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-adrenergic stimulation on ionic
currents of cultured adult guinea pig cardiomyocytes
1 Research Center and Department of Medicine, Montreal Heart Institute, Montreal H1T 1C8, and University of Montreal, Montreal H3C 3J7; and 2 Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Short-term stimulation of 
-receptors
is known to affect cardiac ion channels; however, the impact of
longer-term stimulation on intrinsic channel function is poorly
understood. To evaluate this, cultured guinea pig ventricular myocytes
were exposed to isoproterenol (10 nM), vehicle, or isoproterenol plus
propranolol (1 µM) for 48 h. Sustained exposure to isoproterenol
decreased the density of the inward rectifier
(IK1), slow delayed rectifier (IKs), and L-type Ca2+
(ICa L) currents, effects that were fully
prevented by propranolol. Changes in K+ currents were
prevented by the 1-selective antagonist CGP-20712A, unaffected by the 2-antagonist ICI-118,551, and mimicked
by the membrane-permeable cAMP analog 8-bromo-cAMP. Isoproterenol did not alter the current-voltage relationship of the K+
currents but increased the density of T-type Ca2+ current
(ICa T) and thereby increased the proportion of the total Ca2+ current at more negative potentials. We
conclude that sustained exposure to isoproterenol reduces
IK1, IKs, and
ICa L density and increases the density of
ICa T. The direct ionic current remodeling
effects of sustained -adrenoceptor stimulation resemble changes
reported with heart failure and may be important in arrhythmogenic ionic remodeling.
ion-channel regulation; cardiac arrhythmias; calcium channels; potassium channels; sympathetic nervous system
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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VENTRICULAR TACHYARRHYTHMIAS are a common cause of mortality among patients with congestive heart failure (4, 36, 38). Repolarization abnormalities are prominent in patients and experimental animals with heart failure and are believed to be important in ventricular arrhythmogenesis (31). Several abnormalities in ionic currents have been noted in cardiomyocytes of subjects with severe cardiac dysfunction, and these abnormalities are thought to contribute to arrhythmogenesis and the risk of sudden death in heart failure (26, 38).
The adrenergic nervous system clearly contributes to determining the
prognosis in patients with heart failure. Plasma norepinephrine concentration is a highly significant determinant of mortality (5) and -adrenoceptor antagonists reduce mortality,
including sudden arrhythmic death, in patients with heart failure
(30). Ion channels are potential signal transduction
mediators between physiological stimuli and the hypertrophic response,
and -receptor activation contributes to the development of
myocardial hypertrophy and failure (25). The
mortality-promoting role of -adrenergic activation in patients with
heart failure has been related to its contribution to hypertrophy, as
well as to immediate electrophysiological changes via cAMP-dependent
regulation of cardiac ion-channel function. The possibility that
sustained exposure to adrenergic agonists may regulate ion channel
function has received less attention. This study was designed to
evaluate the effects of 48 h of exposure to isoproterenol on
K+ and Ca2+ currents of adult guinea pig
ventricular myocytes, along with adrenergic receptor subtype(s) and
signal transduction system(s) involved.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Myocyte isolation.
Guinea pigs weighing 350-450 g were euthanized by cervical
dislocation. The hearts were quickly excised and mounted on a
Langendorff apparatus. Retrograde aortic perfusion was performed with
oxygenated (100% O2, pH adjusted to 7.35 with NaOH) Tyrode
solution (for composition, see Solutions) at 37°C. When
clear of blood, the perfusate was changed to a nominally
Ca2+-free Tyrode solution until contraction ceased
(generally ~2 min). Perfusion was continued with the same solution
containing 140 U/ml collagenase (type 2, Worthington Biochemical) and
1% bovine serum albumin (Sigma) until the ventricular tissue was
softened (~20 min). Small pieces of right ventricular free wall
tissue were removed with a forceps and mechanically dissociated by
trituration. The isolated cells were initially kept in a storage
solution containing (in mM) 20 KCl, 10 KH2PO4,
25 glucose, 40 mannitol, 70 L-glutamic acid, 10 -hydroxybutyric acid, 20 taurine, and 10 EGTA, along with 1%
albumin (pH adjusted to 7.35 with KOH). Cells were concentrated by
centrifugation at 250 rpm, and the pellet was removed for culture. All
procedures were performed with aseptic technique.
