Cellular bicarbonate protects rat duodenal mucosa from acid-induced injury

Akiba, Yasutada; Furukawa, Osamu; Guth, Paul H.; Engel, Eli; Nastaskin, Igor; Sassani, Pejvak; Dukkipatis, Ramanath; Pushkin, Alexander; Kurtz, Ira; Kaunitz, Jonathan D.

doi:10.1172/jci12218

Cited by 17 publications

(49 citation statements)

References 58 publications

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“…The inhibitory mechanism of DIDS, a relatively nonspecific stilbene anion transport protein inhibitor, on bicarbonate secretion is less agreed on but may reflect inhibition of either the apical membrane anion exchanger, whose identity is at present controversial (15a), and/or the basolateral membrane sodium-bicarbonate cotransporter NBC1 (3,7,11). In vivo, DIDS and NPPB abolish the HCO 3 Ϫ secretory response to luminal acid (2). Similar to our results obtained in vivo, luminally applied DIDS in vitro in rabbit duodenum abolished the HCO 3 Ϫ secretory response to 100 M (38 g/ml) PGE 2 but not to cAMP (22), and basolaterally applied DIDS abolished the secretory response to 10 g/ml PGE 2 in bullfrog duodenum (7).…”

Section: Discussionmentioning

confidence: 99%

“…be examining the role of basolateral membrane transporters, such as the basolateral sodium-bicarbonate cotransporter NBC1, which is not normally directly accessible in vivo (2,11). One of the major drawbacks of the in vitro approach, however, is that the only accepted physiological stimulus for bicarbonate secretion, namely exposure of the luminal surface to 1-6.3 mM HCl, cannot be used due to the high probability of producing mucosal damage (20).…”

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confidence: 99%

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Low-dose PGE₂mimics the duodenal secretory response to luminal acid in mice

Hirokawa¹,

Furukawa²,

Guth³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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Luminal exposure to concentrated acid, the most accepted physiological stimulus for duodenal bicarbonate secretion (DBS), cannot be used with in vitro preparations due to potential tissue damage. We thus examined whether exposure to PGE(2), a well-characterized physiological duodenal secretagogue, could mimic the effects of acid perfusion. DBS was measured in C57/BL mice by pH-stat/back-titration and measurement of total dissolved CO(2) concentration ([CO(2)](t)). Anion transport inhibitor DIDS, anion channel inhibitor 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), carbonic anhydrase inhibitor methazolamide, and nonselective cyclooxygenase inhibitor indomethacin were used to inhibit separate components of HCO(3)(-) secretory pathway. Baseline DBS was not altered by exposure to methazolamide (0.1 mM) but was slightly reduced by DIDS (0.5 mM). DBS and [CO(2)](t) increased after acid and PGE(2) exposure. DIDS (0.5 mM) and NPPB (0.2 mM) abolished acid-induced DBS increase. Methazolamide (0.1 mM) and DIDS inhibited acid-induced [CO(2)](t) increase. DIDS, NPPB, or methazolamide had little effect on DBS in response to high concentration PGE(2) (100 microg/ml). Low concentration PGE(2) (1 microg/ml) increased DBS that was inhibited by DIDS, NPPB, and methazolamide. Pretreatment with indomethacin (5 mg/kg) inhibited DBS induced by acid exposure but not by PGE(2). High-dose PGE(2) substantially increases DBS by a mechanism that appears to be different than secretory response to luminal acid perfusion. Secretory response to low-dose PGE(2), at least in terms of inhibitor profile, closely resembles secretion in response to perfusion of physiological acid concentrations and may be a useful stimulus for in vitro study of DBS in isolated mouse duodenum.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Low-dose PGE₂mimics the duodenal secretory response to luminal acid in mice

Hirokawa¹,

Furukawa²,

Guth³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…DUODENAL EPITHELIAL CELLS are exposed to the following two forms of intense and highly variable acid stress: luminal gastric acid and high partial pressures (Ͼ80 kPa) of CO 2 liberated from the luminal mixture of gastric acid with duodenal and pancreatic secreted HCO 3 Ϫ (16,32). Luminal hydrogen ion lowers intracellular pH (pH i ; see Refs.…”

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confidence: 99%

“…1, 4, and 25), although the ability of H ϩ to traverse the preepithelial mucous gel is controversial (10,44). A less-well-studied but equally probable source of cellular acid stress is the extreme conditions in the duodenal lumen created by the continuous mixing of secreted HCO 3 Ϫ and gastric HCl. Elevated PCO 2 is a cellular acid stress resulting from the highly permeant nature of CO 2 gas, which can diffuse through the plasma membrane into the cytosol, where it is converted into carbonic acid, which then dissociates into H ϩ and HCO 3 Ϫ , facilitated by the presence of carbonic anhydrase (35).…”

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Mechanism of augmented duodenal HCO₃⁻secretion after elevation of luminal CO₂

