Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles

Su Kiat Chua, Po Cheng Chang, Mitsunori Maruyama, Isik Turker, Tetsuji Shinohara, Mark J. Shen, Zhenhui Chen, Changyu Shen, Michael Rubart-Von Der Lohe, John C. Lopshire, Masahiro Ogawa, James N. Weiss, Shien Fong Lin, Tomohiko Ai, Peng Sheng Chen

Research output: Contribution to journalArticle

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Abstract

Rationale: 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-activated K (SK) channels is responsible for the postshock APD shortening in failing ventricles. Methods and Results: A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca and membrane potential (Vm) 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 APD80 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 APD80 in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K current (IKAS) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial IKAS density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca response of IKAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca sensitivity of IKAS in failing ventricles. The Kd 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 IKAS to intracellular Ca, leading to upregulation of IKAS, postshock APD shortening, and recurrent SVF.

Original languageEnglish (US)
Pages (from-to)971-979
Number of pages9
JournalCirculation research
Volume108
Issue number8
DOIs
StatePublished - Apr 15 2011

Fingerprint

Small-Conductance Calcium-Activated Potassium Channels
Ventricular Fibrillation
Rabbits
Apamin
Muscle Cells
Action Potentials
Heart Failure
Intracellular Membranes
Tachycardia
Membrane Potentials
Up-Regulation

Keywords

  • arrhythmia
  • intracellular calcium
  • ion channels
  • ventricular fibrillation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles. / Chua, Su Kiat; Chang, Po Cheng; Maruyama, Mitsunori; Turker, Isik; Shinohara, Tetsuji; Shen, Mark J.; Chen, Zhenhui; Shen, Changyu; Rubart-Von Der Lohe, Michael; Lopshire, John C.; Ogawa, Masahiro; Weiss, James N.; Lin, Shien Fong; Ai, Tomohiko; Chen, Peng Sheng.

In: Circulation research, Vol. 108, No. 8, 15.04.2011, p. 971-979.

Research output: Contribution to journalArticle

Chua, Su Kiat ; Chang, Po Cheng ; Maruyama, Mitsunori ; Turker, Isik ; Shinohara, Tetsuji ; Shen, Mark J. ; Chen, Zhenhui ; Shen, Changyu ; Rubart-Von Der Lohe, Michael ; Lopshire, John C. ; Ogawa, Masahiro ; Weiss, James N. ; Lin, Shien Fong ; Ai, Tomohiko ; Chen, Peng Sheng. / Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles. In: Circulation research. 2011 ; Vol. 108, No. 8. pp. 971-979.
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T1 - Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles

AU - Chua, Su Kiat

AU - Chang, Po Cheng

AU - Maruyama, Mitsunori

AU - Turker, Isik

AU - Shinohara, Tetsuji

AU - Shen, Mark J.

AU - Chen, Zhenhui

AU - Shen, Changyu

AU - Rubart-Von Der Lohe, Michael

AU - Lopshire, John C.

AU - Ogawa, Masahiro

AU - Weiss, James N.

AU - Lin, Shien Fong

AU - Ai, Tomohiko

AU - Chen, Peng Sheng

PY - 2011/4/15

Y1 - 2011/4/15

N2 - Rationale: 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-activated K (SK) channels is responsible for the postshock APD shortening in failing ventricles. Methods and Results: A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca and membrane potential (Vm) 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 APD80 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 APD80 in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K current (IKAS) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial IKAS density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca response of IKAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca sensitivity of IKAS in failing ventricles. The Kd 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 IKAS to intracellular Ca, leading to upregulation of IKAS, postshock APD shortening, and recurrent SVF.

AB - Rationale: 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-activated K (SK) channels is responsible for the postshock APD shortening in failing ventricles. Methods and Results: A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca and membrane potential (Vm) 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 APD80 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 APD80 in nonfailing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K current (IKAS) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial IKAS density was significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca response of IKAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca sensitivity of IKAS in failing ventricles. The Kd 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 IKAS to intracellular Ca, leading to upregulation of IKAS, postshock APD shortening, and recurrent SVF.

KW - arrhythmia

KW - intracellular calcium

KW - ion channels

KW - ventricular fibrillation

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