Cell culture and treatment.
Nunclon Delta petri dishes (35 mm, Nunc) were used. Medium-199
(GIBCO-BRL, Life Technologies, containing Earle's salts,
L-glutamine, and 2,200 mg/l NaHCO3) with 10%
fetal bovine serum was supplemented with Na-penicillin G (50 U/ml) and
streptomycin sulfate (1 µg/ml) for the cell culture. Cells were
plated at low density (~104 cells/cm2) onto
square glass coverslips coated with laminin (20 µg/ml) and maintained
in the medium at 37°C in a humidified, 5% CO2-enriched atmosphere. After 4 h, any dead or unattached myocytes were washed off to leave a homogeneous layer of rod-shaped cells attached to the
coverslips. Fresh medium was then added containing 10 nM isoproterenol
(Iso medium), 10 nM isoproterenol plus 1 µM propranolol (Iso + Prop medium), or vehicle alone (control medium). The vehicle contained
ascorbic acid (100 µM in distilled water) to prevent isoproterenol
oxidation. In some experiments, subtype-selective -adrenoceptor
antagonists (3, 35, 41) were added to
isoproterenol-containing culture medium: 300 nM CGP-20712A
methanesulfonate to inhibit 1 adrenoceptors or 50 nM
ICI-118,551 hydrochloride (ICI) to inhibit 2 adrenoceptors.
Solutions. Tyrode solution contained (in mM) 136 NaCl, 2 CaCl2, 5.4 KCl, 0.8 MgCl2, 0.33 NaH2PO4, and 10 dextrose, HEPES; pH 7.4 (NaOH). This solution was used for cell isolation and as the extracellular solution for action potential recording and was modified as indicated below when specific currents were studied. The pipette solution for K+ current studies contained (in mM) 0.1 GTP, 110 K-aspartate, 20 KCl, 1.0 MgCl2, 5 Mg2-ATP, 10 HEPES, 5 Na2-phosphocreatine, and 10 EGTA; pH 7.2 (KOH). For action potential recording, the pipette solution was modified by reducing EGTA concentration to 50 µM (to allow for physiological intracellular Ca2+ transients) and setting the pH at 7.2. When K+ currents were recorded, Cd2+ (200 µM) was added to the Tyrode solution to inhibit L-type Ca2+ current (ICa L). In studies of delayed rectifier K+ current (IK) dofetilide (1 µM) was used to separate the drug-sensitive rapid component (IKr) from the drug-resistant slower component (IKs). The extracellular solution for Ca2+ current (ICa) studies contained (in mM) 136 TEA-Cl, 5.4 CsCl, 1.0 MgCl2, 2.0 CaCl2, 0.33 NaH2PO4, 10 dextrose, and 10 HEPES; pH 7.4 (CsOH). The pipette solution for ICa recording contained (in mM) 135 CsF, 5.0 NaCl, 5.0 HEPES, 10 EGTA, and 5 Mg2-ATP (pH adjusted to 7.2 with CsOH). CsF was used to evaluate ICa with full cAMP activation. Additional experiments were conducted with CsCl instead of CsF in the pipette to evaluate effects on unstimulated ICa.
Data acquisition.
