Effects of thyroid hormone on action potential and
repolarizing currents in rat ventricular myocytes
Zhuo-Qian
Sun1,2,
Kaie
Ojamaa2,
William A.
Coetzee1,
Michael
Artman1, and
Irwin
Klein2
1 Pediatric Cardiology, New York University Medical
Center, New York 10016; 2 Division of Endocrinology,
Department of Medicine, North Shore University Hospital/New York
University School of Medicine, Manhasset, New York 11030
 |
ABSTRACT |
Thyroid hormones play an important role
in cardiac electrophysiology through both genomic and nongenomic
mechanisms of action. The effects of triiodothyronine (T3)
on the electrophysiological properties of ventricular myocytes isolated
from euthyroid and hypothyroid rats were studied using whole cell patch
clamp techniques. Hypothyroid ventricular myocytes showed significantly
prolonged action potential duration (APD90) compared with
euthyroid myocytes, APD90 of 151 ± 5 vs. 51 ± 8 ms,
respectively. Treatment of hypothyroid ventricular myocytes with
T3 (0.1 µM) for 5 min significantly shortened APD by 24%
to 115 ± 10 ms. T3 similarly shortened APD in euthyroid
ventricular myocytes, but only in the presence of 4-aminopyridine
(4-AP), an inhibitor of the transient outward current
(Ito), which prolonged the APD by threefold.
Transient outward current (Ito) was not affected by
the acute application of T3 to either euthyroid or
hypothyroid myocytes; however, Ito density was
significantly reduced in hypothyroid compared with euthyroid
ventricular myocytes.
acute effects of triiodothyronine; heart; transient outward
current; delayed rectifier current
 |
INTRODUCTION |
IT IS WELL RECOGNIZED FROM studies of patients with
spontaneously occurring hypothyroidism and hyperthyroidism that thyroid hormone has profound effects on the cardiovascular system (15). The
classically described cellular actions of thyroid hormone are mediated
by nuclear triiodothyronine (T3) receptors that function to
regulate the expression of specific cardiac genes (4, 8) such as plasma
membrane sodium-potassium ATPase (21, 30) and voltage-activated
K+ channel genes including Kv4.2, Kv4.3, and Kv1.5 (24, 26, 29). Changes in cardiac electrophysiology have been well documented for
chronic thyroid disease states (3, 19, 27, reviewed in Ref.16). Early
experimental studies of thyroid hormone effects on transmembrane potentials of sinoatrial node cells and atrial muscle cells showed an
increased rate of diastolic depolarization and decreased duration of
action potential in thyrotoxic animals, suggesting that conductance of
K+ ions may be altered (11, 14).
Recent evidence has shown that thyroid hormones exert effects on the
cardiovascular system that are not mediated by alterations in gene
expression (reviewed in Ref. 17). Sakaguchi and co-workers (25) showed
that T3 caused a shortening of the action potential duration in guinea pig ventricular myocytes by increasing whole cell
inward rectifier potassium current (IK1). Single
IK1 channel recordings showed that T3
increased the open probability mainly resulting from shortening of
interburst duration without any changes in burst behavior. Neither the
number of channels nor unit amplitude of single IK1
was changed by T3. Sodium channel activity has also been
shown to be regulated by T3. Single channel studies by
Dudley and Baumgarten (9) showed an increase of burst activity of the
sodium channel when T3 was applied extracellularly, whereas Cui and Sen (5) and Harris et al. (12) showed that the increase of
sodium current induced by T3 occurred as a result of a
slower rate of inactivation of the current.
In the rat ventricular myocyte, two primary depolarization-activated
outward currents are important in regulating action potential duration:
the Ca2+-independent transient outward K+
current (Ito) and a slowly inactivating
K+ current (IK) (1). Although thyroid
hormone has been shown to regulate the expression of numerous
cardiac-specific genes, the present study was designed to distinguish
the genomic and nongenomic effects of T3 on the action
potential duration and repolarization currents of ventricular myocytes
isolated from both euthyroid and hypothyroid rats.
 |
MATERIALS AND METHODS |
Animals.
