FK-506, a widely used immunosuppressant, has caused a few clinical
cases with QT prolongation and torsades de pointe at high blood concentration.
The proarrhytmogenic potential of FK-506 was investigated in single
rat ventricular cells using the whole cell clamp method to record
action potentials (APs) and ionic currents. Fluorescence measurements
of Ca$^2+$ transients were performed with indo-1 AM using a
multiphotonic microscope. FK-506 (25 micromol/l) hyperpolarized the
resting membrane potential (RMP; -3 mV) and prolonged APs (AP duration
at 90\% repolarization increased by 21\%) at 0.1 Hz. Prolongation
was enhanced by threefold at 3.3 Hz, and early afterdepolarizations
(EADs) occurred in 59\% of cells. EADs were prevented by stronger
intracellular Ca$^2+$ buffering (EGTA: 10 vs. 0.5 mmol/l in the
patch pipette) or replacement of extracellular Na$^+$ by Li+,
which abolishes Na$^+$/Ca$^2+$ exchange Na$^+$/Ca$^2+$
exchanger current (INaCa). In indo-1-loaded cells, FK-506 generated
doublets of Ca$^2+$ transients associated with increased diastolic
Ca$^2+$ in one-half of the cells. FK-506 reversibly decreased
the L-type Ca$^2+$ current (ICaL) by 25\%, although high-frequency-dependent
facilitation of ICaL persisted, and decreased three distinct K$^+$
currents: delayed rectifier K$^+$ current (IK; >80\%), transient
outward K$^+$ current (<20\%), and inward rectifier K$^+$
current (IK1; >40\%). A shift in the reversal potential of IK1 (-5
mV) accounted for RMP hyperpolarization. Numerical simulations,
reproducing all experimental effects of FK-506, and the use of nifedipine
showed that frequency-dependent facilitation of ICaL plays a role
in the occurrence of EADs. In conclusion, the effects of FK-506 on
the cardiac AP are more complex than previously reported and include
inhibitions of IK1 and ICaL. Alterations in Ca$^2+$ release and
INaCa may contribute to FK-506-induced AP prolongation and EADs in
addition to the permissive role of ICaL facilitation at high rates
of stimulation.
%0 Journal Article
%1 Fauc_2005_H778
%A Fauconnier, J�r�my
%A Lacampagne, Alain
%A Rauzier, Jean-Michel
%A Fontanaud, Pierre
%A Frapier, Jean-Marc
%A Sejersted, Ole M
%A Vassort, Guy
%A Richard, Sylvain
%D 2005
%J Am. J. Physiol. Heart Circ. Physiol.
%K 15471978 Action Agents, Animals, Arrhythmia, Artificial, Calcium Calcium, Cardiac, Channels, Electrocardiography, Extracellular Gov't, Heart Immunosuppressive In Inbred Inwardly L-Type, Long Myocytes, Non-U.S. Pacemaker, Patch-Clamp Potassium Potentials, QT Rate, Rats, Rectifying, Research Sodium, Space, Support, Syndrome, Tacrolimus, Techniques, Vitro, WKY,
%N 2
%P H778-86
%R 10.1152/ajpheart.00542.2004
%T Frequency-dependent and proarrhythmogenic effects of FK-506 in rat
ventricular cells.
%U http://dx.doi.org/10.1152/ajpheart.00542.2004
%V 288
%X FK-506, a widely used immunosuppressant, has caused a few clinical
cases with QT prolongation and torsades de pointe at high blood concentration.
The proarrhytmogenic potential of FK-506 was investigated in single
rat ventricular cells using the whole cell clamp method to record
action potentials (APs) and ionic currents. Fluorescence measurements
of Ca$^2+$ transients were performed with indo-1 AM using a
multiphotonic microscope. FK-506 (25 micromol/l) hyperpolarized the
resting membrane potential (RMP; -3 mV) and prolonged APs (AP duration
at 90\% repolarization increased by 21\%) at 0.1 Hz. Prolongation
was enhanced by threefold at 3.3 Hz, and early afterdepolarizations
(EADs) occurred in 59\% of cells. EADs were prevented by stronger
intracellular Ca$^2+$ buffering (EGTA: 10 vs. 0.5 mmol/l in the
patch pipette) or replacement of extracellular Na$^+$ by Li+,
which abolishes Na$^+$/Ca$^2+$ exchange Na$^+$/Ca$^2+$
exchanger current (INaCa). In indo-1-loaded cells, FK-506 generated
doublets of Ca$^2+$ transients associated with increased diastolic
Ca$^2+$ in one-half of the cells. FK-506 reversibly decreased
the L-type Ca$^2+$ current (ICaL) by 25\%, although high-frequency-dependent
facilitation of ICaL persisted, and decreased three distinct K$^+$
currents: delayed rectifier K$^+$ current (IK; >80\%), transient
outward K$^+$ current (<20\%), and inward rectifier K$^+$
current (IK1; >40\%). A shift in the reversal potential of IK1 (-5
mV) accounted for RMP hyperpolarization. Numerical simulations,
reproducing all experimental effects of FK-506, and the use of nifedipine
showed that frequency-dependent facilitation of ICaL plays a role
in the occurrence of EADs. In conclusion, the effects of FK-506 on
the cardiac AP are more complex than previously reported and include
inhibitions of IK1 and ICaL. Alterations in Ca$^2+$ release and
INaCa may contribute to FK-506-induced AP prolongation and EADs in
addition to the permissive role of ICaL facilitation at high rates
of stimulation.