Furukawa

Hirokawa²,

Zhang³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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The proximal duodenum is exposed to extreme elevations of P(CO(2)) because of the continuous mixture of secreted HCO(3)(-) with gastric acid. These elevations (up to 80 kPa) are likely to place the mucosal cells under severe acid stress. Furthermore, we hypothesized that, unlike most other cells, the principal source of CO(2) for duodenal epithelial cells is from the lumen. We hence examined the effect of elevated luminal P(CO(2)) on duodenal HCO(3)(-) secretion (DBS) in the rat. DBS was measured by the pH-stat method. For CO(2) challenge, the duodenum was superfused with a high Pco(2) solution. Intracellular pH (pH(i)) of duodenal epithelial cells was measured by ratio microfluorometry. CO(2) challenge, but not isohydric solutions, strongly increased DBS to approximately two times basal for up to 1 h. Preperfusion of the membrane-permeant carbonic anhydrase inhibitor methazolamide, or continuous exposure with indomethacin, fully inhibited CO(2)-augmented DBS. Dimethyl amiloride (0.1 mM), an inhibitor of the basolateral sodium-hydrogen exchanger 1, also inhibited CO(2)-augumented DBS, although S-3226, a specific inhibitor of apical sodium-hydrogen exchanger 3, did not. DIDS, an inhibitor of basolateral sodium-HCO(3)(-) cotransporter, also inhibited CO(2)-augemented DBS, as did the anion channel inhibitor 5-nitro-2-(3-phenylpropylamino) benzoic acid. CO(2) decreased epithelial cell pH(i), followed by an overshoot after removal of the CO(2) solution. We conclude that luminal CO(2) diffused in the duodenal epithelial cells and was converted to H(+) and HCO(3)(-) by carbonic anhydrase. H(+) initially exited the cell, followed by secretion of HCO(3)(-). Secretion was dependent on a functioning basolateral sodium/proton exchanger, a functioning basolateral HCO(3)(-) uptake mechanism, and submucosal prostaglandin generation and facilitated hydration of CO(2) into HCO(3)(-) and H(+).

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“…DIDS, which is an inorganic anion exchanger blocker including Cl-bicarbonate exchanger, has been used to inhibit NBC activity in in vitro and in vivo experiments [53][54][55]. It was reported that DIDS protected cortical neurons against N-methyl-D-aspartate (NMDA) toxicity and decreased NMDA receptor-mediated increases in intracellular Ca (2?…”

Section: Discussionmentioning

confidence: 99%

Na+/HCO3 − Cotransporter Immunoreactivity Changes in Neurons and Expresses in Astrocytes in the Gerbil Hippocampal CA1 Region After Ischemia/Reperfusion

et al. 2011

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The maintenance of intracellular pH is important in neuronal function. Na(+)/HCO(3)(-) cotransporter (NBC), a bicarbonate-dependent acid-base transport protein, may contribute to cellular acid-base homeostasis in pathophysiological processes. We examined the alterations of NBC immunoreactivity and its protein levels in the hippocampal CA1 region after transient cerebral ischemia in gerbils. In the sham-operated group, moderate NBC immunoreactivity was detected in CA1 pyramidal neurons, and, 12 h after I/R, the immunoreactivity in the pyramidal neurons was markedly increased over controls. Three days after I/R, NBC immunoreactivity nearly disappeared in the CA1 pyramidal neurons. However, NBC immunoreactivity was detected in the non-pyramidal neurons of the ischemic CA1 region at 3 days after I/R. From double immunofluorescence study with glial markers, NBC immunoreactivity was detected in astrocytes, not in microglia, at 4 days after I/R. NBC protein level in the CA1 region was significantly increased at 12 h post-ischemia and significantly decreased at 2 days post-ischemia. Thereafter, NBC protein level was again increased and returned to the level of the sham-operated group at 4 days post-ischemia. On the other hand, treatment with 4,4'-diisothiocyanatostilbene-2,2'-disulfonate (DIDS), an inorganic anion exchanger blocker including Cl-bicarbonate exchanger, protected CA1 pyramidal neurons from I/R injury at 4 days post-ischemia. These results indicate that changes in NBC expressions may play an important role in neuronal damage and astrocytosis induced by transient cerebral ischemia.

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Cellular bicarbonate protects rat duodenal mucosa from acid-induced injury

Cited by 17 publications

References 58 publications

Low-dose PGE₂mimics the duodenal secretory response to luminal acid in mice

Low-dose PGE₂mimics the duodenal secretory response to luminal acid in mice

Mechanism of augmented duodenal HCO₃⁻secretion after elevation of luminal CO₂

Na+/HCO3 − Cotransporter Immunoreactivity Changes in Neurons and Expresses in Astrocytes in the Gerbil Hippocampal CA1 Region After Ischemia/Reperfusion

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Cellular bicarbonate protects rat duodenal mucosa from acid-induced injury

Cited by 17 publications

References 58 publications

Low-dose PGE2mimics the duodenal secretory response to luminal acid in mice

Low-dose PGE2mimics the duodenal secretory response to luminal acid in mice

Mechanism of augmented duodenal HCO3−secretion after elevation of luminal CO2

Na+/HCO3 − Cotransporter Immunoreactivity Changes in Neurons and Expresses in Astrocytes in the Gerbil Hippocampal CA1 Region After Ischemia/Reperfusion

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Low-dose PGE₂mimics the duodenal secretory response to luminal acid in mice

Low-dose PGE₂mimics the duodenal secretory response to luminal acid in mice

Mechanism of augmented duodenal HCO₃⁻secretion after elevation of luminal CO₂