© 1999 American Heart Association, Inc.
Cellular Biology |
Aldosterone Upregulates Ca2+ Current in Adult Rat Cardiomyocytes
From the Laboratoire de Physiopathologie Cardiovasculaire, INSERM U-390, IFR3, Montpellier, France.
Correspondence to Jean-Pierre Bénitah, INSERM U-390, CHU Arnaud de Villeneuve, 34295 Montpellier, Cedex 05, France. E-mail benitah{at}welchlink.welch.jhu.edu
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Abstract |
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Abstract—Aldosterone is associated with the pathogenesis and progression of left ventricular hypertrophy and heart failure, independent of its relation with arterial blood pressure. However, little information exists about the possible influence of this mineralocorticoisteroid on cardiomyocyte electrical activity. The present study was designed to determine the role of aldosterone on whole-cell Ca2+ current (ICa) in isolated adult rat ventricular myocytes using the patch-clamp technique. We found that incubation of cells with 1 µmol/L aldosterone for 24 hours increases the density of ICa significantly. This "long-term" aldosterone treatment had no significant effects on the kinetics and voltage dependence of ICa inactivation. Moreover, no demonstrable influence of aldosterone on ICa could be detected during short-term exposure (up to 6 hours), under our experimental conditions. The classical aldosterone intracellular receptor antagonist spironolactone (250-fold excess) was able to blunt the aldosterone-induced increase in ICa density. These effects were also observed with lower concentrations of aldosterone (10 and 100 nmol/L). Moreover, inhibitors of transcription (actinomycin D, 5 µg/mL) and protein synthesis (cycloheximide, 20 µg/mL) prevented the aldosterone-dependent increase in ICa. Therefore, the long latency ICa stimulation effect of aldosterone might result from an increased channel expression. We suggest that this genomic action contributes to the increased ICa observed during cardiac remodeling.
Key Words: aldosterone • Ca2+current • heart
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Introduction |
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To fully understand the syndrome of heart failure, the interrelationship of underlying causes and regulatory systems must be considered. The activation of several neurohormonal systems has been shown to be an important mechanism contributing to the development of congestive heart failure.1 In this regard, clinical and experimental data have suggested that the renin-angiotensin-aldosterone system might be one of the primary causes, rather than only a secondary cofactor, in the pathogenesis of left ventricular hypertrophy and heart failure.2 Aldosterone is an important determinant of human left ventricular hypertrophy, independent of blood pressure alterations.3 Moreover, exogenous aldosterone has been shown to be arrhythmogenic in dogs after coronary ligation.4 The ability of aldosterone to stimulate myocardial fibrosis is likely to be important.5 6 However, several cellular electrophysiological changes have been observed in myocardial hypertrophy and heart failure that predispose to cardiac arrhythmias.7 A direct effect of aldosterone on myocyte membrane currents has not yet been investigated.
In addition to the classical actions of aldosterone in regulating the membrane ionic movements not only in kidney but also in nonepithelial cells,8 several studies argue in favor of an effect of this hormone on cardiovascular functions through direct actions on myocytes. In fact, aldosterone can bind with high affinity to rat heart.9 An agonist-specific mineralocorticoid receptor has been evidenced in cardiomyocytes.10 11 In addition to the classical adrenal biosynthetic pathway, production of aldosterone has been demonstrated within cardiac tissue.12 Moreover, a recent study provides evidence that chronic myocardial infarction is associated with an increase in myocardial aldosterone production.13 This raises further questions about how aldosterone might affect the heart directly.
Little information exists about the possible influence of
aldosterone on myocyte ionic homeostasis. De Mello and
Motta14 reported a depolarizing action of
aldosterone on atria muscle and pacemaker fibers of rabbit.
More recently, it has been established that aldosterone can
regulate membrane Na+ transport in cardiac cells.
Experimental data demonstrate that aldosterone directly
stimulates Na+, K+-ATPase 
1
subunit mRNA synthesis and protein accumulation in cardiac
cells.15 Moreover, it has been shown in vitro that the
exposure of cardiac myocytes to aldosterone rapidly
activates the Na+-K+-2Cl-
cotransporter to enhance Na+ influx and stimulate the
Na+-K+ pump.16 By affecting the
activity of the ionic transporter, aldosterone modulates
acid-base balance in cardiac cells.17 These data suggest
that aldosterone plays a role in the regulation of cardiac
function.
