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

Abstract

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.

Protective Effects of Gastric Mucus

“…However, lafutidine by itself does not have any direct effects on cell migration or proliferation. An earlier study demonstrated that lafutidine does not influence the impaired healing of epithelial wounds in RGM1 cells under in vitro conditions without neuronal innervations (Murashima et al, 2009), again confirming the importance of sensory neurons in the healing-promoting action of this agent. Several studies show that luminal lafutidine stimulates capsaicin-sensitive afferent nerves via presumably direct diffusion rather than after its absorption from intestine followed by via circulation, suggesting the rapid local diffusion reaching to the afferents before H 2 -receptor blockade from the circulation (Onodera et al, 1999b;Nagahama et al, 2003).…”

“…Cimetidine and ranitidine belong to the conventional group characterized by a fivemembered aromatic ring. Recently, some of the newer H 2 -blockers (so-called secondgeneration H 2 -blockers) have been reported to promote the gastric mucosal defense mechanisms (Fukushima et al, 2006;Harada et al, 2007;Marazova et al 1998;Murashima et al, 2009;Saegusa et al, 2008;Ichikawa et al, 2009a). Second-generation H 2 -blockers contain a six-membered aromatic ring, instead of a five-membered heterocyclic ring.…”

“…Although the exact mechanisms that underlie the gastroprotective activity of the secondgeneration H 2 -receptor antagonists are not well understood, recent findings suggest that the activation of capsaicin-sensitive sensory neurons is associated with their maintenance of gastric mucosal integrity (Fukushima et al, 2006;Harada et al, 2007;Murashima et al, 2009;Sugiyama et al, 2008). The gastrointestinal tract is known to possess a rich neural network, among which afferent neurons of extrinsic origin are reported to operate as the emergency protective system.…”