title: Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles.
abstract: BACKGROUND
  Fibrillation/defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF).
  
  
  OBJECTIVE
  We hypothesized that activation of apamin-sensitive small-conductance Ca(2+)-activated K(+) (SK) channels is responsible for the postshock APD shortening in failing ventricles.
  
  
  RESULTS
  A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca(2+) and membrane potential (V(m)) was performed in failing and nonfailing ventricles. Three failing ventricles developed SVF (SVF group); 9 did not (no-SVF group). None of the 10 nonfailing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 μmol/L) eliminated recurrent SVF and increased postshock APD(80) in the SVF group from 126±5 to 153±4 ms (P<0.05) and from 147±2 to 162±3 ms (P<0.05) in the no-SVF group but did not change APD(80) in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K(+) current (I(KAS)) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial I(KAS) density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca(2+) response of I(KAS) was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca(2+) sensitivity of I(KAS) in failing ventricles. The K(d) was 232±5 nmol/L for failing myocytes and 553±78 nmol/L for normal myocytes (P=0.002).
  
  
  CONCLUSIONS
  Heart failure heterogeneously increases the sensitivity of I(KAS) to intracellular Ca(2+), leading to upregulation of I(KAS), postshock APD shortening, and recurrent SVF.
authors.affiliation: Krannert Institute of Cardiology, Division of Cardiology, Indiana University School of Medicine, Indianapolis, USA.
authors.forename: Su-Kiat
authors.initials: SK
authors.lastname: Chua
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chang
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Maruyama
authors.forename: Isik
authors.initials: I
authors.lastname: Turker
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Shinohara
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shen
authors.forename: Zhenhui
authors.initials: Z
authors.lastname: Chen
authors.forename: Changyu
authors.initials: C
authors.lastname: Shen
authors.forename: Michael
authors.initials: M
authors.lastname: Rubart-von der Lohe
authors.forename: John C
authors.initials: JC
authors.lastname: Lopshire
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ogawa
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ai
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000818:Animals; D001030:Apamin / Q000627:therapeutic use; D020013:Calcium Signaling / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D011817:Rabbits; D055502:Secondary Prevention; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000096:biosynthesis* / Q000502:physiology; D014693:Ventricular Fibrillation / Q000188:drug therapy / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin