Proximal duodenal prostaglandin E2 release and mucosal bicarbonate secretion are altered in patients with duodenal ulcer

Bukhave, Klaus; Rask-Madsen, J; Hogan, Daniel L.; Koss, Michael A.; Isenberg, Jon I.

doi:10.1016/0016-5085(90)90612-5

Cited by 55 publications

(49 citation statements)

References 18 publications

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“…In addition, during HCO 3 Ϫ substitution experiments, the mucosal and serosal surfaces of all tissues were treated with the carbonic anhydrase inhibitor acetazolamide (100 M) and the HCO 3 Ϫ -free solution gassed with 100% O2. Indomethacin (1 M) was added to both the mucosal and serosal baths to prevent endogenous generation of prostanoids and the serosal surface was exposed to tetrodotoxin (0.1 M) to minimize variations in the intrinsic neural tone (7,10,44). All tissues were pretreated with 50 M amiloride (mucosal) to inhibit epithelial Na ϩ channel activity (45).…”

Section: Methodsmentioning

confidence: 99%

AE2 Cl⁻/HCO₃⁻exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon

Gawenis

Bradford

Alper

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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Gawenis LR, Bradford EM, Alper SL, Prasad V, Shull GE. AE2 Cl Ϫ /HCO 3 Ϫ exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon. Am J Physiol Gastrointest Liver Physiol 298: G493-G503, 2010. First published January 28, 2010 doi:10.1152/ajpgi.00178.2009.-Anion secretion by colonic epithelium is dependent on apical CFTR-mediated anion conductance and basolateral ion transport. In many tissues, the NKCC1 NaϪ cotransporter mediates basolateral Cl Ϫ uptake. However, additional evidence suggests that the AE2 Cl Ϫ /HCO 3 Ϫ exchanger, when coupled with the NHE1 Na ϩ /H ϩ exchanger or a Na ϩ -HCO 3 Ϫ cotransporter (NBC), contributes to HCO 3 Ϫ and/or Cl Ϫ uptake. To analyze the secretory functions of AE2 in proximal colon, short-circuit current (Isc) responses to cAMP and inhibitors of basolateral anion transporters were measured in muscle-stripped wild-type (WT) and AE2-null (AE2 Ϫ/Ϫ ) proximal colon. In physiological Ringer, the magnitude of cAMP-stimulated Isc was the same in WT and AE2 Ϫ/Ϫ colon. However, the Isc response in AE2 Ϫ/Ϫ colon exhibited increased sensitivity to the NKCC1 inhibitor bumetanide and decreased sensitivity to the distilbene derivative SITS (which inhibits AE2 and some NBCs), indicating that loss of AE2 results in a switch to increased NKCC1-supported anion secretion. Removal of HCO 3 Ϫ resulted in robust cAMP-stimulated Isc in both AE2Ϫ/Ϫ and WT colon that was largely mediated by NKCC1, whereas removal of Cl Ϫ resulted in sharply decreased cAMP-stimulated Isc in AE2 Ϫ/Ϫ colon relative to WT controls. Inhibition of NHE1 had no effect on cAMP-stimulated Isc in AE2 Ϫ/Ϫ colon but caused a switch to NKCC1-supported secretion in WT colon. Thus, in AE2 Ϫ/Ϫ colon, Cl Ϫ secretion supported by basolateral NKCC1 is enhanced, whereas HCO 3 Ϫ secretion is diminished. These results show that AE2 is a component of the basolateral ion transport mechanisms that support anion secretion in the proximal colon.