Evidence to support this has accumulated since the late 1950s, suggesting that corticosteroids exert a positive inotropic effect on the heart somewhat similar to digitalis. For instance, aldosterone has been shown to exert a cardiotonic effect in a rat heart-lung preparation18 and in cat papillary muscle.19 Despite this, some investigators have failed to obtain inotropic effects of corticosteroids in isolated heart preparations.20 These data suggest that aldosterone might have an effect on Ca2+ influx. Hence, it has been proposed that the Na+/Ca+ exchanger could be a target for steroids in heart.21 Moreover, it has been shown that aldosterone increased free [Ca2+]i in vascular smooth muscle and endothelial cells.22 23
Considering the above data, the aim of the present study was to investigate whether aldosterone has an effect on Ca2+ current (ICa) of cardiac myocytes. We report that treatment of rat ventricular myocytes with aldosterone for 24 hours increased ICa density, whereas no rapid aldosterone effect (<6 hours) could be detected. Moreover, this "long-term" effect of aldosterone, which did not modify voltage dependence and kinetics of the current, was prevented by a mineralocorticoid receptor antagonist and by inhibitors of transcription and protein synthesis.
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Materials and Methods |
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This investigation conforms to the Guide for the Care and Use of Laboratory Animals (NIH publication No. 85-23, revised 1996). Isolated cardiac ventricular myocytes from adult male Wistar rats (250 to 350 g; Elevage JANVIER, France) were prepared using a collagenase (Worthington type II) perfusion method as previously described.24 This procedure yielded quiescent rod-shaped myocytes, viable for up to 2 days when incubated at 37°C in Tyrode’s solution containing (in mmol/L) NaCl 130, NaH2PO4 0.4, NaHCO3 5.8, MgCl2 0.5, CaCl2 1, KCl 5.4, glucose 22, HEPES 25, and insulin 10-3 supplemented with 1 mg/mL BSA, 100 IU/mL penicillin and 0.1 µg/mL streptomycin (titrated to pH 7.4 with NaOH).
Electrophysiological Procedure
The whole-cell patch-clamp method25 was used
(Axopatch 1D amplifier, Axon Instruments). Micropipettes had tip
resistances ranging from 1 to 1.5 M
. The capacitive current was
determined as previously described.26 Electronic
compensation (40% to 60%) was then used to reduce the series
resistance. Membrane currents sampled at 10 kHz, were filtered at 2
kHz, and digitized using pClamp6 software (Axon Instruments).
ICa was measured at room temperature (23°C to
25°C) while cells were bathed in the external solution containing
(in mmol/L) NaCl 140, MgCl2 1.1, CaCl2
1.8, CsCl 4, glucose 10, and HEPES 10 (pH adjusted to 7.4 with LiOH).
The internal pipette solution contained (in mmol/L) CsCl 135,
MgCl2 4, EGTA 5, glucose 10, HEPES 10, Na2ATP
5, and Na2 creatine phosphate 3 (pH adjusted to 7.2 with
LiOH). The currents were elicited at 0.1-Hz frequency from a holding
potential of -80 mV. Before each pulse, a rapid voltage ramp (80 mV/s)
to -40 mV was used to inactivate Na+ current
and T-type Ca2+ channels.
Drugs
D-Aldosterone and spironolactone (Sigma)
were first dissolved in 100% EtOH. Then, stock solutions of 0.1
mmol/L for aldosterone and 25 mmol/L for
spironolactone were prepared in H2O. This gave 0.1% EtOH
in the final solutions, which had no effect on the currents measured
(data not shown). Actinomycin D mannitol (AmD; Sigma) and cycloheximide
(CHX, Sigma) were both directly dissolved in H2O.
Statistics
Data are expressed as mean±SD in the text and as mean±SEM in
the graphs. Statistical changes induced by aldosterone or
other treatments were analyzed by Student t test for
unpaired samples.