In accordance with institutional animal care committee standards, male
Sprague-Dawley rats, each weighing ~170 g, were divided into two
groups and treated for 5-6 wk. Group I remained untreated and served as the euthyroid control; group II received
6-n-propyl-2-thiouracil (PTU) at a concentration of 750 mg/l in
the drinking water to induce the hypothyroid state. Heart weights and
myocyte size were used to determine the efficacy of the treatment regimen.
Myocyte isolation and electrophysiological recordings.
Single ventricular myocytes were isolated as previously described (22).
The hearts were rapidly removed from anesthetized rats (pentobarbital
sodium, 50 mg/kg) and perfused for 5 min in a constant-pressure
Langendorff system with standard Tyrode's solution (in mM: 10 HEPES pH
7.4, 137 NaCl, 5.4 KCl, 1 MgCl2, 0.33 NaH2PO4, 1.8 CaCl2, 10 glucose).
The perfusate was oxygenated and maintained at 37°C. The hearts
were then perfused with Ca2+-free Tyrode solution for 5 min
followed by the addition of 0.114% (wt/vol) collagenase type I plus
0.014% (wt/vol) protease type XIV (Sigma, St. Louis, MO) for 10 min.
The enzyme-containing solution was then washed out by perfusing with
Ca2+-free Tyrode solution for 5 min, and the ventricles
were separated from the rest of the heart. Myocytes were isolated by
mechanical agitation in solution containing (in mM): 20 taurine, 50 glutamic acid, 10 HEPES pH 7.2, 0.5 EGTA, 3 MgSO4, 30 KH2PO4, 30 KCl and were used for patch clamp
experiments up to 8 h after isolation. The pipette solution containing
(in mM) 110 potassium aspartate, 20 KCl, 5 Na2-ATP, 5.92 MgCl2, 10 EGTA, and 10 HEPES pH 7.2 was passed through a
0.2-µm sterile filter (Gelman Sciences, Ann Arbor, MI).
Isolated ventricular cells were allowed to adhere for several minutes
to a freshly coated polylysine surface in a bath (~200 µl volume)
on the stage of an inverted microscope (Nikon Diaphot, Tokyo, Japan).
The cells were then superfused (1-2 ml/min) for 5 min with
standard Tyrode solution and nonadherent cells were removed. Myocytes
were identified by their morphology and clamped using an Axopatch 200A
amplifier with a CV-201AU headstage and pClamp software (Axon
Instruments, Foster City, CA) in the whole cell configuration. Suction
pipettes were made from thin-walled glass capillaries using a
horizontal puller (Zeitz Instrument Universal Puller, Augsburg,
Germany) and heat polished. When filled with a pipette solution,
pipette tip resistance ranged between 2 and 4 M
. The liquid junction
potential (14.2 mV, pipette negative) was calculated using Axoscope
(Axon Instruments) and was zeroed before the formation of the
membrane-pipette seal in a standard Tyrode solution. The plasma
membrane was ruptured by applying negative pressure in the pipette.
Five-millisecond depolarizing current pulses, sufficient to reach the
threshold for sodium current (INa) activation, were used to initiate action potentials using current clamp in whole cell
configuration. Action potentials (AP) were recorded at 1 Hz after the
APs had reached steady state. Recordings were made from hypothyroid and
euthyroid ventricular myocytes in standard Tyrode solution and from
euthyroid myocytes in the presence of 4-aminopyridine (4-AP, 3 mM) to
inhibit the transient outward current (Ito).
Triiodo-L-thyronine (T3, 0.1-1.0 µM) was
added to the superfusate and action potentials were recorded after 2 min, which represented the earliest measureable response to hormone. The average of ten episodes of action potentials was used for data analysis.
Ito was recorded by depolarizing potentials ranging
between
30 and +80 mV from a holding potential of
45 mV
to inactivate the Na+ channels in standard Tyrode solution
containing 500 µM CdCl2 to block the calcium channels.