After 2 days in culture, medium was washed out with Tyrode solution,
the coverslip was placed in an inverted microscope, and the cells were
perfused with Tyrode solution containing 1 µM propranolol to block
any potential effects of residual isoproterenol bound to the membrane
(except in experiments assessing the response to acute isoproterenol
administration, for which propranolol was omitted). A limited number of
selected experiments were also performed in freshly isolated myocytes,
as specified in RESULTS. Experiments were performed at
36 ± 1°C with the use of a temperature control system (model
TC-202, Medical Systems). The whole cell patch-clamp technique was used
to record currents in voltage-clamp mode and action potentials in
current-clamp mode. Borosilicate glass electrodes (1.0 mm outer
diameter) were filled with a pipette solution and connected to a
patch-clamp amplifier (Axopatch 200A, Axon Instruments). Electrodes
with tip resistances of 1-3 M
were used to record whole cell
currents, and tip resistances were 3-5 M when action potentials
were recorded. Action potentials were elicited by 2 ms, twice-threshold
pulses, and were recorded at 1 Hz. Action potential duration (APD) was
measured to 20 (APD20), 50 (APD50), and 90%
(APD90) of full repolarization. Only cells in which action potentials were stable for at least 10 min were used for analysis. Action potential measurements were begun 5 min after cell rupture. Voltage command pulses were generated by a 12-bit digital-to-analog converter controlled by pCLAMP6 software (Axon). Recordings were low-pass filtered at half the sampling frequency. Data were sampled at
rates varying from 2 to 10 kHz (with sampling at 10 kHz used for the
action potential and the rapidly activating currents such as
ICa and sampling at 2 kHz used for slower
currents like IK) and then stored on the hard
disk of an IBM-compatible computer.
), gentle suction was applied to rupture the membrane for
whole cell recording. Cell capacitance was measured as the integral of
the current carried during the capacitive surge upon 5-mV
hyperpolarizations from 
60 mV divided by the voltage drop.
Capacitance was larger in isoproterenol-treated myocytes (87.0 ± 2.6 pF, n = 111 vs. 76.6 ± 2.4 pF for vehicle alone,
n = 108; P = 0.004). To control for differences
in cell size, all mean current data are expressed as current densities (i.e., normalized to capacitance). The deactivating current after repolarization following an activating pulse
(IK tail) and ICa
current amplitudes were measured from the peak current amplitude to the
steady-state values at the end of the voltage step.
IK step was measured from the initial current
value at the onset of each depolarizing step to the value at the end of
the pulse. IK1 was measured in two ways: both
from the holding current to the peak value during a test pulse (peak
IK1) and to the steady-state level at the end of
the pulse (steady-state IK1). Series resistance
averaged 7.7 ± 0.2 and 1.9 ± 0.1 M before and after
compensation, respectively. Cells with significant leak currents were
rejected, and leakage compensation was not applied.
Statistical analysis. Group data are expressed as means ± SE. Nonlinear curve fitting was performed with the Clampfit routine in pCLAMP (Chebyshev algorithm). Statistical comparisons among groups were performed with analysis of variance (ANOVA). A t-test with Bonferroni's correction was used to evaluate differences between individual mean values. A two-tailed P < 0.05 was taken to indicate statistical significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Changes in cellular phenotype in culture.
To evaluate the effects of 48 h of isoproterenol exposure on ion
channel properties, the cell had to be maintained in primary culture
for this period. Cell culture resulted in a mild decrease in cell size,
from 174 ± 4 × 24 ± 1 µm in 30 fresh cells, to
156 ± 4 (P < 0.01) × 23 ± 1 µm in
30 cultured cells. Isoproterenol slightly, but significantly, increased
dimensions in cultured cells (n = 30) to 178 ± 3 (P < 0.001 vs. control cultured cells, P = not signifcant vs. fresh cells) × 26 ± 1 (P < 0.01 vs. control cultured cells,
P = not significant vs. fresh cells) µm. Action potentials from fresh cells showed a positive plateau and very rapid
phase 3 repolarization (Fig. 1). Cultured
cells maintained relatively normal action potentials, but phase 3 repolarization became somewhat slower and the resting potential was
slightly depolarized. IK1 density was reduced by
cell culture (Fig. 2A), consistent with the reduced resting potential and phase 3 slope. ICa density was also decreased (Fig.
