title: Cyclosporin a, but not FK506, induces osmotic lysis of pancreas zymogen granules, intra-acinar enzyme release, and lysosome instability by activating K+ channel.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Physiology & Pathophysiology, University of Witten/Herdecke, Witten, Germany.
authors.forename: Wing-Kee
authors.initials: WK
authors.lastname: Lee
authors.forename: Matthias
authors.initials: M
authors.lastname: Braun
authors.forename: Christian
authors.initials: C
authors.lastname: Langelüddecke
authors.forename: Frank
authors.initials: F
authors.lastname: Thévenod
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism; D000681:Amylases / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D016572:Cyclosporine / Q000009:adverse effects*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009995:Osmosis / Q000187:drug effects; D010179:Pancreas / Q000098:blood supply / Q000187:drug effects*; D016035:Pancreas Transplantation; D055589:Pancreatitis, Graft / Q000209:etiology; D010539:Permeability / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000209:etiology; D022142:Secretory Vesicles / Q000187:drug effects* / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D015221:Potassium Channels; D016572:Cyclosporine; D000681:Amylases; D002401:Cathepsin B; C533916:Ctsb protein, rat; D016559:Tacrolimus