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Results |
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ICa Increase in Rat Ventricular Cells After 24 Hours of Aldosterone Treatment
The basic hormonal effect of aldosterone, ie, stimulation of Na+ transport, involves a time-dependent process, in which the mineralocorticoid binds to the intracellular receptor and stimulates protein synthesis.27 In the present study, we have investigated the effects of a long-term exposure of myocytes to aldosterone on the functional expression of high voltage–activated ICa. Isolated adult rat ventricular myocytes were incubated for at least 24 hours at 37°C in Tyrode’s solution supplemented with antibiotics (see Materials and Methods), to which 1 µmol/L D-aldosterone was added. Control recordings were made from cells maintained in Tyrode’s storage solution, in the absence of aldosterone.
Figure 1A
, left, shows typical examples
of the voltage- and time-dependent inward Ca2+ currents
recorded in myocytes incubated for 24 hours in the absence
(control, left panel) or presence of aldosterone (right
panel). Membrane currents were elicited by 300-ms steps from -40 to
the -50 to +30-mV range in increments of 10 mV applied at 0.1-Hz
frequency. In the two groups, the currents peaked within about 10 ms
after the onset of depolarization and gradually declined, with maximal
peak current at a potential of -10 mV. Exposure to
aldosterone induced an increase in the magnitude of peak
currents compared with control.
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Because variations in cell size might account for this difference,
ICa amplitudes, measured as the difference
between the peak current and the steady-state current at the end of the
voltage steps, were normalized to the membrane capacitance
(Cm). Before electronic compensation for Cm and
series resistance, the mean Cm (in pF, ±SD) was
172.9±65.8 for control cells (n=13) and 170.5±50.4 (n=10) for 24-hour
aldosterone-treated cells. There was no significant
statistical difference between the two groups (P<0.5). On
average, the current density-voltage (I-V) relationships for
whole-cell ICa in control and
aldosterone-treated myocytes show a similar
characteristic "bell shape" and voltage dependence (Figure 1A
, right). There was a significant increase (P<0.05) in
current densities in the -30 to +30-mV voltage range after
aldosterone treatment. The peak ICa
density at -10 mV was larger in aldosterone-treated
cells (-20.0±3.7 pA/pF, n=10) than in control cells (-13.2±1.6
pA/pF, n=13).
ICa Voltage Dependence and Kinetics Are
Unaltered by Long-Term Exposure to Aldosterone
To further compare the voltage-dependent properties of
ICa in the presence or absence of
aldosterone treatment, the steady-state inactivation was
determined in 8 cells of each group. A conventional 2-pulse protocol
was used to establish steady-state inactivation relationships.
Prepulses (in the -50- to +60- mV range, from -40 mV) of 1- second
duration were used to inactivate the current. The degree of
inactivation was determined by applying a second pulse (test pulse) to
0 mV. The test current amplitude (I) normalized to the
maximum test current (Imax) was plotted against
the prepulse potential in Figure 1B.
There were only minor differences in steady-state inactivation between
cells incubated for 24 hours without (
, n=8) or with 10
µmol/L aldosterone (•, n=8). Individual experimental
points were fitted to the Boltzmann equation:
I/Imax=1/(1+exp[(V-V50/k]),
where I/Imax is the normalized
test-pulse current amplitude, V is the prepulse potential,
V50 is the prepulse potential of half-maximal
inactivation, and k is the slope factor. Because of relief
of inactivation for voltages, positive to 0 mV, only data negative to 0
mV were fit. Resulting V50 and k
values were (in mV, ±SD) -33.4±2.2 and 4.9±0.5 mV in the presence
of aldosterone and -32.9±2.7 and 4.6±0.3 mV in the
absence of aldosterone, respectively. The lack of effect of
aldosterone on Ca2+ channel availability was
also observed with Na+-free solution (choline chloride
substituting NaCl in the external solution) and longer prepulses (5
seconds). Under this experimental condition, after
aldosterone treatment, the peak ICa
density at 0 mV was significantly larger (-17.9±2.0 pA/pF, n=6) than
in control cells (-11.5±3.9 pA/pF, n=5). Moreover, the availability
of the Ca2+ channel was unaltered. The
V50 and k values were (in mV, ±SD)
-36.6±2.2 and 4.9±0.9 mV in the presence of aldosterone
and -34.5±2.3 mV and 3.8±1.5 mV in control, respectively.
