Impairment of Gastric Ulcer Healing by Alendronate, a Nitrogen-Containing Bisphosphonate, in Rats

Amagase, Kikuko; Hayashi, Satoru; Nishikawa, Kaoru; Aihara, Eitaro; Takeuchi, Koji

doi:10.1007/s10620-007-9769-5

Cited by 22 publications

(35 citation statements)

References 33 publications

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“…Indomethacin, a non steroidal anti-infl ammatory drug, delayed the healing of experimental gastric ulcers in rats, concomitant with down-regulation of such growth factors as well as suppression of the angiogenic response (Amagase et al, 2003;2006). Chakroborty et al (2004) reported that dopamine signifi cantly inhibited the VEGF-mediated angiogenesis in rat malignant gastric tumor.…”

Section: Discussionmentioning

confidence: 99%

Effect of dopamine on the healing of acetic acid-induced gastric ulcers in rats

2007

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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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Section: Discussionmentioning

confidence: 99%

Effect of dopamine on the healing of acetic acid-induced gastric ulcers in rats

2007

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“…Amagase et al (1) showed previously that bFGF is essential for angiogenesis in the healing of gastric ulcers induced by alendronate. In addition, Ernst et al (8) demonstrated that local injection of bFGF to the base of gastric ulcers significantly accelerated healing, in association with an increase in the amount of microvasculature and mucosal blood flow in the ulcerated area.…”

Section: Discussionmentioning

confidence: 99%

Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing of gastric ulcers

Ohno

Hattori

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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The importance of prostaglandin E(2) in various pathophysiological events emphasizes the necessity of understanding the role of PGE synthases (PGESs) in vivo. However, there has been no report on the functional relevance of microsomal PGES-1 (mPGES-1) to the physiological healing processes of gastric ulcers, or to angiogenesis, which is indispensable to the healing processes. In this report, we tested whether mPGES-1 plays a role in the healing of gastric ulcers and in the enhancement of angiogenesis using mPGES-1 knockout mice (mPGES-1 KO mice) and their wild-type (WT) counterparts. Gastric ulcers were induced by the serosal application of 100% acetic acid, and the areas of the ulcers were measured thereafter. mPGES-1 together with cyclooxygenase-2 were induced in the granulation tissues compared with normal stomach tissues. The healing of acetic acid-induced ulcers was significantly delayed in mPGES-1 KO mice compared with WT. This was accompanied with reduced angiogenesis in ulcer granulation tissues, as estimated by CD31 mRNA levels determined by real-time PCR and the microvessel density in granulation tissues. The mRNA levels of proangiogenic growth factors, such as transforming growth factor-β, basic fibroblast growth factor, and connective tissue growth factor in ulcer granulation tissues determined were reduced in mPGES-1 KO mice compared with WT. The present results suggest that mPGES-1 enhances the ulcer-healing processes and the angiogenesis indispensable to ulcer healing, and that a selective mPGES-1 inhibitor should be used with care in patients with gastric ulcers.

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“…On the other hand, Elliott et al [11] reported that BPPs at relatively low doses exert a deleterious influence on the healing of gastric ulcers and potentiated the healing impairment action of NSAIDs, frequently prescribed together with BPPs in patients with arthritis or osteroprosis. We also found that alendronate delayed the healing of gastric ulcers in rats, with concomitant impairment of vasculariza tion/granulation at the ulcer base [9,12,13]. Because the mechanism underlying these adverse reactions of BPPs remains unclear, an effective therapy for the prevention of these side effects is not currently available.…”

Section: Introductionmentioning

confidence: 95%

“…Furthermore, it was also shown that rebamipide increases mucosal prostaglandin (PG) production and mucus secretion, the important factors contributing to the mucosal defensive ability [20,21]. We have reported the beneficial influences of this agent on the adverse reactions induced in the stomach by alendronate [9,10,12,13].…”

Section: Introductionmentioning

confidence: 99%

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Gastric Ulcerogenic and Healing Impairment Actions of Alendronate, A Nitrogen- Containing Bisphosphonate - Prophylactic Effects of Rebamipide

Takeuchi¹,

Kato²,

Amagase

2011

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Alendronate, a nitrogen containing bisphosphonate (BPP), when given p.o., decreases the transmucosal potential difference by direct irritating action, resulting in non-hemorrhagic lesions in both the corpus and antrum of fasted rats, and after re-feeding produces large ulcers in the antrum with increased vascular permeability and submucosal edema. The pathogenesis of these ulcers may be explained by the impairment of the mucosal anti-oxidative system and does not involve acid digestion as well as a deficiency of prostaglandins (PGs). Alendronate, although does not affect cyclooxygenase/ PGE(2) production in the ulcerated mucosa, but impairs the healing of gastric ulcers in rats, and this effect may be related to the down-regulation of vascular endothelial growth factor and basic fibroblast growth factor (bFGF), the important growth factors for the vascularization/granulation as well as the suppression of the stimulatory action of epidermal growth factor on the epithelial proliferation/migration. Rebamipide, a mucosal protective and antiulcer drug, does not affect the direct irritating action of alendronate in the gastric mucosa but prevents the alendronate-induced antral ulceration, probably due to anti-oxidative and anti-inflammatory actions. In addition, this agent also antagonizes the healing impairment action of alendronate by counteracting the down-regulation of bFGF expression in the ulcerated mucosa. It is assumed that rebamipide is a promising drug that can be used as a prophylactic against the adverse effects of BPPs in the stomach.

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Impairment of Gastric Ulcer Healing by Alendronate, a Nitrogen-Containing Bisphosphonate, in Rats

Cited by 22 publications

References 33 publications

Effect of dopamine on the healing of acetic acid-induced gastric ulcers in rats

Effect of dopamine on the healing of acetic acid-induced gastric ulcers in rats

Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing of gastric ulcers

Gastric Ulcerogenic and Healing Impairment Actions of Alendronate, A Nitrogen- Containing Bisphosphonate - Prophylactic Effects of Rebamipide

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