Substance P inhibits bicarbonate secretion from guinea pig pancreatic  ducts by modulating an anion exchanger

Hegyi, Péter; Gray, Michael A.; Argent, Barry E.

doi:10.1152/ajpcell.00574.2002

Cited by 49 publications

(73 citation statements)

References 33 publications

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“…where ␤ tot is the total buffering capacity [ϭ intrinsic buffering capacity of the guinea pig pancreatic duct cell (␤int) (11,38) ϩ buffering capacity of the CO 2/HCO3 Ϫ system (␤ CO 2 )] and is a function of pHi. In Fig.…”

Section: Methodsmentioning

confidence: 99%

Functional coupling of apical Cl⁻/HCO₃⁻ exchange with CFTR in stimulated HCO₃⁻ secretion by guinea pig interlobular pancreatic duct

Stewart

Yamamoto²,

Nakakuki³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ϫ -rich fluid in response to stimulation by the adenylyl cyclase-coupled hormone secretin. The Cl Ϫ -rich secretion of pancreatic acinar cells is modified as it flows along the pancreatic ductal system, ultimately producing pancreatic juice with final concentrations of ϳ140 mM HCO 3 Ϫ and ϳ20 mM Cl Ϫ (31). In the guinea pig pancreatic duct, the uptake of bicarbonate across the basolateral membrane is mediated by Na ϩ -HCO 3 Ϫ cotransport (NBC1) and by Na ϩ /H ϩ exchange (19). HCO 3 Ϫ efflux across the apical membrane has been proposed to be mediated by CFTR, in concert with apical Cl Ϫ /HCO 3 Ϫ exchanger activity (9). Proximal pancreatic duct HCO 3 Ϫ secretion by apical Cl Ϫ / HCO 3 Ϫ exchange is favored by the high luminal Cl Ϫ concentrations resulting from pancreatic acinar Cl Ϫ secretion. However, since this proximal fluid flows distally toward the ampullary terminus of the duct, its Cl Ϫ concentration progressively decreases in parallel with a gradual increase in its HCO 3 Ϫ concentration. These inverse changes in Cl Ϫ and HCO 3 Ϫ concentrations are predicted to alter relative contributions of apical membrane Cl Ϫ /HCO 3 Ϫ exchange and CFTR-mediated HCO 3 Ϫ conductance and have been suggested to reflect axial variation in expression and regulation of these transport activities (18). The Cl Ϫ /HCO 3 Ϫ exchangers Slc26a3 and Slc26a6 have been detected in mouse pancreatic duct and in the human pancreatic cell line CFPAC-1 (10, 22), leading to the proposal that Cl Ϫ -dependent HCO 3 Ϫ secretion by pancreatic proximal ducts represents combined activities of Slc26a6 and Slc26a3 anion exchangers, positively regulated by activated CFTR, with reciprocal positive regulation of CFTR by the anion exchangers (4, 5, 22, 23). However, a study in native mouse pancreatic duct suggests negative regulation of CFTR by Slc26a6 (43).Secretin-stimulated HCO 3 Ϫ secretion in guinea pig pancreatic duct is not dependent on elevated luminal [Cl Ϫ ] (21) (brackets denote concentration) and occurs even in the presence of luminal fluid containing 125 mM HCO 3 Ϫ and 23 mM Cl Ϫ (17). As luminal [Cl Ϫ ] falls to or below this level (with corresponding elevation of [HCO 3 Ϫ ]), CFTR Cl Ϫ permeability may fall while that for HCO 3 Ϫ may rise (34). Measurements of membrane potential (V m ) and intracellular pH (pH i ) in luminally perfused interlobular ducts from guinea pig pancreas suggest that CFTR HCO 3 Ϫ conductance can account for observed levels of stimulated bicarbonate secretion (15,18,20). A computational model of pancreatic duct HCO 3 Ϫ secretion predicted for similar conditions that ϳ94% of HCO 3 Ϫ efflux across the apical membrane was mediated by HCO 3 Ϫ conductance (36), although the model did not consider contributions from electrogenic Cl Ϫ /HCO 3 Ϫ exchange. Thus the HCO 3 Ϫ conductance of CFTR could provide the main route for apical HCO 3 Ϫ secretion in distal pancreatic ducts from species in which, like human and guinea pig, pancreatic juice contains high concentrations of HCO 3 Ϫ (ϳ140 mM). Studies of the role of SLC26-media...