The IK was measured by holding the cells at
45 mV and stepping up to more positive voltages (
30 to
+80 mV) for 500 ms. In this protocol, 4-AP (3 mM), BaCl2 (200 µM), and CdCl2 (500 µM) were added to the
superfusate to inhibit Ito,
IK1, and calcium channels, respectively. After
Ito or IK measurements were
made in myocytes under control conditions, T3
(10
6-10
5
M) was added to the superfusate, and after 2 min the voltage protocol
was repeated over a period of ~120 s. Reverse T3
(rT3) was tested to determine the specificity of the
T3 effects. Another series of experiments measured the
dose-response relationship of IK with
T3
(10
9-10
5
M) using a test pulse of +80 mV. Cell capacitance was calculated by
integrating the area under the uncompensated capacitance transient produced by 10 mV, hyperpolarizing step from 0 mV, and dividing this
area by the voltage step. Currents were digitized at 4 kHz and filtered
at 1 kHz. Cell capacitance and pipette series resistance were both
compensated. All of the experiments were performed at room temperature
(~25°C).
The data were analyzed using pClamp software (Axon Instruments).
Ito was measured as the peak current at the
beginning of the test pulses. IK was measured as
the difference between the current at the end of 500-ms pulses and the
holding current. The current-voltage relationship was evaluated by
plotting the current density (current normalized to the cell
capacitance) as a function of the test potentials.
Statistical Analysis.
All data are expressed as means ± SE. The statistical significance
for any differences was assessed using Student's t-test (paired or unpaired where appropriate).
 |
RESULTS |
Animal thyroid status.
As a measure of thyroid status, heart weights were measured at the end
of the 6-wk treatment period. Hypothyroid hearts were significantly
smaller than euthyroid controls, 1,077 ± 20 mg vs. 1,658 ± 10 mg,
respectively (P < 0.01; n = 4/group). As a measure of
myocyte size, hypothyroid myocyte capacitance (92.5 ± 2.6 pF, n = 22) was significantly reduced (P < 0.05) compared
with that of the euthyroid myocyte (158.1 ± 6.1, n = 26).
Characteristic of hypothyroidism, the action potential duration was
prolonged in ventricular myocytes from the PTU-treated animals.
Effects of T3 on APD.
Action potentials were recorded under whole cell current clamp
configuration in ventricular myocytes isolated from euthyroid and
hypothyroid rats (Fig. 1). Administration
of T3 (1 µM) to the superfusate had no effect on the APD
of euthyroid myocytes (Fig. 1A). The APD at 90% repolarization
(APD90) was 52.6 ± 9.4 ms after T3 addition
compared with 51.3 ± 8.3 ms in control conditions without
T3 addition (n = 6). The APD range in euthyroid
myocytes was from 30 to 70 ms, as illustrated by the two tracings in
Fig. 1 A and B. Figure 1 B shows that
APD90 of euthyroid myocytes could be prolonged to 199.0 ± 16.8 ms (n = 12, P < 0.05) in the presence of 4-AP (3 mM), which blocks the Ito. The addition of
T3 to the superfusate caused a significant shortening of
APD90 in the presence of 4-AP to 175.9 ± 14.9 ms
(n = 12, P < 0.05), suggesting that T3
had an effect on a 4-AP insensitive current. Figure 1 C shows that the APD90 in the hypothyroid ventricular myocyte was
prolonged (151 ± 4.6 ms, n = 6) and that the addition of
T3 (0.1 µM) significantly shortened (P < 0.05)
the APD90 to 115.3 ± 10.2 ms.

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Fig. 1.
Effects of triiodothyronine (T3) on transmembrane action
potentials recorded from euthyroid (A, B) and
hypothyroid (C) rat ventricular myocytes. Action potential
duration (APD) was shortened in the euthyroid myocyte only in the
presence of 4-aminopyridine (4-AP)(B), whereas the prolonged
APD (APD90) in hypothyroid myocytes was shortened by
T3 alone (C). Control conditions represent
recordings in the absence of added reagents. Under control conditions,
the APD90 ranged from 30 to 70 ms in euthyroid myocytes and
from 140 to 160 ms in hypothyroid myocytes.