2C). On the other hand, IK density
was unaltered (Fig. 2C).
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Effects of isoproterenol on action potentials and
K+ currents of cultured cells.
Typical action potentials from cells cultured in Iso medium had a
shortened plateau and triangular shape (Fig. 1C), whereas cells in Iso + Prop medium had action potentials (Fig.
1D) similar to cells (Fig. 1B) cultured in
control medium. Mean action potential characteristics are provided in
Table 1 and indicate that isoproterenol significantly decreased resting potential and early phase APD but that
with phase 3 repolarization slowing, terminal repolarization time
remained unaffected.
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) but significantly
accelerated the intermediate-phase time constant at all voltages. The
deactivation of IKtail currents was
biexponential, with similar among groups [e.g., following a pulse
to +50 mV, IKtail at 30 mV had a fast (fast) averaging 65 ± 3 ms for control (n
= 78) and 65 ± 3 ms (n = 69) for Iso medium, and
slow (slow) averaged 349 ± 11 and 367 ± 16 ms, respectively].
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-adrenergic
responsiveness and examined the acute response of
IK in cultured cells to isoproterenol. The left
panels in Fig. 5 show
IK recorded in the absence of isoproterenol in
cells that had been cultured in control medium (top), Iso
medium (middle), and Iso + Prop medium
(bottom). The right panels show currents after acute
exposure to 1 µM isoproterenol in the same cells shown at the left.
The mean data in the right panels are percent increases at +60 mV in
13, 16, and 10 cells from each group. Isoproterenol increased
IK to a comparable extent in all three groups
(P = not significant for intergroup differences), arguing
against changes in -adrenergic regulation of
IK in cells cultured in Iso medium. We also
evaluated the effect of acute isoproterenol exposure (100 nM) on
IK1 in fresh cells. Isoproterenol decreased
IK1 density at 100 mV in six fresh cells from
39.5 ± 1.7 pA/pF to 33.1 ± 1.8 pA/pF (P < 0.02), a response qualitatively similar to that produced by 48-h
isoprotererol exposure.
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-adrenergic receptor blockers: 300 nM
CGP-20712A (CGP) and 50 nM ICI (1- and
2-selective, respectively) (3, 35, 41).
Figure 6 shows original recordings and
mean data for each group of cells. CGP, the 1-receptor
antagonist, fully prevented isoproterenol-induced downregulation of
IK, whereas ICI, the
2-antagonist, had no effect: IK
was just as small in the isoproterenol-ICI-cultured cells as in the
cells cultured in Iso medium alone. These results indicate that the
isoproterenol response is mediated solely by
1-adrenoreceptors.
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-Adrenergic agonists are capable of modifying ionic currents via
either indirect mechanisms involving cAMP or by direct
membrane-delimited signaling (8). To evaluate the
potential role of cAMP in isoproterenol-induced current downregulation,
additional parallel studies were performed with cells cultured in
control medium, Iso medium, and membrane-permeable 8-bromo-cAMP
(8-Br-cAMP, 50 µM). The density of IK (Fig.
7A) and IK1 (Fig. 7B) was reduced
significantly by 8-Br-cAMP, with changes quantitatively very similar to
those caused by isoproterenol. Thus the downregulation of
K+ channels by sustained -adrenergic stimulation is
likely due to consequent increases in intracellular cAMP
concentrations, rather than a direct, membrane-delimited pathway.
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Effects of isoproterenol on calcium current.
Figure 8 shows typical
ICa recordings with CsF-containing pipettes from
cells cultured in control medium (A), Iso medium
(B), and Iso + Prop medium (C).
Current rundown was excluded by using a standard depolarizing pulse to
+10 mV after each protocol and measuring peak
ICa. If ICa decreased by
over 5%, the experiment was terminated and the data were discarded.