@article{Fauc_2005_H778,
abstract = {FK-506, a widely used immunosuppressant, has caused a few clinical
cases with QT prolongation and torsades de pointe at high blood concentration.
The proarrhytmogenic potential of FK-506 was investigated in single
rat ventricular cells using the whole cell clamp method to record
action potentials (APs) and ionic currents. Fluorescence measurements
of {C}a$^{2+}$ transients were performed with indo-1 {AM} using a
multiphotonic microscope. FK-506 (25 micromol/l) hyperpolarized the
resting membrane potential (RMP; -3 mV) and prolonged APs (AP duration
at 90\% repolarization increased by 21\%) at 0.1 Hz. Prolongation
was enhanced by threefold at 3.3 Hz, and early afterdepolarizations
(EADs) occurred in 59\% of cells. EADs were prevented by stronger
intracellular {C}a$^{2+}$ buffering (EGTA: 10 vs. 0.5 mmol/l in the
patch pipette) or replacement of extracellular {N}a$^{+}$ by Li+,
which abolishes {N}a$^{+}$/{C}a$^{2+}$ exchange [{N}a$^{+}$/{C}a$^{2+}$
exchanger current (INaCa)]. In indo-1-loaded cells, FK-506 generated
doublets of {C}a$^{2+}$ transients associated with increased diastolic
{C}a$^{2+}$ in one-half of the cells. FK-506 reversibly decreased
the L-type {C}a$^{2+}$ current (ICaL) by 25\%, although high-frequency-dependent
facilitation of ICaL persisted, and decreased three distinct {K}$^{+}$
currents: delayed rectifier {K}$^{+}$ current (IK; >80\%), transient
outward {K}$^{+}$ current (<20\%), and inward rectifier {K}$^{+}$
current (IK1; >40\%). A shift in the reversal potential of IK1 (-5
mV) accounted for {RMP} hyperpolarization. Numerical simulations,
reproducing all experimental effects of FK-506, and the use of nifedipine
showed that frequency-dependent facilitation of ICaL plays a role
in the occurrence of EADs. In conclusion, the effects of FK-506 on
the cardiac AP are more complex than previously reported and include
inhibitions of IK1 and ICaL. Alterations in {C}a$^{2+}$ release and
INaCa may contribute to FK-506-induced AP prolongation and EADs in
addition to the permissive role of ICaL facilitation at high rates
of stimulation.},
added-at = {2009-06-03T11:20:58.000+0200},
author = {Fauconnier, J�r�my and Lacampagne, Alain and Rauzier, Jean-Michel and Fontanaud, Pierre and Frapier, Jean-Marc and Sejersted, Ole M and Vassort, Guy and Richard, Sylvain},
biburl = {https://www.bibsonomy.org/bibtex/260cb8c7572a424017a24c8fdc2cc5b81/hake},
description = {The whole bibliography file I use.},
doi = {10.1152/ajpheart.00542.2004},
file = {Fauc_2005_H778.pdf:Fauc_2005_H778.pdf:PDF},
interhash = {089e92e167e8f7d5afe31b4a401e808b},
intrahash = {60cb8c7572a424017a24c8fdc2cc5b81},
journal = {Am. J. Physiol. Heart Circ. Physiol.},
key = 32,
keywords = {15471978 Action Agents, Animals, Arrhythmia, Artificial, Calcium Calcium, Cardiac, Channels, Electrocardiography, Extracellular Gov't, Heart Immunosuppressive In Inbred Inwardly L-Type, Long Myocytes, Non-U.S. Pacemaker, Patch-Clamp Potassium Potentials, QT Rate, Rats, Rectifying, Research Sodium, Space, Support, Syndrome, Tacrolimus, Techniques, Vitro, WKY,},
month = Feb,
number = 2,
pages = {H778-86},
pii = {00542.2004},
timestamp = {2009-06-03T11:21:11.000+0200},
title = {Frequency-dependent and proarrhythmogenic effects of FK-506 in rat
ventricular cells.},
url = {http://dx.doi.org/10.1152/ajpheart.00542.2004},
volume = 288,
year = 2005
}