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Effects of T3 on ionic currents.
To determine the mechanisms underlying the rapid effects of thyroid
hormone on ventricular myocyte action potentials, the two predominant
depolarization-induced potassium currents, Ito and
IK, were examined in a series of experiments using
whole cell voltage clamp techniques. The rapidly inactivating
Ito can be blocked by 4-AP, whereas the
4-AP-insensitive or delayed rectifier current (IK)
can be blocked by high concentrations of tetraethylammonium (TEA) (1).
The Ito was recorded in the presence of
CdCl2 using 500-ms depolarizing pulses from a holding
potential of
45 mV as shown in Fig.
2. Figure 2A shows
Ito current traces in a single euthyroid myocyte
before and after the addition of T3 (1 µM) to the
superfusate, and Fig. 2B shows similar traces in a hypothyroid
myocyte. No effect of T3 on Ito in
either euthyroid or hypothyroid myocytes was observed; however,
Ito amplitude was significantly reduced (P < 0.05) in the hypothyroid compared with the euthyroid myocyte. Figure 2C shows a summary of the data of peak
Ito density as a function of test potentials in
response to T3 from an average of eight euthyroid and
hypothyroid myocytes.

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Fig. 2.
Data are means ± SE. Effect of T3 on the transient
outward current (Ito) in ventricular myocytes
isolated from euthyroid and hypothyroid animals. From a holding
potential of 45 mV, the cells were depolarized to progressively
more positive potentials (from 30 to +80 mV) for 500 ms.
Currents were recorded before (upper panel) and after T3 (1 µM) (lower panel) in euthyroid myocytes (A) and in
hypothyroid myocytes (B). Peak current densities of
Ito (pA/pF) are plotted as a function of test pulse
voltage in euthyroid and hypothyroid myocytes with and without
T3 treatment (C). P < 0.05 between
euthyroid vs hypothyroid; n = 8.
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The IK was recorded by depolarizing pulses ranging
from
30 to +80 mV for 500 ms from a holding potential of
45 mV in the presence of CdCl2, 4-AP, and
BaCl2. Figure 3 shows typical
current traces recorded before and after administration of
T3 (0.1 and 1.0 µM) in euthyroid (A) and
hypothyroid (B) ventricular myocytes. The
IK densities in euthyroid and hypothyroid myocytes
are plotted against the test potentials, showing no differences between
the two conditions when measured under control conditions without T3 superfusion. However, in response to 1 µM
T3, significant increases in IK were
observed at test potentials more positive than +20 mV and +10 mV in
euthyroid and hypothyroid myocytes, respectively. At a lower
concentration of T3 (0.1 µM), a significant increase in
IK was observed at test potentials more positive
than +20 mV (P < 0.05) in the hypothyroid myocyte compared
with +70 mV in the euthyroid condition, suggesting a higher sensitivity
or responsiveness to T3 in the hypothyroid myocyte.

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Fig. 3.
Data are means ± SE; n = 5/treatment group. Effect of
T3 on delayed rectifier current (IK) of
euthyroid and hypothyroid myocytes. Cells were bathed in normal Tyrode
solution consisting of CdCl2 (500 µM), 4-AP (3 mM), and
BaCl2 (200 µM). Currents were elicited by progressively
more positive test voltages ranging between 30 and +80 mV for
500 ms from a holding potential of 45 mV. Currents tracings were
recorded before and after superfusion with T3 (1 µM) in
euthyroid (A) and hypothyroid (B) myocytes.
IK measurements taken at the end of 500-ms test
pulses are plotted as a function of test pulse voltages for both
euthyroid and hypothyroid cells under control conditions and after
T3 (0.1, 1.0 µM) superfusion (right panels). *P < 0.05 vs. control IK at same test voltage.