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Section: Methodsmentioning

confidence: 99%

AE2 Cl⁻/HCO₃⁻exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon

Gawenis

Bradford

Alper

et al. 2010

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The peptide hormones, VIP, glucagon and GIP, are important mediators of DBS and in this way may contribute to the protection of the duodenal epithelium against acid-induced injury [1,2]. Stimulation of bicarbonate secre tion was shown to result from an elevation of intracellular cAMP levels [4] and can also be elicited by receptor-independent AC activa tors like forskolin [5], as well as by cAMP ana logues [6], There is controversy regarding the amount of bicarbonate secreted actively ver sus the quantity that diffuses passively from blood to lumen [12,13].…”

Section: Discussionmentioning

confidence: 99%

“…Bicarbonate secretion by the proximal du odenal mucosa is an important factor protect ing this organ from the potentially ulcerogenic effects of hydrochloric acid and pepsin [1], Duodenal bicarbonate secretion (DBS) is stimulated by intraluminal acid, prostaglan dins, opioids, the vagus and peptide hor mones that include vasoactive intestinal poly peptide (VIP), gastric inhibitory polypeptide (GIP) and glucagon [2], Bicarbonate secretion stimulated by m-cholinoceptor activators is mediated, at least in part, via release of VIP, since a specific VIP antagonist significantly inhibited carbachol-stimulated DBS [3]. Se cretin does not affect DBS [2],…”

Section: Introductionmentioning

confidence: 99%

Bicarbonate Secretion in the Guinea Pig Duodenum: Functional Characterization of Peptide Hormone Receptors in Duodenal Enterocytes

et al. 1996

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To get information about the peptide hormone receptors involved in duodenal bicarbonate secretion (DBS) and their cellular location, we determined DBS and adenylate cyclase (AC) activity in response to hormones of the vasoactive intestinal polypeptide (VΙP)/secretin family of peptides. DBS was determined in an isolated, perfused (24 mmol/l NaHCO₃) loop of the proximal duodenum in urethane- and indometacin-treated guinea pigs. AC stimulation was measured in isolated, homogenized duodenal enterocytes, the histological evaluation of which revealed their villous origin. VIP (10^–9 to 10^–7 mol × kg^–1) dose-dependently increased DBS 3.5-fold (p < 0.01); this effect was completely inhibited by the VIP antagonist [D-p-Cl-Phe6, Leul 7]VIP (10^–6 mol × kg^–1). Glucagon (10^–8 to 10^–6 mol × kg^–1) increased DBS 2.1-fold, while secretin (10^–9 to 10^–6 mol × kg^–1) had no effect on DBS, but stimulated pancreatic bicarbonate secretion. VIP concentra-tion-dependently increased AC activity 5.6-fold with an EC₅₀ of 1.3 × 10^–9 mol/l. [ D-p-Cl-Phe6, Leul 7] VIP caused a right-ward shift of the VIP concentration-response curve. A Schild plot analysis yielded a slope of 0.85 ± 0.11, indicating competitive inhibition. While secretin also stimulated AC activity, although 1,000-fold less potent than VIP, glucagon was ineffective. These data indicate that specific VIP receptors, which mediate VIP-stimulated bicarbonate secretion, are present on villous enterocytes. Stimulation of AC by secretin seems to be of pharmacological relevance only and is consistent with the lack of effect of this hormone on DBS. Glucagon likely activates a second transmitter of bicarbonate secretion, or works independently of AC.

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“…Until now there has been no study investigating the specific enzyme(s) involved in acid-stimulated DBS. The reason for the missing information is mainly due to the lack of isoform-specific enzyme inhibitors (15).The acid-induced duodenal bicarbonate secretory response involves multiple pathways, including neural circuits (1,3,16,17), and can therefore only be tested in vivo. The purpose of present study was to elucidate role of CAII in the regulation of acid-induced DBS.…”

mentioning

confidence: 99%

“…The acid-induced duodenal bicarbonate secretory response involves multiple pathways, including neural circuits (1,3,16,17), and can therefore only be tested in vivo. The purpose of present study was to elucidate role of CAII in the regulation of acid-induced DBS.…”

mentioning

confidence: 99%

Duodenal acidity “sensing” but not epithelial HCO ₃ ⁻ supply is critically dependent on carbonic anhydrase II expression