A change in the kinetics of ICa could result in
an alteration of Ca2+ influx. Visual inspection of the
current traces, as those presented in Figure 1A, does not
suggest that the time course of activation or inactivation of
ICa was modified by aldosterone
treatment. To further quantify this observation, the kinetics of
ICa for each cell were analyzed.
The activation kinetic of ICa was measured for
every depolarizing step as the time from the onset of the voltage step
to the peak of current. Time-to-peak values are plotted against voltage
in Figure 1C. Over the whole voltage
range, the time-to-peak values were not significantly different between
myocytes maintained for 24 hours in the presence or absence of
aldosterone.
The time course of inactivation of ICa was
determined by analysis of the decay phase of current traces in
response to voltage steps. Best fits were obtained with an equation
including a sum of two exponentials plus a constant expressed as
Afastexp(-t/
fast)+Aslowexp(-t/slow)+A0,
where and A are the time constant and the initial
amplitude of the two components subscripted fast and slow,
respectively, and A0 is the amplitude of the
time-independent component. The pooled mean values for the fast
(fast) and slow (slow) time constants of
inactivation as a function of voltage are shown in Figure 1D. Both the slow and fast components
of ICa inactivation at all voltages studied were
similar in the presence or absence of aldosterone. At -10
mV (in ms±SD), fast was 12.8±4.1 versus 11.8±3.4 and
slow was 72.2±16.1 versus 68.0±8.5, in 13 control
myocytes versus 10 aldosterone-treated myocytes,
respectively.
Lack of Short Latency Effects of Aldosterone on
ICa of Rat Ventricular Myocytes
In contrast to the classical long latency effect of
aldosterone, a short-term effect on cells has been
proposed.28 Among the data suggesting that
aldosterone has a nongenomic, short latency effect is the
increased free [Ca2+], observed in vascular smooth muscle
cells23 and porcine aortic endothelial
cells.22 The role of the phosphoinositide
and cAMP as important second messengers in aldosterone
effects has been documented.29 30 Because cardiac
ICa is enhanced by these intracellular
messengers, we examined the possible rapid actions of
aldosterone on ICa. Figure 2A shows an example of the effect of
direct perfusion of aldosterone on
ICa. The bottom panel shows
representative Ca2+ current amplitude in
response to consecutive 300-ms depolarizing pulses (from -40 to 0 mV,
0.1 Hz) in freshly dissociated rat ventricular myocytes.
ICa was insensitive to 10 nmol/L and then 1
µmol/L aldosterone for >7 minutes. The upper panel shows
current traces before (a) and after exposure to aldosterone
(b and c); the kinetics of these currents did not change, suggesting
that neither the amplitude nor the gating was affected. Similar results
were consistently observed in 10 cells. To further check the
lack of rapid effect of aldosterone, we examined the effect
of a short incubation (3 to 6 hours) of the myocytes with
aldosterone at 37°C. Figure 2B, top, shows that
ICa recorded in a cell treated for 6 hours
with 1 µmol/L aldosterone (right) was similar when
compared with ICa recorded in a cell in
control conditions (left). To avoid error in pooling data from
different-sized myocytes, we normalized the ICa
amplitude by the cell capacitance to obtain ICa
density. Membrane capacitance was of similar magnitude in control cells
and in cells that were incubated with aldosterone
(162.4±50.9 [n=9] versus 170.4±57.1 pF [n=10] in control versus
aldosterone). The I-V relationships of
ICa are shown in Figure 2B, bottom. The current
density of ICa was not significantly different
after a short-term incubation with aldosterone
(P>0.5). This observation rules out a rapid nongenomic
action of aldosterone on cardiac
ICa.
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Specificity of the Aldosterone-Induced Increase
in ICa
To confirm that the ICa increase after 24
hours of exposure of myocytes to aldosterone occurs via
classical intracellular mineralocorticoid receptor (MR), the effect of
the classical MR antagonist spironolactone was examined.