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Figure 4 shows in greater detail the
IK current in a euthyroid myocyte in response to
T3 to illustrate that both the activation and the
inactivation properties of the current were altered by the hormone. A
slower rate of activation was observed at +70 mV in the presence of
T3 with an increase of the time-to-peak
IK of 69 ± 6 ms compared with 44 ± 7 ms without
T3 (n = 6, P < 0.05). Although not shown
in this figure, the inactivation time constants were derived from a
series of experiments using a test step duration of 3 s. Curve-fitting
by monoexponential function to the first 1,500 ms of current traces
showed that T3 (1 µM) increased the time constant of
inactivation (at +70 mV) from 353 ± 28 to 420 ± 31 ms (n = 5; P < 0.05). The amplitude of this exponential component was
unchanged by T3 (420.5 ± 91.9 vs. 474.3 ± 95.0 pA).

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Fig. 4.
Effects of T3 on IK activation and
inactivation characteristics. Raw current traces from a euthyroid
ventricular myocyte were recorded with a depolarizing pulse of +70 mV
for 500 ms. Dotted line shows control pA recording; solid line shows pA
recording after addition of T3 (1 µM).
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To determine the specificity of the T3 effect on
IK, the effects of the biologically inactive
metabolite rT3 were examined. Current density measurements
as a function of test voltages before and after rT3
addition showed no effect on IK in either
hypothyroid or euthyroid myocytes (Fig. 5).
These data support the specificity of the observed effects on myocyte
ion currents to the biologically active hormone T3.

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Fig. 5.
Data are means ± SE; n = 5/treatment group. Effect of reverse
T3 (rT3) on IK of myocytes
from hypothyroid rats. Current traces were recorded using similar
voltage protocols as in Fig. 3, conducted in the absence and presence
of 1 µM rT3 and plotted as a function of test pulse
voltage.
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Dose responsiveness of T3 on IK.
Concentration dependence of T3 on IK
current density in both euthyroid and hypothyroid myocytes is shown in
Fig. 6. The current magnitudes measured at
the end of a 500-ms test pulse of +80 mV were normalized by the
amplitude of IK under control conditions in each
experiment and analyzed as a function of T3 concentration added to the superfusate. The increase of IK by
T3 in hypothyroid myocytes was significantly greater than
in the euthyroid myocyte at 10
7 and
10
8 M concentrations, indicating a
greater sensitivity to T3 in the hypothyroid condition.

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Fig. 6.
Concentration-response relationship of T3-induced increase
of IK in euthyroid and hypothyroid ventricular
myocytes. T3-induced increase in IK
amplitude measured at end of a 500-ms test pulse of +80 mV was
normalized by the amplitude of IK under control
conditions. The increase of IK by T3 in
hypothyroid myocytes was significantly greater than that in euthyroid
myocyte at 10 7 and
10 8 M T3 (*P < 0.05).
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 |
DISCUSSION |
The present study has shown that the APD of ventricular myocytes
isolated from hypothyroid rats and 4-AP-treated myocytes from euthyroid
animals can be shortened by acute exposure to T3, at least
in part by increasing the IK. Superfusion of the
hypothyroid myocyte with T3 shortened the APD by 24%;
however, this did not restore the APD to euthyroid values and can be
attributed to a primary role of the Ito on the APD
in the rat myocyte. The transient outward K+ current was
significantly lower in the hypothyroid myocyte and was not altered by
acute exposure to T3. Our findings are somewhat in contrast
to a report by Sakaguchi et al. (25), who showed that T3
shortened APD in euthyroid guinea pig ventricular myocytes in the
absence of 4-AP treatment. This difference in results may reflect the
longer APD90 in the euthyroid guinea pig compared with the
rat myocyte (647 ± 13 vs. 51 ± 8 ms, respectively), reflecting species differences.
