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- W2321424300 abstract "Objectives The immunosuppressant tacrolimus (FK506) has improved pancreas allograft survival compared with cyclosporin A (CsA), possibly because of reduced acute pancreatitis following ischemia-reperfusion injury. Ion permeabilities in zymogen granule (ZG) membranes, including a KCNQ1 K+ channel, promote hormone-stimulated enzyme secretion. We investigated whether a differential modulation of ZG and lysosomal ion permeabilities and enzyme secretion by CsA/FK506 contributes to pancreatitis. Methods Rat ZGs and lysosomes were isolated by gradient centrifugation, ion permeabilities assayed by osmotic lysis, and single-channel currents recorded in a planar lipid bilayer. Amylase release was measured in permeabilized acini and lysosomal cathepsin B release detected by immunoblotting. Results CsA (1–10 μM), but not FK506, enhanced ZGs osmotic lysis by selectively increasing K+ permeability up to 5-fold. Zymogen granule membrane K+ channels showed ∼2-fold increased single-channel open probability with CsA only. Cyclosporin A selectively increased basal (∼2-fold), but not cholecystokinin-octapeptide (1 nM)–induced amylase secretion in K+ medium only. Cyclosporin A (5 μM), but not FK506, increased cathepsin B release from lysosomes. Conclusions Cyclosporin A selectively opens the ZG K+ channel and induces cathepsin B release from lysosomes, which cause increased in situ lysis of ZGs and may aggravate or fuel acute allograft pancreatitis following hypoxia-reperfusion injury." @default.
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- W2321424300 date "2012-05-01" @default.
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- W2321424300 title "Cyclosporin A, But Not FK506, Induces Osmotic Lysis of Pancreas Zymogen Granules, Intra-Acinar Enzyme Release, and Lysosome Instability by Activating K+ Channel" @default.
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- W2321424300 doi "https://doi.org/10.1097/mpa.0b013e318239c6e5" @default.
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