Repolarization reserve evolves dynamically during the cardiac action potential: effects of transient outward currents on early afterdepolarizations

Circulation. Arrhythmia and Electrophysiology
Thao P NguyenJames N Weiss

Abstract

Transient outward K currents (Ito) have been reported both to suppress and to facilitate early afterdepolarizations (EADs) when repolarization reserve is reduced. Here, we used the dynamic clamp technique to analyze how Ito accounts for these paradoxical effects on EADs by influencing the dynamic evolution of repolarization reserve during the action potential. Isolated patch-clamped rabbit ventricular myocytes were exposed to either oxidative stress (H2O2) or hypokalemia to induce bradycardia-dependent EADs at a long pacing cycle length of 6 s, when native rabbit Ito is substantial. EADs disappeared when the pacing cycle length was shortened to 1 s, when Ito becomes negligible because of incomplete recovery from inactivation. During 6-s pacing cycle length, EADs were blocked by the Ito blocker 4-aminopyridine, but reappeared when a virtual current with appropriate Ito-like properties was reintroduced using the dynamic clamp (n=141 trials). During 1-s pacing cycle length in the absence of 4-aminopyridine, adding a virtual Ito-like current (n=1113 trials) caused EADs to reappear over a wide range of Ito conductance (0.005-0.15 nS/pF), particularly when inactivation kinetics were slow (τinact≥20 ms) and the pedestal (noninactivati...Continue Reading

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Citations

Nov 27, 2018·PLoS Computational Biology·Xiaodong HuangZhilin Qu
Dec 24, 2018·American Journal of Physiology. Heart and Circulatory Physiology·Haibo NiWayne R Giles
Nov 4, 2016·The Journal of Physiology·Nipavan ChiamvimonvatJeanne M Nerbonne
Dec 5, 2016·Naunyn-Schmiedeberg's Archives of Pharmacology·Luiz Fernando Rodrigues JuniorJosé Hamilton Matheus Nascimento
Jan 2, 2021·American Journal of Physiology. Heart and Circulatory Physiology·Julian LandawZhilin Qu
Aug 10, 2021·Frontiers in Physiology·Yali ZhaoThao P Nguyen
Oct 27, 2021·The Journal of General Physiology·Marina AngeliniRiccardo Olcese

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