Targeting the late component of the cardiac L-type Ca2+ current to suppress early afterdepolarizations.
Early afterdepolarizations (EADs) associated with prolongation of the cardiac action potential (AP) can create heterogeneity of repolarization and premature extrasystoles, triggering focal and reentrant arrhythmias. Because the L-type Ca(2+) current (ICa,L) plays a key role in both AP prolongation and EAD formation, L-type Ca(2+) channels (LTCCs) represent a promising therapeutic target to normalize AP duration (APD) and suppress EADs and their arrhythmogenic consequences. We used the dynamic-clamp technique to systematically explore how the biophysical properties of LTCCs could be modified to normalize APD and suppress EADs without impairing excitation-contraction coupling. Isolated rabbit ventricular myocytes were first exposed to H2O2 or moderate hypokalemia to induce EADs, after which their endogenous ICa,L was replaced by a virtual ICa,L with tunable parameters, in dynamic-clamp mode. We probed the sensitivity of EADs to changes in the (a) amplitude of the noninactivating pedestal current; (b) slope of voltage-dependent activation; (c) slope of voltage-dependent inactivation; (d) time constant of voltage-dependent activation; and (e) time constant of voltage-dependent inactivation. We found that reducing the amplitude of the noninactivating pedestal component of ICa,L effectively suppressed both H2O2- and hypokalemia-induced EADs and restored APD. These results, together with our previous work, demonstrate the potential of this hybrid experimental-computational approach to guide drug discovery or gene therapy strategies by identifying and targeting selective properties of LTCC.
Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
Roshni V
RV
Madhvani
Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
Marina
M
Angelini
Department of Pharmacology, University of California, Davis, Davis, CA 95616.
Yuanfang
Y
Xie
Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
Antonios
A
Pantazis
Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
Silvie
S
Suriany
Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
Nils P
NP
Borgstrom
Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095 Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095 Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
Alan
A
Garfinkel
Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095 Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
Zhilin
Z
Qu
Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095 Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095 Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095.
James N
JN
Weiss
Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095 Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095 Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095 Division of Molecular Medicine, Department of Anesthesiology, Department of Medicine (Cardiology), Department of Physiology, Department of Integrative Biology and Physiology, Cardiovascular Research Laboratory, and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095 rolcese@ucla.edu.
Riccardo
R
Olcese
D000200:Action Potentials; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002478:Cells, Cultured; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D011817:Rabbits
D020746:Calcium Channels, L-Type