title: Function of Ca(2+) release channels in Purkinje cells that survive in the infarcted canine heart: a mechanism for triggered Purkinje ectopy.
abstract: BACKGROUND
  Triggered Purkinje ectopy can lead to the initiation of serious ventricular arrhythmias in post-myocardial infarction patients. In the canine model, Purkinje cells from the subendocardial border of the healing infarcted heart can initiate ventricular arrhythmias. Intracellular Ca(2+) abnormalities underlie these arrhythmias, yet the subcellular reasons for these abnormalities remain unknown.
  
  
  RESULTS
  Using 2D confocal microscopy, we directly quantify and compare typical spontaneous Ca(2+) events in specific subcellular regions of normal Purkinje cells with those Purkinje cells from the subendocardium of the 48-hour infarcted canine heart (IZPCs). The Ca(2+) event rate was higher in the subsarcolemmal region of IZPCs when compared with normal Purkinje cells; IZPC amplitudes were higher, yet the spatial extents of these events were similar. The amplitude of caffeine-releasable Ca(2+) in either the subsarcolemmal or core regions of IZPCs did not differ from normal Purkinje cells, suggesting that Ca(2+) overload was not related to the frequency change. In permeabilized Purkinje cells from both groups, the event rate was related to free [Ca(2+)] in both subsarcolemmal and core, but in IZPCs, this event rate was significantly increased at each free Ca(2+), suggesting an enhanced sensitivity to Ca(2+) release. Furthermore, decays of wide long lasting Ca(2+) release events in IZPC's core were significantly accelerated compared with those in normal Purkinje cells. JTV519 (K201) suppressed IZPC cell wide Ca(2+) waves as well as normalized the enhanced event rate and its response to free Ca(2+).
  
  
  CONCLUSIONS
  Increased spontaneous Ca(2+) release events in IZPCs are due to uniform regionally increased Ca(2+) release channel sensitivity to Ca(2+) without a change in sarcoplasmic reticulum content. In addition, Ca(2+) reuptake in IZPCs is accelerated. These properties would lower the threshold of Ca(2+) release channels, setting the stage for the highly frequent arrhythmogenic cell wide Ca(2+) waves observed in IZPCs.
authors.affiliation: Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, NY, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hirose
authors.forename: Bruno D
authors.initials: BD
authors.lastname: Stuyvers
authors.forename: Wen
authors.initials: W
authors.lastname: Dun
authors.forename: Henk E D J
authors.initials: HE
authors.lastname: ter Keurs
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Boyden
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002110:Caffeine / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002470:Cell Survival; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D018613:Microscopy, Confocal; D009203:Myocardial Infarction / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D010539:Permeability; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012503:Saponins; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013748:Tetracaine / Q000494:pharmacology; D013841:Thiazepines / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D012503:Saponins; D013841:Thiazepines; D013748:Tetracaine; C109183:K201 compound; D002110:Caffeine