU), an anti-tumor agent, on the healing of gastric lesions generated by 0.6 M HCl in rats and the effect of lafutidine, a histamine H(2) receptor antagonist, on the impaired healing. Animals fasted for 18 h were given 1 ml of 0.6 M HCl p.o., fed normally from 1 h later, and killed 1-96 h thereafter. 5-FU was given i.v. twice, 1 h and 24 h after the HCl. The gastric lesions healed spontaneously within 96 h. Although it decreased acid secretion, 5-FU markedly delayed the healing. Lafutidine, but not cimetidine, given p.o. immediately after each dosing of 5-FU significantly reversed the delay in healing by 5-FU, and this effect was attenuated by the chemical ablation of capsaicin-sensitive afferent neurons. Capsaicin also significantly reversed the delay in healing. The mucosal application of 50 mM HCl did not affect gastric mucosal blood flow (GMBF) in the normal stomach, but significantly increased it in the stomach damaged by 0.6 M HCl. The increases in GMBF were attenuated by 5-FU; however, the co-administration of lafutidine significantly restored the response. In addition, 5-FU inhibited both cell proliferation and migration in rat gastric epithelial cells (RGM1) in vitro. These results suggest that 5-FU delayed the healing of gastric lesions generated by 0.6 M HCl, probably through the inhibition of cell migration and proliferation, as well as the impairment of GMBF, and lafutidine reversed the delay in healing, mainly through the amelioration of the GMBF response mediated by capsaicin-sensitive afferent neurons.
Murashima
Yukiko
Y
Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, 607-8414, Japan.
Kotani
Tohru
T
Hayashi
Shusaku
S
Komatsu
Yoshino
Y
Nakagiri
Akari
A
Amagase
Kikuko
K
Takeuchi
Koji
K
D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects; D005472:Fluorouracil / Q000009:adverse effects* / Q000494:pharmacology; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects / Q000294:innervation; D006635:Histamine H2 Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006851:Hydrochloric Acid; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D018689:Sensory System Agents / Q000494:pharmacology; D013272:Stomach Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects
D000081:Acetamides; D000964:Antimetabolites, Antineoplastic; D006635:Histamine H2 Antagonists; D010880:Piperidines; D011725:Pyridines; D018689:Sensory System Agents; C076948:lafutidine; D006851:Hydrochloric Acid; D002211:Capsaicin; D005472:Fluorouracil