Revisiting the ionic mechanisms of early afterdepolarizations in cardiomyocytes: Predominant by Ca waves or Ca currents?

TY - JOUR

T1 - Revisiting the ionic mechanisms of early afterdepolarizations in cardiomyocytes

T2 - Predominant by Ca waves or Ca currents?

AU - Zhao, Zhenghang

AU - Wen, Hairuo

AU - Fefelova, Nadezhda

AU - Allen, Charelle

AU - Baba, Akemichi

AU - Matsuda, Toshio

AU - Xie, Lai Hua

PY - 2012/4/15

Y1 - 2012/4/15

N2 - Early afterdepolarizations (EADs) have been implicated in severe cardiac arrhythmias and sudden cardiac deaths. However, the mechanism(s) for EAD genesis, especially regarding the relative contribution of Ca 2+ wave (CaW) vs. L-type Ca current (I Ca,L), still remains controversial. In the present study, we simultaneously recorded action potentials (APs) and intracellular Ca 2+ images in isolated rabbit ventricular myocytes and systematically compared the properties of EADs in the following two pharmacological models: 1) hydrogen peroxide (H 2O 2; 200 μ M); and 2) isoproterenol (100 nM) and BayK 8644 (50 nM) (Iso + BayK). We assessed the rate dependency of EADs, the temporal relationship between EADs and corresponding CaWs, the distribution of EADs over voltage, and the effects of blockers of I Ca,L, Na/Ca exchangers,and ryanodine receptors. The most convincing evidence came from the AP-clamp experiment, in which the cell membrane clamp was switched from current clamp to voltage clamp using a normal AP waveform without EAD; CaWs disappeared in the H 2O 2 model, but persisted in the Iso + BayK model. We postulate that, although CaWs and reactivation of I Ca,L may act synergistically in either case, reactivation of I Ca,L plays a predominant role in EAD genesis under oxidative stress (H 2O 2 model), while spontaneous CaWs are a predominant cause for EADs under Ca 2+ overload condition (Iso + BayK model).

AB - Early afterdepolarizations (EADs) have been implicated in severe cardiac arrhythmias and sudden cardiac deaths. However, the mechanism(s) for EAD genesis, especially regarding the relative contribution of Ca 2+ wave (CaW) vs. L-type Ca current (I Ca,L), still remains controversial. In the present study, we simultaneously recorded action potentials (APs) and intracellular Ca 2+ images in isolated rabbit ventricular myocytes and systematically compared the properties of EADs in the following two pharmacological models: 1) hydrogen peroxide (H 2O 2; 200 μ M); and 2) isoproterenol (100 nM) and BayK 8644 (50 nM) (Iso + BayK). We assessed the rate dependency of EADs, the temporal relationship between EADs and corresponding CaWs, the distribution of EADs over voltage, and the effects of blockers of I Ca,L, Na/Ca exchangers,and ryanodine receptors. The most convincing evidence came from the AP-clamp experiment, in which the cell membrane clamp was switched from current clamp to voltage clamp using a normal AP waveform without EAD; CaWs disappeared in the H 2O 2 model, but persisted in the Iso + BayK model. We postulate that, although CaWs and reactivation of I Ca,L may act synergistically in either case, reactivation of I Ca,L plays a predominant role in EAD genesis under oxidative stress (H 2O 2 model), while spontaneous CaWs are a predominant cause for EADs under Ca 2+ overload condition (Iso + BayK model).

KW - Ca wave

KW - L-type Ca current

KW - Na/Ca exchanger

KW - Reactive oxygen species

KW - β-adrenergic stimulation

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U2 - https://doi.org/10.1152/ajpheart.00742.2011

DO - https://doi.org/10.1152/ajpheart.00742.2011

M3 - Article

C2 - 22307670

SN - 0002-9513

VL - 302

SP - H1636-H1644

JO - AM.J.PHYSIOL.

JF - AM.J.PHYSIOL.

IS - 8

ER -