Regulatory mechanism of duodenal bicarbonate secretion

Takeuchi, Koji; Kita, Kazutomo; Hayashi, Satoru; Aihara, Eitaro

doi:10.1016/j.pharmthera.2010.12.006

Cited by 36 publications

(30 citation statements)

References 54 publications

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“…GLP-2-induced mesenteric hyperemia is mediated by VIP and NO (Guan et al, 2006), suggesting that released GLP-2 activates GLP-2R expressed on myenteric neurons, releasing VIP or NO, which increases HCO 3 Ϫ secretion via the cellular cAMP or cGMP pathways, respectively, as reported previously (Yao et al, 1993;Takeuchi et al, 2011). These pathways are consistent with our results that L-Glu/IMP-induced HCO 3 Ϫ secretion was inhibited by a GLP-2R antagonist, a VIP-R antagonist, and an NO synthase inhibitor.…”

Section: Discussionsupporting

confidence: 60%

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Umami Receptor Activation Increases Duodenal Bicarbonate Secretion via Glucagon-Like Peptide-2 Release in Rats

Wang¹,

Inoue²,

Higashiyama³

et al. 2011

J Pharmacol Exp Ther

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Luminal nutrient chemosensing during meal ingestion is mediated by intestinal endocrine cells, which regulate secretion and motility via the release of gut hormones. We have reported that luminal coperfusion of L-Glu and IMP, common condiments providing the umami or proteinaceous taste, synergistically increases duodenal bicarbonate secretion (DBS) possibly via taste receptor heterodimers, taste receptor type 1, member 1 (T1R1)/R3. We hypothesized that glucose-dependent insulinotropic peptide (GIP) or glucagon-like peptide (GLP) is released by duodenal perfusion with L-Glu/IMP. We measured DBS with pH and CO 2 electrodes through a perfused rat duodenal loop in vivo. GIP, exendin (Ex)-4 (GLP-1 receptor agonist), or GLP-2 was intravenously infused (0.01-1 nmol/kg/h). L-Glu (10 mM) and IMP (0.1 mM) were luminally perfused with or without bolus intravenous injection (3 or 30 nmol/kg) of the receptor antagonists Pro 3 GIP, Ex-3(9-39), or GLP-2(3-33). GIP or GLP-2 infusion dose-dependently increased DBS, whereas Ex-4 infusion gradually decreased DBS. Luminal perfusion of L-Glu/IMP increased DBS, with no effect of Pro 3 GIP or Ex-3(9-39), whereas GLP-2(3-33) inhibited L-Glu/IMP-induced DBS. Vasoactive intestinal peptide (VIP)(6 -28) intravenously or N G -nitro-L-arginine methyl ester coperfusion inhibited the effect of L-Glu/IMP. Perfusion of L-Glu/IMP increased portal venous concentrations of GLP-2, followed by a delayed increase of GLP-1, with no effect on GIP release. GLP-1/2 and T1R1/R3 were expressed in duodenal endocrine-like cells. These results suggest that luminal L-Glu/IMPinduced DBS is mediated via GLP-2 release and receptor activation followed by VIP and nitric oxide release. Because GLP-1 is insulinotropic and GLP-2 is intestinotrophic, umami receptor activation may have additional benefits in glucose metabolism and duodenal mucosal protection and regeneration.

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Section: Discussionsupporting

confidence: 60%

“…COX inhibition inhibited L-Glu/IMP effects only during the late period. Because NO increases PGs release (Takeuchi et al, 2011), release of PGs in response to NO release may affect the sustained increase of HCO 3 Ϫ secretion during L-Glu/IMP perfusion.…”

Section: Discussionmentioning

confidence: 99%

Umami Receptor Activation Increases Duodenal Bicarbonate Secretion via Glucagon-Like Peptide-2 Release in Rats

Wang¹,

Inoue²,

Higashiyama³

et al. 2011

J Pharmacol Exp Ther

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“…The doses of these EP and CFTR antagonists were chosen to induce the respective pharmacologic action, according to the findings of previous studies (Takeuchi et al, , 2011Kunikata et al, 2002a;Hatazawa et al, 2006;Aihara et al, 2007;Norimatsu et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

Lubiprostone Prevents Nonsteroidal Anti-Inflammatory Drug–Induced Small Intestinal Damage by Suppressing the Expression of Inflammatory Mediators via EP4 Receptors

Hayashi

Kurata²,

Yamaguchi

et al. 2014

J Pharmacol Exp Ther

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Lubiprostone, a bicyclic fatty acid derived from prostaglandin E 1 , has been used to treat chronic constipation and irritable bowel syndrome, and its mechanism of action has been attributed to the stimulation of intestinal fluid secretion via the activation of the chloride channel protein 2/cystic fibrosis transmembrane regulator (ClC-2/CFTR) chloride channels. We examined the effects of lubiprostone on indomethacin-induced enteropathy and investigated the functional mechanisms involved, including its relationship with the EP4 receptor subtype. Male Sprague-Dawley rats were administered indomethacin (10 mg/kg p.o.) and killed 24 hours later to examine the hemorrhagic lesions that developed in the small intestine. Lubiprostone (0.01-1 mg/kg) was administered orally twice 30 minutes before and 9 h after the indomethacin treatment. Indomethacin markedly damaged the small intestine, accompanied by intestinal hypermotility, a decrease in mucus and fluid secretion, and an increase in enterobacterial invasion as well as the up-regulation of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor a (TNFa) mRNAs. Lubiprostone significantly reduced the severity of these lesions, with the concomitant suppression of the functional changes. The effects of lubiprostone on the intestinal lesions and functional alterations were significantly abrogated by the coadministration of AE3-208 [4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid], a selective EP4 antagonist, but not by CFTR(inh)-172, a CFTR inhibitor. These results suggest that lubiprostone may prevent indomethacin-induced enteropathy via an EP4 receptor-dependent mechanism. This effect may be functionally associated with the inhibition of intestinal hypermotility and increase in mucus/fluid secretion, resulting in the suppression of bacterial invasion and iNOS/ TNFa expression, which are major pathogenic events in enteropathy. The direct activation of CFTR/ClC-2 chloride channels is not likely to have contributed to the protective effects of lubiprostone.

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“…The stimulatory effect of PGE 2 on duodenal HCO 3 2 is mediated intracellularly by cAMP, PI3K, and Ca 2+ (Tuo et al, 2007;Takeuchi et al, 2011). Although there is no direct evidence that a downstream signaling mechanism of EP4 is involved in duodenal HCO 3 2 response, several studies have suggested that EP4 receptor signaling and EP3 receptor signaling could act in coordination to maintain duodenal mucosal integrity against acid through intracellular cAMP and PI3K and Ca 2+ elevation.…”

Section: Other Immune Cellsmentioning

confidence: 99%