1. Pancreatic HCOצ and fluid secretion were studied by monitoring luminal pH (pHL) and luminal volume simultaneously in interlobular duct segments isolated from guinea-pig pancreas. The secretory rate and HCOצ flux were estimated from fluorescence images obtained following microinjection of BCECF-dextran (70 kDa, 20 ìÒ) into the duct lumen. 2. Ducts filled initially with a Cl¦-rich solution swelled steadily (2·0 nl min¢ mm¦Â) when HCOצÏCOµ was introduced, and the luminal pH increased to 8·08. When Cl¦ was replaced by glucuronate, spontaneous fluid secretion was reduced by 75%, and pHL did not rise above 7·3. 3. Cl¦-dependent spontaneous secretion was largely blocked by luminal HµDIDS (500 ìÒ). We conclude that, in unstimulated ducts, HCOצ transport across the luminal membrane is probably mediated by Cl¦-HCOצ exchange. 4. Secretin (10 nÒ) and forskolin (1 ìÒ) both stimulated HCOצ and fluid secretion. The final value of pHL (8·4) and the increase in secretory rate (1·5 nl min¢ mm¦Â) after secretin stimulation were unaffected by substitution of Cl¦. 5. The Cl¦-independent component of secretin-evoked secretion was not affected by luminalHµDIDS. This suggests that a Cl¦-independent mechanism provides the main pathway for luminal HCOצ transport in secretin-stimulated ducts. 6. Ducts filled initially with a HCOצ-rich fluid (125 mÒ HCOצ, 23 mÒ Cl¦) secreted a Cl¦-rich fluid while unstimulated. This became HCOצ-rich when secretin was applied. 7. Addition of HµDIDS and MIA (10 ìÒ) to the bath reduced the secretory rate by 56 and 18%, respectively. Applied together they completely blocked fluid secretion. We conclude that basolateral HCOצ transport is mediated mainly by Na¤-HCOצ cotransport rather than by Na¤-H¤ exchange.7803
The location of purinoceptors in the pancreatic duct and their role in regulating ductal secretion have been investigated by applying ATP and UTP to basolateral and luminal surfaces of pancreatic ducts isolated from the guinea‐pig pancreas. Changes in intracellular Ca2+ concentration were measured by microfluorometry in microperfused interlobular duct segments. Fluid and HCO3− secretion were estimated by monitoring luminal pH and luminal volume in sealed duct segments microinjected with BCECF‐dextran. Both ATP and UTP (1 μm) caused biphasic increases in intracellular Ca2+ concentration in pancreatic duct cells when applied to either the basolateral or luminal membrane. Luminal application of both ATP and UTP evoked fluid and HCO3− secretion. The maximum response to 1 μm ATP or UTP was about 75 % of that evoked by secretin. By contrast, basolateral application of ATP or UTP inhibited spontaneous secretion by 52 % and 73 %, respectively, and secretin‐evoked secretion by 41 % and 38 %, respectively. The data suggest that luminal nucleotides may act in an autocrine or paracrine fashion to enhance ductal secretion while basolateral nucleotides, perhaps released from nerve terminals, may have an inhibitory effect. The fact that both apical and basolateral purinoceptors elevate intracellular Ca2+, but that they have opposite effects on secretion, suggests that additional signalling pathways are involved.
Permeabilities of the luminal and basolateral membranes of pancreatic duct cells to CO2 and HCO3− were examined in interlobular duct segments isolated from guinea‐pig pancreas. Intracellular pH (pHi) was measured by microfluorometry in unstimulated, microperfused ducts loaded with the pH‐sensitive fluoroprobe 2′7′‐bis(2‐carboxyethyl)‐5(6)‐carboxyfluorescein (BCECF). When HCO3−/CO2 was admitted to the bath, pHi decreased transiently as a result of CO2 diffusion and then increased to a higher value as a result of HCO3− uptake across the basolateral membrane by Na+‐HCO3− cotransport. When HCO3−/CO2 was admitted to the lumen, pHi again decreased but no subsequent increase was observed, indicating that the luminal membrane was permeable to CO2 but did not allow HCO3− entry to the cells from the lumen. Only when the luminal HCO3− concentration was raised above 125 mm was HCO3− entry detected. The same was true of duct cells stimulated with forskolin. Recovery of pHi from an acid load, induced by exposure to an NH4+ pulse, was dependent on basolateral but not luminal Na+ and could be blocked by basolateral application of methylisobutylamiloride and H2DIDS. This indicates that the Na+‐H+ exchangers and Na+‐HCO3− cotransporters are located exclusively at the basolateral membrane. In the presence of HCO3−/CO2, substitution of basolateral Cl− with glucuronate caused larger increases in pHi than substitution of luminal Cl−. This suggests that the anion exchanger activity in the basolateral membrane is greater than that in the luminal membrane. We conclude that the luminal and basolateral membranes are both freely permeable to CO2, but while the basolateral membrane has both uptake and efflux pathways for HCO3−, the luminal membrane presents a significant barrier to the re‐entry of secreted HCO3−, largely through the inhibition of the luminal anion exchanger by high luminal HCO3− concentrations.
Our study indicates that high cholesterol intake is significantly associated with an increased risk of pancreatic cancer and that high vitamin C intake decreases the risk of pancreatic cancer.
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