W1238 Proton Pump Inhibitor (PPI) Lansoprazole Prevents Indomethacin-Induced Small Intestinal Ulceration in Rats: Involvement of Heme Oxygenase (HO)-1

Yoda, Yukiko; Higuchi, Kazuhide; Takeuchi, Koji; Umegaki, Eiji; Tokioka, Satoshi; Kato, Shinichi; Amagase, Kikuko

doi:10.1016/s0016-5085(09)63151-6

Cited by 20 publications

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“…Kuroda et al (2006) first reported that LPZ had an inhibitory effect on IND-induced small intestinal lesions in rats and suggested that LPZ prevented intestinal lesions by anti-inflammatory and antioxidant mechanisms, because LPZ inhibited INDinduced increase of myeloperoxidase activity and thiobarbituric acid-reactive substance in the intestinal mucosa. Higuchi et al (2009) and Yoda et al (2010) reported that LPZ, but not OPZ, prevented IND-induced intestinal lesions in rats and suggested that LPZ protected the intestinal mucosa by up-regulation of hemoxygenase-1 production in the mucosa. We reported previously that LPZ protects the gastric mucosa by a mechanism independent from its antisecretory action, and both CSSN and NO are involved in the protective mechanism of LPZ on the gastric mucosa (Murakami et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Lesions by Antisecretory Drugs in Rats: The Role of Intestinal Motility

Satoh

Amagase

Takeuchi

2012

J Pharmacol Exp Ther

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Antisecretory drugs such as histamine H 2 -receptor antagonists (H 2 -RAs) and proton pump inhibitors (PPIs) are commonly used for the treatment of gastric and duodenal ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs). However, the effects of these drugs on NSAID-induced small intestinal ulcers are not fully understood. The effects of H 2 -RAs and PPIs on NSAID-induced gastrointestinal lesions and small intestinal motility were examined in rats. Male Wistar rats (180 -220 g) were used. Indomethacin (10 mg/kg) was administered orally in fasted or fed rats, and gastrointestinal lesions were examined 24 h after indomethacin administration. Intestinal motility was measured by using a balloon method under urethane anesthesia. Indomethacin produced multiple lesions in the gastric corpus in fasted rats and in the small intestine in fed rats: 1) H 2 -RAs (cimetidine, ranitidine, and famotidine) and PPIs (omeprazole, lansoprazole, and rabeprazole) markedly inhibited the formation of gastric lesions. 2) The drugs, except for lansoprazole, increased intestinal lesions. 3) H 2 -RAs augmented the increase in intestinal motility caused by indomethacin, and the effects of H 2 -RAs on motility and intestinal lesions were markedly inhibited by atropine. 4) Lansoprazole inhibited the formation of intestinal lesions, and the effect was prevented by both pharmacological ablation of capsaicin-sensitive sensory neurons and pretreatment with N-nitro-L-arginine methyl ester, a selective inhibitor of nitric-oxide synthesis. The results suggest that: 1) inhibition of acid secretion by antisecretory drugs may exacerbate NSAID-induced intestinal lesions, 2) H 2 -RAs further aggravate lesions by increasing intestinal motility via the activation of cholinergic pathways, and 3) lansoprazole protects the intestinal mucosa against NSAID-related ulcerative stimuli.

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Section: Discussionmentioning

confidence: 99%

Exacerbation of Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Lesions by Antisecretory Drugs in Rats: The Role of Intestinal Motility

Satoh

Amagase

Takeuchi

2012

J Pharmacol Exp Ther

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“…Because a selective inhibitor for HO-1 or HO-2 is not available at present, it remains undetermined which isozyme is mainly responsible for generation of CO involved in modulating the HCO 3 Ϫ response. Notwithstanding, because HO-1 was up-regulated in the duodenum after mucosal acidification and because other studies reported that several agents exhibited cytoprotection in the gastrointestinal mucosa through the HO-1/CO system (Takagi et al, 2009;Yoda et al, 2010), it is believed that HO-1 may also play a role in the duodenal mucosal protection via the stimulation of HCO 3 Ϫ secretion, in addition to Given the findings of the present study, we concluded that exogenous CO stimulates HCO 3 Ϫ secretion in the duodenum, and this action is mediated by endogenous PGs. Furthermore, the present study suggests that endogenous CO is involved in the mechanism of acid-induced HCO 3 Ϫ secretion and contributes to the maintenance of mucosal integrity in the duodenum.…”

