Pancreatic duct epithelium secretes a HCO3−-rich fluid by a mechanism dependent on cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. However, the exact role of CFTR remains unclear. One possibility is that the HCO3− permeability of CFTR provides a pathway for apical HCO3− efflux during maximal secretion. We have therefore attempted to measure electrodiffusive fluxes of HCO3− induced by changes in membrane potential across the apical membrane of interlobular ducts isolated from the guinea pig pancreas. This was done by recording the changes in intracellular pH (pHi) that occurred in luminally perfused ducts when membrane potential was altered by manipulation of bath K+ concentration. Apical HCO3− fluxes activated by cyclic AMP were independent of Cl− and luminal Na+, and substantially inhibited by the CFTR blocker, CFTRinh-172. Furthermore, comparable HCO3− fluxes observed in ducts isolated from wild-type mice were absent in ducts from cystic fibrosis (ΔF) mice. To estimate the HCO3− permeability of the apical membrane under physiological conditions, guinea pig ducts were luminally perfused with a solution containing 125 mM HCO3− and 24 mM Cl− in the presence of 5% CO2. From the changes in pHi, membrane potential, and buffering capacity, the flux and electrochemical gradient of HCO3− across the apical membrane were determined and used to calculate the HCO3− permeability. Our estimate of ∼0.1 µm sec−1 for the apical HCO3− permeability of guinea pig duct cells under these conditions is close to the value required to account for observed rates of HCO3− secretion. This suggests that CFTR functions as a HCO3− channel in pancreatic duct cells, and that it provides a significant pathway for HCO3− transport across the apical membrane.

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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The purpose of this study was to clarify whether delayed onset muscle soreness (DOMS) and muscle damage after eccentric exercise (ECC) could affect the ventilatory and circulatory responses at the onset of exercise, and whether those effects would continue after the disappearance of DOMS. Ten males participated in this study. We measured ventilatory and circulatory responses at the onset of exercise, for the first 20 s, during knee extension-relaxation voluntary exercise (VOL) and passive movement (PAS), which was achieved by the experimenter alternatively pulling ropes connected to the subjects' ankles for the same period and frequency as during VOL. VOL and PAS were performed before, 2 days after, and 7 days after ECC. The following results were found: (1) the gain of minute ventilation at the onset of VOL at 2 days after ECC was significantly larger than that of before ECC; (2) the gain of minute ventilation at 7 days after ECC during both VOL and PAS was also enhanced significantly as compared to that of before ECC; and (3) heart rate and blood pressure responses were unchanged throughout the experimental period. In conclusion, ventilatory response at the onset of exercise is augmented during DOMS and EIMD after ECC and the enhanced ventilatory response continued after the disappearance of DOMS. It is suggested that enhanced ventilatory response during exercise after ECC is attributed to at least the changes in neural factors and that the mechanisms inducing these augmented ventilatory responses should be different during the period after ECC.

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