Sjöblom

Singh

Zheng

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Carbonic anhydrase (CA) is strongly expressed in the duodenum and has been implicated in a variety of physiological functions including enterocyte HCO 3 ؊ supply for secretion and the ''sensing'' of luminal acid and CO 2. Here, we report the physiological role of the intracellular CAII isoform involvement in acid-, PGE 2, and forskolin-induced murine duodenal bicarbonate secretion (DBS) in vivo. CAII-deficient and WT littermates were studied in vivo during isoflurane anesthesia. An approximate 10-mm segment of the proximal duodenum with intact blood supply was perfused under different experimental conditions and DBS was titrated by pH immediately. Two-photon confocal microscopy using the pH-sensitive dye SNARF-1F was used to assess duodenocyte pH i in vivo. After correction of systemic acidosis by infusion of isotonic Na 2CO3, basal DBS was not significantly different in CAII-deficient mice and WT littermates. The duodenal bicarbonate secretory response to acid was almost abolished in CAII-deficient mice, but normal to forskolin-or 16,16-dimethyl PGE 2 stimulation. The complete inhibition of tissue CAs by luminal methazolamide and i.v. acetazolamide completely blocked the response to acid, but did not significantly alter the response to forskolin. While duodenocytes acidified upon luminal perfusion with acid, no significant pH i change occurred in CAII-deficient duodenum in vivo. The results suggest that CA II is important for duodenocyte acidification by low luminal pH and for eliciting the acid-mediated HCO 3 ؊ secretory response, but is not important in the generation of the secreted HCO 3 ؊ ions.bicarbonate secretion ͉ duodenal mucosal protection ͉ duodenal ulcers ͉ gastrointestinal phenotype ͉ gastric acid T he proximal duodenum serves as a key segment in neutralizing the high amounts of hydrochloric acid expelled from the stomach (1). As a physiological defense to these acidic challenges, the proximal duodenum secretes HCO 3 Ϫ in higher rates than more distal parts of the small intestine in all species tested, including humans, and even a short contact with luminal acid causes a long lasting increase in duodenal bicarbonate secretion (DBS) (1). A deficiency in basal as well as acid-stimulated DBS is observed in patients with duodenal ulcer disease (2). Thus, DBS is accepted as an important duodenal mucosal defense mechanism (1, 3).CO 2 has been suggested to be a key transmitting factor in sensing the acidic luminal content (4-6), diffusing through the continuous layer of viscoelastic mucus gel on top of the epithelial surface and further through the apical cell-membrane. The generation of CO 2 from luminal acid has been suggested to depend on the action of extracellular carbonic anhydrases (5, 6). Because CA inhibitors suppressed duodenal HCO 3 Ϫ secretion, CO 2 entry and hydration in the enterocyte was thought to be a major supply pathway for basal and stimulated duodenal HCO 3 Ϫ secretion (7, 8), although this issue has remained controversial (9, 10).CAs are heavily expressed in duodenal epithelial cells...

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Proximal duodenal prostaglandin E2 release and mucosal bicarbonate secretion are altered in patients with duodenal ulcer

Cited by 55 publications

References 18 publications

AE2 Cl⁻/HCO₃⁻exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon

AE2 Cl⁻/HCO₃⁻exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon

Bicarbonate Secretion in the Guinea Pig Duodenum: Functional Characterization of Peptide Hormone Receptors in Duodenal Enterocytes

Duodenal acidity “sensing” but not epithelial HCO ₃ ⁻ supply is critically dependent on carbonic anhydrase II expression

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Proximal duodenal prostaglandin E2 release and mucosal bicarbonate secretion are altered in patients with duodenal ulcer

Cited by 55 publications

References 18 publications

AE2 Cl−/HCO3−exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon

AE2 Cl−/HCO3−exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon

Bicarbonate Secretion in the Guinea Pig Duodenum: Functional Characterization of Peptide Hormone Receptors in Duodenal Enterocytes

Duodenal acidity “sensing” but not epithelial HCO 3 − supply is critically dependent on carbonic anhydrase II expression

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AE2 Cl⁻/HCO₃⁻exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon

AE2 Cl⁻/HCO₃⁻exchanger is required for normal cAMP-stimulated anion secretion in murine proximal colon

Duodenal acidity “sensing” but not epithelial HCO ₃ ⁻ supply is critically dependent on carbonic anhydrase II expression