Section: Discussionmentioning

confidence: 99%

Carbon Monoxide Involved in Modulating HCO₃⁻ Secretion in Rat Duodenum

Takasuka

Hayashi²,

Koyama³

et al. 2011

J Pharmacol Exp Ther

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We examined the effect of the tricarbonyl-dichlororuthenium (II) dimer (CORM-2), a carbon monoxide (CO) donor, on duodenal HCO 3 Ϫ secretion in rats and investigated whether endogenous CO produced by heme oxygenase (HO) is involved in the regulation of this secretion. Under urethane anesthesia, a duodenal loop was perfused with saline, and HCO 3 Ϫ secretion was measured at pH 7.0 using a pH stat method. CORM-2, biliverdin, FeCl 2 , or ruthenium (III) chloride hydrate (RuCl 3 ) was applied to the loop for 5 min. The mucosal application of CORM-2 dose-dependently increased HCO 3 Ϫ secretion, whereas neither RuCl 3 , FeCl 2 , nor biliverdin had an effect. The stimulatory effect was significantly attenuated by indomethacin but not N G -nitro-L-arginine methyl ester. The application of CORM-2 increased the mucosal prostaglandin (PG) E 2 content of the duodenum. The acid-induced HCO 3 Ϫ response was markedly inhibited by indomethacin and Sn(IV) protoporphyrin IX dichloride (SnPP; an inhibitor of HO) but not Cu(II) protoporphyrin dichloride, and the inhibitory effect of SnPP was significantly reversed by pretreatment with hemin, a substrate of HO. Perfusion of the duodenal loop with 100 mM HCl for 2 h caused a few hemorrhagic lesions in the mucosa, and this response was significantly worsened by the prior administration of SnPP and indomethacin. The expression of HO-1 but not HO-2 protein was up-regulated in the duodenum after the acid treatment. These results suggest that CO, generated endogenously or exogenously, stimulates HCO 3 Ϫ secretion in the duodenum, and this effect is mediated by endogenous PGs. It is assumed that HO/CO plays a role in maintaining the integrity of the duodenal mucosa.

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“…In addition, lansoprazole has been reported to induce HO-1 [1,66] and thus, HO-1 is thought to be involved in the inhibition of NSAID-associated small bowel injuries. Pretreatment with SnPP, an HO-1 inhibitor, aggravated small bowel injuries induced by indomethacin [67]. On the contrary, pretreatment with both lansoprazole and SnPP clearly aggravated mucosal injuries.…”

Section: Prevention and Treatment Of Small Intestinal Mucosal Injury mentioning

confidence: 94%

Present status and strategy of NSAIDs-induced small bowel injury

et al. 2009

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Non-steroidal anti-inflammatory drugs (NSAIDs) are well known to cause gastroduodenal mucosal lesions as an adverse effect. Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and balloon enteroscopy are available for the detection of small intestinal lesions. Such lesions have been of great concern in clinical settings, and their treatment and prevention must be devised as soon as possible. The prevalence of NSAIDs-induced small intestinal injury is higher than had been expected. Recent studies show that more than 50% of patients taking NSAIDs have some mucosal damage in the small intestine. The gross appearance of NSAIDinduced enteropathy varies, appearing variously as diaphragm-like strictures, ulcers, erosions, and mucosal redness. To investigate NSAID-induced enteropathy, and to rule out other specific enteropathies, other useful methods (in addition to capsule endoscopy and balloon enteroscopy) include such modalities as radiological examination of the small intestine, the permeability test, scintigraphy or the fecal excretion test using 111 Indium-labeled white blood cells, and measurement of the fecal calprotectin concentration. Diaphragm-like strictures and bleeding from mucosal breaks may be treatable with interventional enteroscopy. Misoprostol, metronidazole, and sulfasalazine are frequently used to treat NSAID-induced enteropathy, but have undesirable effects in some cases. In the experimental model, we confirmed that several existing drugs for gastroduodenal ulcers prevented indomethacin-induced small intestinal injury. Such drugs may be useful for preventing the adverse effects of NSAIDs not only in the stomach but also in the small intestine. We hope to examine these drugs in future clinical studies.

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W1238 Proton Pump Inhibitor (PPI) Lansoprazole Prevents Indomethacin-Induced Small Intestinal Ulceration in Rats: Involvement of Heme Oxygenase (HO)-1

Cited by 20 publications

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Exacerbation of Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Lesions by Antisecretory Drugs in Rats: The Role of Intestinal Motility

Exacerbation of Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Lesions by Antisecretory Drugs in Rats: The Role of Intestinal Motility

Carbon Monoxide Involved in Modulating HCO₃⁻ Secretion in Rat Duodenum

Present status and strategy of NSAIDs-induced small bowel injury

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W1238 Proton Pump Inhibitor (PPI) Lansoprazole Prevents Indomethacin-Induced Small Intestinal Ulceration in Rats: Involvement of Heme Oxygenase (HO)-1

Cited by 20 publications

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Exacerbation of Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Lesions by Antisecretory Drugs in Rats: The Role of Intestinal Motility

Exacerbation of Nonsteroidal Anti-Inflammatory Drug-Induced Small Intestinal Lesions by Antisecretory Drugs in Rats: The Role of Intestinal Motility

Carbon Monoxide Involved in Modulating HCO3− Secretion in Rat Duodenum

Present status and strategy of NSAIDs-induced small bowel injury

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Carbon Monoxide Involved in Modulating HCO₃⁻ Secretion in Rat Duodenum