Compared with control medium, ICa density was
significantly reduced in Iso medium at voltages positive to 20 mV
(Fig. 8D). Isoproterenol added a "shoulder" to the
normalized current-voltage relation negative to 10 mV (Fig.
8E), consistent with increased T-type Ca2+
current (ICa T), which could explain the lack
of isoproterenol-induced ICa decrease at test
potentials negative to 10 mV (Fig. 8D). Isoproterenol did
not alter the inactivation time course of ICa (Fig. 8F). Additional experiments were performed with
CsCl-containing pipettes to measure unstimulated
ICa. Iso-medium cells had a peak ICa at +10 mV averaging 6.7 ± 0.9 pA/pF
(n = 11) compared with 13.5 ± 1.1 pA/pF (n
= 14, P < 0.001) for control medium. As shown in Fig.
7C, isoproterenol downregulation of
ICa was mimicked by 8-Br-cAMP, indicating that
it is mediated by increased intracellular cAMP.
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90 and 50 mV in each cell, with
ICa T given by digital subtraction of
recordings at a holding potential of 50 mV from those at a holding
potential of 90 mV. Figure
9A shows resulting recordings of ICa T in myocytes cultured in control medium
(top) and in Iso medium (bottom). The form of the
ICa T density voltage relation (Fig.
9B) was similar for both sets of cells, but Iso medium
significantly increased ICa T over the entire
voltage range.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We have shown that 48 h of isoproterenol exposure
downregulates IK1, IKs,
and ICa L in guinea pig ventricular myocytes and increases the density of ICa T. The actions
of isoproterenol on IK were mediated by
1-adrenergic receptors and were mimicked by a
membrane-permeable form of cAMP, indicating the involvement of cAMP as
a second messenger.
Relationship to previously observed effects of -adrenergic
stimulation on cardiac ion channels.
Sympathetic stimulation of the heart is well known to be associated
with the initiation of cardiac arrhythmias with -adrenoceptor activation known to play a particularly important role
(42). Acute -adrenergic stimulation enhances a variety
of cardiac ionic currents, including IKs
(34), ICa L (32), and
cAMP-dependent Cl
current (10), and reduces
IK1 (14). Much less is known about the effects on cardiac ion channels of longer term exposure to -adrenergic agonists. Sympathetic innervation increases
ICa L density of cultured neonatal rat
ventricular myocytes (28), an effect likely mediated by
-adrenoceptors via increased intracellular cAMP content
(18). Sympathetic innervation of newborn rat hearts increases the transient outward current (Ito)
and IK1 density (17). The only
study we could identify of -adrenergic effects on adult
cardomyocytes showed that norepinephrine and isoproterenol increase
Ito density in cultured adult canine ventricular
myocytes without normalizing slowed inactivation kinetics
(29). Meszaros et al. evaluated the effects of sustained
isoproterenol administration in vivo to rats, observing decreases in
Ito with no changes in voltage dependence of
kinetics (22) and increased ICa but
no changes in current density or kinetics (23). These
results show that in vivo isoproterenol administration produces ionic
remodeling and are consistent with results in other models of cardiac
hypertrophy and failure (38); however, because of changes
in cardiac work, hemodynamics, and oxygen consumption in the in vivo
system, they do not permit differentiation between effects secondary to
these factors and direct actions of -adrenergic stimulation.
Comparison between isoproterenol-induced changes in the present study and previous observations of ionic remodeling in disease states. A variety of changes in cardiac ionic currents have been observed in patients or experimental models with cardiac disease, particularly congestive heart failure (26, 38). Decreased IK1 has been observed in both patients (2) and experimental animals (12) with severe cardiac dysfunction. Changes in ICa L are more variable, with some studies reporting no change and others reporting a decrease. Of 19 studies of ICa L and/or dihydropyridine receptors in severe hypertrophy and failure presented by a recent detailed review (38), 6 report no change and 13 describe a decrease. Recent studies have also pointed to a decrease in IKs in cardiac hypertrophy and failure (13, 15, 16, 40). Cardiac hypertrophy has been shown to elicit the appearance of ICa T in feline ventricular myocytes (27). Many of the effects of 48-h isoproterenol exposure in the present study, including decreased IK1, IKs, and ICa L, as well as increased ICa T, resemble changes associated with congestive heart failure. Although many other signaling systems likely play a role in ventricular remodeling, including that of ion channels in heart failure, the possibility should be considered that at least some of the ionic current abnormalities could be due to downregulation by the associated chronically elevated plasma catecholamine concentrations (5).