Because spironolactone exhibits a low affinity for the MR
receptor,27 a 250-fold concentration was used to
antagonize the aldosterone treatment. Figure 3 compares the effect of a mixture of
aldosterone and spironolactone to 24 hours of incubation of
myocytes without or with aldosterone alone. In the presence
of spironolactone, the aldosterone-induced increase of
ICa was prevented. Aldosterone
stimulated ICa density at -10 mV by 
144%
(P<0.001), whereas in the presence of spironolactone,
ICa density was not significantly different from
control (-12.7±1.5 [n=8] versus -13.9±1.3 pA/pF [n=13], for
cells incubated with aldosterone and spironolactone versus
control, respectively [P>0.5]).
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Spironolactone alone was without effect on ICa density (data not shown). This inhibition by a specific antagonist demonstrates the involvement of classical intracellular MR in the aldosterone effect.
Aldosterone is known to possess glucocorticoid-like action that has been reported to upregulate cardiac ICa.31 32 With the high aldosterone concentration used (1 µmol/L), it is thus dangerous to form a conclusion about the specific effect of aldosterone. Therefore, we repeated the experiments with lower, more physiological concentrations of aldosterone and spironolactone.
The right part of Figure 3
summarizes the results of 24 hours of treatment with either 100 or 10
nmol/L aldosterone. Both lower aldosterone
concentrations stimulated significantly maximum
ICa peak density, and these effects were
prevented in the presence of 250-fold excess of spironolactone.
Inhibitors of Transcription and Protein Synthesis
Prevent Aldosterone-Induced Increase in
ICa
Classical mineralocorticoid action is achieved through the
interaction of intracellular MR proteins and promoters of target genes
that enhance the transcription and protein synthesis. Thus,
aldosterone modulation of cardiac
ICa could involve an increase in channel number
through a stimulation of mRNA and protein synthesis. To test this
hypothesis, we analyzed the effects on
ICa density of cell incubation with both
aldosterone (1 µmol/L) and either the
inhibitor of transcription actinomycin D (5 µg/mL) or the
protein synthesis inhibitor cycloheximide (20 µg/mL) for
24 hours. These data are summarized in Figure 4. The I-V relationships in
the different conditions were fitted with a function combining the
Goldman-Hodgkin-Katz equation and the Boltzmann relationship to
estimate maximal conductance:
I=(V-Vrev)Gmax{[1+exp[(V-V0.5)/]]+1},
where V is the voltage and the parameters
estimated by the fit, where Vrev is the reversal
potential; Gmax, the maximal conductance;
V0.5, the half point of the relationship; and
the slope factor. On average, cell incubation with
aldosterone alone augmented the Gmax
of Ca2+ channel 1.3-fold in a voltage-independent manner
compared with control. Both inhibitors did completely blunt
aldosterone-induced increase in
Gmax. It is worth noting that in both the
cycloheximide-treated and actinomycin D–treated groups, no significant
changes in Gmax or in any of the
parameters estimated by the fit (data not shown) were
denoted compared with control (P>0.5). Thus, the increase
in cardiac ICa after incubation of cells with
aldosterone for 24 hours seems to involve a gene
regulation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study establishes for the first time that the mineralocorticoid hormone aldosterone upregulates ICa in rat ventricular myocytes through a specific genomic regulation. This conclusion is supported by the finding that incubation of cells with aldosterone for 24 hours increases ICa density without any modification of the kinetics and the voltage dependence of the current. Even though no rapid aldosterone electrophysiological effect (<6 hours) could be detected, this increase was prevented by the MR antagonist spironolactone or by inhibitors of transcription and protein synthesis. These results are of potential interest at a number of levels: cardiac role for MR per se and possible pathophysiological and clinical implications.
