Bisphosphonates such as alendronate have been developed as antiresorptive agents capable of treating diseases related to bone remodeling. In the present study, we examined the effect of alendronate on the healing of acetic acid-induced gastric ulcers in rats and investigated the mechanism involved in this action both in vivo and in vitro using the rat gastric epithelial cell line (RGM1). Acetic acid-induced gastric ulcers healed spontaneously, with up-regulation of COX-2/prostaglandin E2 production as well as expression of vascular endothelium-derived growth factor (VEGF) and basic fibroblast growth factor (bFGF) in ulcerated mucosa. The healing of ulcers was impaired by indomethacin (2 mg/kg, s.c.) or alendronate (60 mg/kg, p.o.) given once daily for 7 days, starting 3 days after acid application. Indomethacin, but not alendronate, inhibited mucosal prostaglandin E2 production. Alendronate as well as indomethacin decreased the protein expression of both VEGF and bFGF in ulcerated mucosa, resulting in a reduction of angiogenesis in the ulcer base. Supplementation of recombinant bFGF significantly reverted the delay in ulcer healing caused by alendronate. On the other hand, the size of cell-free areas in RGM1 cells in vitro decreased with time after wound induction, and this process was promoted by epidermal growth factor (EGF; 10 ng/ml). Co-incubation with alendronate (1 mM) did not affect the spontaneous healing but significantly suppressed the accelerated wound healing caused by EGF. These results suggest that alendronate impairs the healing of gastric ulcers in rats, and this effect may be related to down-regulation of VEGF and bFGF, the important growth factors for vascularization/granulation, as well as suppression of the stimulatory action of EGF on epithelial proliferation/migration.
Dopamine, as a neurotransmitter in the brain, is also present in the gastroduodenal mucosa and has been implicated in several functions in these tissues. Recent study showed that dopamine acts as a potent antitumor/angiogenic activity through suppression of growth factor expression. Since growth factors are known to play a crucial role in the mechanism of wound healing, it is possible that dopamine has a deleterious influence on the healing of gastric ulcers. In the present study, we examined the effect of dopamine on the healing of acetic acid-induced gastric ulcers in rats. Gastric ulcers were induced in male SD rats by serosal application of acetic acid for 60 sec. Dopamine was subcutaneously given twice daily for 7 days, starting 3 days after ulceration. In some case, the osmotic mini-pump filled with dopamine was implanted into the dorsal subcutaneous space in rats for 7 days. VEGF and Flk-1 mRNA expressions were determined by RT-PCR. Dopamine (3, 10 and 30 mg/kg) given subcutaneously for 7 days did not significantly affect the healing of gastric ulcers. The expression of VEGF and Flk-1 mRNA in the ulcerated mucosa was up-regulated after ulceration, and these expressions were not affected by dopamine. Likewise, dopamine (0.6 mg/kg/hr) infused continuously using the osmotic mini-pump also had no effect on the healing of these ulcers. These results suggest that dopamine, although reportedly shows a potent antitumor/angiogenic activity, does not cause any influence on the healing of the pre-existing gastric ulcers in rats.
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