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Section: Methodsmentioning

confidence: 99%

Functional coupling of apical Cl⁻/HCO₃⁻ exchange with CFTR in stimulated HCO₃⁻ secretion by guinea pig interlobular pancreatic duct

Stewart

Yamamoto²,

Nakakuki³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The total buffering capacity (β total ) of colonic epithelial cells was estimated according to the NH 4 + prepulse technique [16,47]. Colonic epithelial cells were exposed to various concentrations of NH 4 Cl in a Na + -and …”

Section: Determination Of Buffering Capacity and Base Effluxmentioning

confidence: 99%

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

Pallagi-Kunstár

Farkas

Maléth

et al. 2014

Pflugers Arch - Eur J Physiol

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Abstract:Bile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhea. In this study our aim was to characterise the cellular pathomechanism of bile-induced diarrhea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileumresected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na+/H+ exchanger (NHE) and Cl-/HCO3-exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhea, compared to control patients. Acute treatment of colonic crypts with 0.3mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 AbstractBile acids play important physiological role in the solubilisation and absorption of dietary lipids. However, under pathophysiological conditions, such as short bowel syndrome, they can reach the colon in high concentrations inducing diarrhea. In this study our aim was to characterise the cellular pathomechanism of bile-induced diarrhea using human samples. Colonic crypts were isolated from biopsies of patients (controls with negative colonoscopic findings) and of cholecystectomised/ileum-resected patients with or without diarrhoea. In vitro measurement of the transporter activities revealed impaired Na + /H + exchanger (NHE) and Cl -/HCO 3 -exchanger (CBE) activities in cholecystectomised/ileum-resected patients suffering from diarrhea, compared to control patients. Acute treatment of colonic crypts with 0.3mM chenodeoxycholate caused dose-dependent intracellular acidosis; moreover, the activities of acid/base transporters (NHE and CBE) were strongly impaired. This concentration of chenodeoxycholate did not cause morphological changes in colonic epithelial cells, although significantly reduced the intracellular ATP level, decreased mitochondrial transmembrane potential and caused sustained intracellular Ca 2+ elevation. We also showed that chenodeoxycholate induced Ca 2+ release from the endoplasmic reticulum and extracellular Ca 2+ influx contributing to the Ca 2+ elevation. Importantly, our results suggest that the chenodeoxycholate induced inhibition of NHE activities was ATP-dependent, whereas the inhibition of CBE activity was mediated by the sustained Ca 2+ elevation.We suggest that bile acids inhibit the function of ion transporters via cellular energy breakdown and Ca 2+ overload in human colonic epithelial cells, which can reduce fluid and electrolyte absorption in the colon and promote ...

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“…Both somatostatin (20,32) and peptide YY (1,34) have been shown to inhibit secretion from the intact pancreas and probably work by interfering with the neural and/or hormonal mechanisms that control the gland. In contrast, substance P (SP) (6,18), 5-hydroxytryptamine (45), arginine vasopressin (29), and basolateral ATP (22) all have been shown to inhibit fluid and/or HCO 3 Ϫ secretion from isolated pancreatic ducts. Therefore, these agents must exert their effects directly on the ductal epithelium.…”

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confidence: 99%

Protein kinase C mediates the inhibitory effect of substance P on HCO₃⁻ secretion from guinea pig pancreatic ducts