Genomic Regulation of Cardiac ICa by
Aldosterone
Aldosterone, like other steroid hormones, initiates
its effects by binding to intracellular receptors; these receptors are
then able to control the transcription of several genes. For instance,
it has been shown that aldosterone regulates the expression
of amiloride-sensitive Na+ channels in colon, lung, and
kidney33 and of ATP-regulated K+ channels in
kidney.34 In both neonatal and adult
cardiomyocytes, aldosterone can regulate the
expression of the major cardiac Na+, K+-ATPase
isoform gene.15 Moreover, it has been shown that long-term
treatment (24 hours) of cultured neonatal rat cardiac cells with
aldosterone stimulates the activities of
Na+/H+ antiport and
Cl-/HCO3-
exchanger.17 To our knowledge, this is the first time that
an aldosterone-induced functional expression of
Ca2+ current is reported. However, it is noteworthy that
cardiac MR binds minerals and glucocorticoids with equal affinity, in
contrast with classical target tissues such as kidney and
colon,35 and that expression of Ca2+ channel
subunit 1C mRNA is upregulated by
glucocorticoids,31 32 including in atria and ventricles of
rat heart.36 In addition, it has been shown that
MR–hormone complex can activate transcription of a target gene
by binding an upstream transcription regulatory element that contains
an interacting glucocorticoid-responsive element.37 Thus,
the aldosterone-induced increase in
ICa might be due to the upregulated expression
of the 1C gene in cardiomyocytes. However,
if a control of transcription is involved in the effect of
aldosterone on ICa (Figure 4), it cannot be concluded whether this
genomic effect is direct or indirect. In any case, it is plausible that
aldosterone may induce the transcription of gene(s)
encoding regulatory protein(s) and hence increases Ca2+
channel activity.
Absence of Rapid, Nongenomic Effect of Aldosterone
Over the past 10 years, there has been an increased amount of
evidence for rapid, nongenomic effect of aldosterone in
various tissues.8 22 23 28 29 30 Concerning cardiac
myocytes, it has been reported that activation of sarcolemmal
Na+ transport can occur within the first 30 minutes of
aldosterone exposure.16 In the present
study, there was no evidence of rapid action of aldosterone
on ICa (see Figure 2). However,
aldosterone application causes a rapid increase (within <1
hour) in free [Ca2+]i level in
endothelial cells and vascular smooth muscle
cells.22 23 The mechanisms underlying this rapid effect
are not completely understood; however, they involve
phosphoinositide hydrolysis29 and
cAMP,30 which might induce Ca2+ channel
phosphorylation. Under our experimental conditions,
[Ca2+]i is expected to be clamped at a low
level by EGTA in the pipette filling solution. This may have prevented
detection because release of Ca2+ from intracellular stores
and changes in cytosolic levels of Ca2+ are thought to be
involved in the second messenger cascade for short-latency, nongenomic
effects of aldosterone.38 Thus, we could not
exclude this possibility. Nevertheless, the absence of alterations of
the voltage dependence and kinetics of ICa (see
Figure 1), even after short-term incubation with
aldosterone (data not shown), suggests that none of the
potential phosphorylation systems that have been
involved in the rapid nongenomic effect of
aldosterone28 29 30 is implicated in the
present study.
Pathophysiological Implications
The presence of MRs in heart9 10 11 and in the steroid
hormone biosynthetic pathway12 suggests that
aldosterone may play a role in the regulation of cardiac
function. An increase in myocardial aldosterone
production in the rat model of chronic myocardial infarction,
with a slight cardiac hypertrophy,13 has been
reported recently. This might be in relation to cardiac fibrosis and/or
to Ca2+ channel adaptation during the hypertrophic process.
Indeed, cardiac hypertrophy results from a selective
activation of the expression of various genes and protein
synthesis.39 The
electrophysiological alteration pattern
observed during cardiac hypertrophy and failure, crucial
for arrhythmia risk, has recently been reviewed.7
Notably, it has been shown that ICa density is
unchanged in both rat hypertrophy and cardiac
failure.24 26 The unchanged Ca2+ channel
number per surface area with increased cell size implies that the total
number of channels increases proportionally with the degree of
hypertrophy. Therefore, a genomic regulation of the
Ca2+ channel has been invoked.26 These authors
suggested that during the hypertrophic process, a synthesis of
Ca2+ channels was first induced before an increase in cell
size. We therefore suggest that the aldosterone genomic
action reported in the present study contributes to the increased
ICa amplitude observed during cardiac
remodeling.
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Acknowledgments |
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This study was supported by a grant from the European Society of Aldosterone Council. We are indebted to Benoît-Gilles Kerfant for his technical assistance. We thank Drs A.-M. Gomez, A. Lacampagne, and P. Lorente for help with improving the text of the manuscript.
Received July 28, 1999; accepted October 18, 1999.
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