Role of carbonic anhydrase in basal and stimulated bicarbonate secretion by the guinea pig duodenum

Muallem, R; Reimer, R.; Odes, H S; Schwenk, Michael; Beil, W.; Sewing, K.‐Fr.

doi:10.1007/bf02087561

Cited by 16 publications

(15 citation statements)

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“…Early studies applied carbonic anhydrase inhibitors luminally or systemically and found that these maneuvers reduced stimulation of DBS (7,8). The obvious, but as it now turns out incorrect or insufficient, interpretation of these results was that carbonic anhydrase is needed to convert CO 2 , entering the cells from the blood, into HCO 3 Ϫ , destined for secretion, and H ϩ , destined for basolateral export.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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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“…stimulated active bicarbonate transport in the duodenum. The low effective concentration ofTPA , calculated to be lQ-10mol/ml body [9] and PGFi,, [5]. For these agonists, inositol phospholipids, Ca2+ and PKC would have to play a role as mediators [10].…”

Section: Discussionmentioning

confidence: 99%

“…Electrical vagal stimulation [4] and the mcholinoceptor agonists, carbachol [5][6][7] and bethanechol [8], stimulate DBS in laboratory animals and man. Prostaglandin F2a (PGF2a) and dibutyryl 3',5'-cyclic guanosine monophosphatate (dBcGMP) are agonists of this secretion [9]. These data challenge a role for protein kinase C (PKC) and intracellular Ca2+ in DBS, as was described in pancreatic bicar bonate secretion [10].…”

Section: Introductionmentioning

confidence: 98%

Role of Protein Kinase C in Duodenal Mucosal Bicarbonate Secretion in the Guinea Pig

et al. 1996

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Since duodenal bicarbonate secretion (DBS) is increased by m-cholinoceptor agonists, it was postulated that protein kinase C (PKC) has a role in this secretion. This premise was examined in guinea pigs, using 12-O-tetradecanoyl-phorbol 13-acetate (TPA) to stimulate bicarbonate production in the perfused duodenum in vivo, and to activate PKC in isolated duodenal enterocytes. TPA (10^–7 mol·kg^–1) infused intravenously stimulated active DBS from basal values of 3.64 ± 0.66 to 8.73 ± 1.59 µmol·cm^–1 10 min^–1. This effect was completely blocked by verapamil (4 × 10^–7 mol·kg^–1). PKC activity in duodenal enterocytes in the basal state was most abundant in the cytosolic fraction (2,221 ± 444 U/mg protein) and very low in the particulate fraction (227 ± 51 U/mg protein). TPA (10^–7 mol·kg^–1) caused a time-dependent translocation of the cytosolic, lipid-dependent activity of PKC into the particulate fraction. The effect was maximal at 5 min incubation and was reversed by 30 min. In the particulate fraction, this activity was no longer lipid-dependent, but could be stimulated by Ca²⁺ alone. These data support the hypothesis that translocation of PKC may contribute to DBS.

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“…The amiloride-sensitive Na ϩ ͞H ϩ exchanger extrudes protons at both the apical and basolateral membranes. Suppression of CA activity with acetazolamide decreases the basal and stimulated duodenal mucosal HCO 3 Ϫ secretion in humans (12), rabbits (13), and guinea pigs (14). In rats, acetazolamide has been reported to decrease bicarbonate secretion (4), whereas other authors have found no effect (15).…”

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confidence: 99%

Carbonic anhydrase isozyme-II-deficient mice lack the duodenal bicarbonate secretory response to prostaglandin E ₂

Leppilampi

Parkkila²,

Karttunen³

et al. 2005

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

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Duodenal bicarbonate secretion (DBS) is accepted as the primary mucosal defense against acid discharged from the stomach and is impaired in patients with duodenal ulcer disease. The secretory response to luminal acid is the main physiological stimulus for DBS and involves mediation by PGE 2 produced by mucosal cells. The aim of this investigation is to elucidate the role of carbonic anhydrases (CAs) II and IX in PGE 2-mediated bicarbonate secretion in the murine duodenum. CA II-and IX-deficient mice and different combinations of their heterozygous and WT counterparts were studied. A 10-mm segment of the proximal duodenum with intact blood supply was isolated, and DBS was titrated by pH-stat (TitroLine-easy, Schott, Mainz, Germany). Mean arterial blood pressure (MAP) was continuously recorded, and blood acid͞base balance and gastrointestinal morphology were analyzed. The duodenal segment spontaneously secreted HCO 3 ؊ at a steady basal rate of 5.3 ؎ 0.6 mol⅐cm ؊1 ⅐h ؊1 . Perfusing the duodenal lumen for 20 min with 47 M PGE2 caused a significant increase in DBS to 13.0 ؎ 2.9 mol⅐cm ؊1 ⅐h ؊1 , P < 0.0001. The DBS response to PGE2 was completely absent in Car2 ؊/؊ mice, whereas basal DBS was normal. The CA IX-deficient mice with normal Car2 alleles showed a slight increase in DBS. Histological abnormalities were observed in the gastroduodenal epithelium in both CA II-and IX-deficient mice. Our data demonstrate a gastrointestinal phenotypic abnormality associated with CA II deficiency. The results show that the stimulatory effect of the duodenal secretagogue PGE 2 completely depends on CA II. duodenal mucosal protection ͉ gastroduodenal histological abnormalities ͉ gastrointestinal phenotype

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Role of carbonic anhydrase in basal and stimulated bicarbonate secretion by the guinea pig duodenum

Cited by 16 publications

References 16 publications

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

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

Role of Protein Kinase C in Duodenal Mucosal Bicarbonate Secretion in the Guinea Pig

Carbonic anhydrase isozyme-II-deficient mice lack the duodenal bicarbonate secretory response to prostaglandin E ₂

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Role of carbonic anhydrase in basal and stimulated bicarbonate secretion by the guinea pig duodenum

Cited by 16 publications

References 16 publications

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

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

Role of Protein Kinase C in Duodenal Mucosal Bicarbonate Secretion in the Guinea Pig

Carbonic anhydrase isozyme-II-deficient mice lack the duodenal bicarbonate secretory response to prostaglandin E 2

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

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

Carbonic anhydrase isozyme-II-deficient mice lack the duodenal bicarbonate secretory response to prostaglandin E ₂