Hegyi¹,

Rakonczay²,

Tiszlavicz³

et al. 2005

American Journal of Physiology-Cell Physiology

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Ϫ secretion may be physiologically important in terms of limiting the hydrostatic pressure developed within the ducts and in terms of switching off pancreatic secretion after a meal. Substance P (SP) inhibits secretin-stimulated HCO 3Ϫ secretion by modulating a Cl Ϫ -dependent HCO 3 Ϫ efflux step at the apical membrane of the duct cell (Hegyi P, Gray MA, and Argent BE. Am J Physiol Cell Physiol 285: C268 -C276, 2003). In the present study, we have shown that SP is present in periductal nerves within the guinea pig pancreas, that PKC mediates the effect of SP, and that SP inhibits an anion exchanger on the luminal membrane of the duct cell. Secretin (10 nM) stimulated HCO 3 Ϫ secretion by sealed, nonperfused, ducts about threefold, and this effect was totally inhibited by SP (20 nM). Phorbol 12,13-dibutyrate (PDBu; 100 nM), an activator of PKC, reduced basal HCO 3 Ϫ secretion by ϳ40% and totally blocked secretin-stimulated secretion. In addition, bisindolylmaleimide I (1 nM to 1 M), an inhibitor of PKC, relieved the inhibitory effect of SP on secretin-stimulated HCO 3 Ϫ secretion and also reversed the inhibitory effect of PDBu. Western blot analysis revealed that guinea pig pancreatic ducts express the ␣-, ␤ I-, ␦-, ⑀-, -, -, -, and -isoforms of PKC. In microperfused ducts, luminal H 2DIDS (0.5 mM) caused intracellular pH to alkalinize and, like SP, inhibited basal and secretinstimulated HCO 3 Ϫ secretion. SP did not inhibit secretion further when H 2DIDS was present in the lumen, suggesting that SP and H2DIDS both inhibit the activity of an anion exchanger on the luminal membrane of the duct cell.pancreas; Cl Ϫ /HCO 3 Ϫ exchanger; inhibition; epithelium THE PANCREATIC DUCTAL EPITHELIUM secretes an alkaline fluid that may contain up to 140 mM NaHCO 3 (4, 5). While the regulatory pathways that stimulate pancreatic ductal HCO 3 Ϫ secretion have been described well in the literature (4, 5), much less is known about inhibitory pathways. Such inhibitory pathways may be physiologically important in terms of limiting the hydrostatic pressure within the lumen of the duct (thus preventing leakage of enzymes into the parenchyma of the gland) and in terms of switching off pancreatic secretion after a meal (1). Both somatostatin (20, 32) and peptide YY (1, 34) have been shown to inhibit secretion from the intact pancreas and probably work by interfering with the neural and/or hormonal mechanisms that control the gland. In contrast, substance P (SP) (6, 18), 5-hydroxytryptamine (45), arginine vasopressin (29), and basolateral ATP (22) all have been shown to inhibit fluid and/or HCO 3 Ϫ secretion from isolated pancreatic ducts. Therefore, these agents must exert their effects directly on the ductal epithelium.SP has been identified in the pancreas of the dog, rat, and mouse (36), and the peptide has been shown to inhibit secretion from the intact gland of the dog (26, 31) and rat (27). Moreover, SP is a potent inhibitor of basal fluid secretion from isolated rat pancreatic ducts as well as of fluid secretion stimulated by secr...

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Substance P inhibits bicarbonate secretion from guinea pig pancreatic ducts by modulating an anion exchanger

Cited by 49 publications

References 33 publications

Functional coupling of apical Cl⁻/HCO₃⁻ exchange with CFTR in stimulated HCO₃⁻ secretion by guinea pig interlobular pancreatic duct

Functional coupling of apical Cl⁻/HCO₃⁻ exchange with CFTR in stimulated HCO₃⁻ secretion by guinea pig interlobular pancreatic duct

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

Protein kinase C mediates the inhibitory effect of substance P on HCO₃⁻ secretion from guinea pig pancreatic ducts

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Substance P inhibits bicarbonate secretion from guinea pig pancreatic ducts by modulating an anion exchanger

Cited by 49 publications

References 33 publications

Functional coupling of apical Cl−/HCO3− exchange with CFTR in stimulated HCO3− secretion by guinea pig interlobular pancreatic duct

Functional coupling of apical Cl−/HCO3− exchange with CFTR in stimulated HCO3− secretion by guinea pig interlobular pancreatic duct

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

Protein kinase C mediates the inhibitory effect of substance P on HCO3− secretion from guinea pig pancreatic ducts

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Functional coupling of apical Cl⁻/HCO₃⁻ exchange with CFTR in stimulated HCO₃⁻ secretion by guinea pig interlobular pancreatic duct

Functional coupling of apical Cl⁻/HCO₃⁻ exchange with CFTR in stimulated HCO₃⁻ secretion by guinea pig interlobular pancreatic duct

Protein kinase C mediates the inhibitory effect of substance P on HCO₃⁻ secretion from guinea pig pancreatic ducts