The rapidity of the T3 effect on IK
suggests that the mechanism by which T3 acts does not
involve changes in the expression of specific T3-responsive
cardiac genes because this would require a finite period of time for
transcription, RNA processing, and protein synthesis before the
manifestation of a biological effect (4, 8). Nonnuclear effects of
T3 that are rapid in onset have been previously reported to
change adrenergic receptor responses in the heart, sarcolemmal
Ca2+-ATPase activity, the inward rectifier
IK1 channel, and sodium channels (5, 9, 12, 25, reviewed in Ref. 6). Because we have recently shown that the content of
Kv1.5 mRNA (half-time ~2 h) in ventricles of hypothyroid rats was
increased to euthyroid levels within 1 h of T3 treatment in
vivo (24), the present studies were conducted to record the earliest
electrophysiological responses to T3. Significant effects
on IK in this study were observed within 5 min of
T3 exposure, whereas a significant effect on
IK1 was not reported until 15 min after superfusion
with T3 (25).
In contrast to these rapid T3 effects, the current density
of Ito was significantly reduced in hypothyroid
compared with euthyroid ventricular myocytes, suggesting that the
molecular components of Ito that include the Kv4.2
and Kv4.3 gene products are regulated by thyroid hormone at the
transcriptional level (26). The reduction in density of the
Ito in chronic hypothyroidism, as shown in the present study and by others (27), can partially explain the prolongation of APD and the prolonged Q-T interval observed in electrocardiogram tracings. Contrary to the rapid effects of
T3 on IK , addition of T3
to isolated ventricular myocytes from either euthyroid or hypothyroid
animals had no effect on the ionic characteristics of
Ito, further supporting the observation that the
rapid-onset effects of T3 are distinct from its
transcriptional effects and are selective to specific ion channels.
Potential molecular mechanisms by which T3 may elicit the
observed rapid effects on ion flux may involve direct binding of T3 to either an intracellular or extracellular site on the
IK channel, or alternatively, that T3
triggers intracellular signaling events that regulate the
IK channel gating activity. Dudley and Baumgarten
(9) used patch excision methodology to show that the rapid (within 30 s) effects of T3 on Na+ channel gating required
exposure of the hormone to the extracellular face of the
Na+ channel and that soluble second messengers were
unlikely to be involved. The voltage clamp protocol in the whole cell
configuration used in the present study is unable to distinguish among
these possibilities.
The mechanism for the increased sensitivity of IK
to T3 in the hypothyroid compared with the euthyroid
myocyte is not known. It is possible that expression of functionally
different isoforms of IK channel subunits may
underlie the changes in the sensitivity to T3 or
alternatively, that the intracellular signaling pathways may be
different between the two conditions. Recently, several studies have
shown that protein kinases are involved in regulating specific
potassium channels (2, 13, 22). Published data have also indicated that
T3 activates protein kinase C and cAMP-dependent protein
kinase signaling pathways in other cell types (20) and modulates
sarcoplasmic reticulum calcium transients in cardiac cells (reviewed in
Refs. 6, 7). These results have been used to explain the rapid
inotropic effect of T3 on cardiac myocytes (28) and on
enhanced cardiac contractility in vivo using an isolated perfused heart
preparation (18). Our previously published data have shown the presence
of high-affinity T3-binding sites on the plasma membrane of
vascular smooth muscle cells that may be necessary for the rapid
vasodilatory effects of T3 (23).
In summary, our data show that T3 shortens the APD in
hypothyroid rats due at least in part to the increase of the delayed rectifier current IK. The Ito
appears to be regulated by thyroid hormone at the transcriptional
level, whereas the IK is regulated by a nongenomic
mechanism of action. These results have important implications in the
treatment of ventricular arrhythmias in patients with varying degrees
of overt and subclinical hypothyroidism.
 |
ACKNOWLEDGEMENTS |
This study was supported by funds from National Heart, Lung, and
Blood Institute R01 HL-58849 (I. Klein) and HL-03775 (K. Ojamaa).
 |
FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: K. Ojamaa,
Division of Endocrinology, Dept. of Medicine, North Shore Univ.
Hospital, 300 Community Drive, Manhasset, NY 11030 (E-mail:
kojamaa{at}nshs.edu).
Received 13 May 1999; accepted in final form 27 September 1999.
 |
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