Novel aspects and potential significance.
We found that 48-h isoproterenol exposure had significant effects on a
variety of ionic currents in guinea pig ventricular myocytes. These
effects were opposite to the actions of acute isoproterenol in the case
of IK and ICa and similar
in the case of IK1. The effects of 48-h
isoproterenol exposure were not contaminated by agonist occupancy of
-adrenergic receptors, because the medium was thoroughly washed out
and propranolol (1 µM) added to the extracellular solution when
measurements were made. In considering the role of -adrenergic
stimulation and the well-recognized protective effect of
-adrenoceptor blockers in patients with heart disease, acute effects
on ionic currents and electrophysiology are generally invoked. However,
our study indicates an additional possibility that needs to be
considered: the potential regulatory effect of the chronic level of
-adrenoceptor occupancy on the density of cardiac ion currents.
-adrenergic stimulation may therefore play a significant role in the
electrophysiological abnormalities caused by heart failure. Consistent
with this notion, dogs with congestive heart failure and spontaneous
ventricular tachyarrhythmias have higher plasma norepinephrine
concentrations (~6.6 nM) compared with dogs with similar cardiac
dysfunction and no ventricular tachyarrhythmias (3.6 nM)
(33). Our findings may also be relevant to the effects of
drug therapy on mortality in patients with heart failure,
providing potential mechanisms involved in the ability of
-adrenoceptor antagonists to prevent sudden death (21)
and in the mortality-promoting properties of agents that stimulate
-receptors or increase cardiac cAMP concentrations
(19).
Potential limitations.
The properties of cultured heart cells are never identical to those of
acutely isolated myocytes, a limitation common to all studies using
cultured cardiac cell models (24). On the other hand,
there is no other approach that would permit the study of the effects
of sustained exposure to -adrenergic stimulation without the
important changes in hemodynamics, concentrations of other
neurohormones, heart rate, etc., inevitable for in vivo models.
Effects unrelated to -adrenoceptor activation and due to nonspecific
drug actions or the effect of the diluents need to be considered;
however, the use of a control group of cells exposed to diluent alone
and cells exposed to isoproterenol and a -blocker for each set of
experiments should have excluded such possibilities.
-adrenergic stimulation
reduces the density of a variety of cardiac currents, including IK1, IKs, and
ICa L, and upregulates
ICa T, by 1-receptor, cAMP-mediated mechanisms. These findings suggest that, in addition to
altering ion channel function acutely, -adrenergic agonists can have
important longer term effects on ionic current density. These actions
may be relevant to ionic remodeling in situations (like heart failure)
with sustained increases in plasma catecholamine concentrations.
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ACKNOWLEDGEMENTS |
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The authors thank Chantal St-Cyr for technical help, as well as Luce Bégin and Diane Campeau for secretarial help.
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FOOTNOTES |
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The work was supported by operating grants from the Medical Research Council of Canada and the Heart and Stroke Foundation of Quebec. Z. Wang is a Research Scholar of the Heart and Stroke Foundation of Canada.
Address for reprint requests and other correspondence: S. Nattel, Research Center, Montreal Heart Institute, 5000 Belanger St., East, Montreal, Quebec H1T 1C8, Canada (E-mail: nattel{at}icm.umontreal.ca).
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. Section 1734 solely to indicate this fact.
10.1152/ajpheart.01138.2000
Received 13 December 2000; accepted in final form 2 November 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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