Department of Cardiology, 1 Royal North Shore Hospital, and 2 University of Sydney, Sydney, New South Wales 2065, Australia
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ABSTRACT |
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To examine the effect of aldosterone on sarcolemmal
Na+ transport, we measured
ouabain-sensitive electrogenic
Na+-K+
pump current
(Ip) in
voltage-clamped ventricular myocytes and intracellular
Na+ activity
(aiNa) in right ventricular
papillary muscles. Aldosterone (10 nM) induced an increase in both
Ip and the rate
of rise of aiNa during
Na+-K+
pump blockade with the fast-acting cardiac steroid dihydroouabain. The
aldosterone-induced increase in
Ip and rate of
rise of aiNa was eliminated by
bumetanide, suggesting that aldosterone activates Na+ influx through the
Na+-K+-2Cl
cotransporter. To obtain independent support for this, the
Na+,
K+, and
Cl
concentrations in the
superfusate and solution of pipettes used to voltage clamp myocytes
were set at levels designed to abolish the inward electrochemical
driving force for the
Na+-K+-2Cl
cotransporter. This eliminated the aldosterone-induced increase in
Ip. We conclude
that in vitro exposure of cardiac myocytes to aldosterone activates the
Na+-K+-2Cl
cotransporter to enhance Na+
influx and stimulate the
Na+-K+
pump.
ion transport; intracellular sodium; sodium-potassium-two chloride cotransport; mineralocorticoid receptor; cell membrane
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INTRODUCTION |
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THE KIDNEY IS regarded as the classical target organ
for aldosterone. However, aldosterone can also bind with high affinity to other organs, including the heart in rat (23), rabbit (18), and
humans (17). A functional role for aldosterone in the heart has been
suggested by a study demonstrating aldosterone-induced cellular uptake
of Na+ in isolated rat cardiac
myocytes maintained under tissue-culture conditions. This, in turn,
activates synthesis of 1- and
1-subunits of the sarcolemmal
Na+-K+
pump. These effects occur with a considerable delay and can only be
demonstrated ~6-12 h after the onset of exposure (15). In several noncardiac tissues, aldosterone has been shown to have effects
on membrane Na+ transport that
develop with a much shorter latency.
Aldosterone has regulatory effects on the plasmalemmal Na+/H+ exchanger of amphibian (22) and canine kidney cells (27) with a latency of 10-20 min and of human lymphocytes with a latency of 1-2 min (28, 29). The effects on intracellular Na+ levels were not reported in the study on kidney cells. However, in the lymphocytes, exposure to aldosterone eliminated a spontaneous decline in the intracellular Na+ concentration that occurred in control cells. Aldosterone has also been reported to stimulate Na+-K+ pump-mediated 86Rb+ uptake in renal cortical collecting tubules isolated from rats (10). This effect was evident within the first 30 min of exposure, and it was concluded that the aldosterone-induced pump stimulation precedes any induction of synthesis of new pumps.
Although it is well established that aldosterone can regulate membrane Na+ transport in cardiac cells with long latency via a genomic effect (15), it is not known if effects of aldosterone on sarcolemmal Na+ transport can also occur with short latency. An effect with short latency is of interest because it would imply that aldosterone can modify functional properties of preexisting sarcolemmal transport mechanisms. We have therefore examined early effects of aldosterone on regulation of intracellular Na+ in cardiac myocytes. We used the whole cell patch-clamp technique to measure electrogenic Na+-K+ pump current (Ip) in ventricular myocytes, and we used the ion-sensitive microelectrode technique to measure intracellular pH (pHi) and intracellular Na+ activity (aiNa) in papillary muscles.
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MATERIALS AND METHODS |
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Male New Zealand White rabbits were used for the study. They were anesthetized with ketamine (50 mg/kg) and xylazine hydrochloride (20 mg/kg) given intramuscularly, and the heart was excised when deep anesthesia was achieved.
Measurement of Ip. Single myocytes from either ventricle were isolated as described previously (14). They were stored at room temperature in modified Tyrode solution until used for experimentation. The solution contained (in mM) 140 NaCl, 5.6 KCl, 2.16 CaCl2, 0.44 NaH2PO4, 10 glucose, 1.0 MgCl2, and 10 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). The solution also contained 16 mg/l gentamicin to inhibit bacterial growth and 0.5% bovine serum albumin. It was titrated to a pH of 7.40 ± 0.01 at 35°C with 1 M NaOH. The Na+ concentration in the final titrated solution was 146 mM. The solution used subsequently when Ip was to be measured was of an identical composition in most experiments except that the bovine serum albumin was omitted. These solutions were warmed to 35°C. When indicated, additional superfusates used were designed to alter transmembrane electrochemical driving gradients.
The myocytes were voltage clamped using wide-tipped (4-5 µm) patch pipettes manufactured as described previously (14). Three different filling solutions were used. In an initial series of experiments, they contained (in mM) 70 potassium glutamate, 1 KH2PO4, 5 HEPES, 5 ethylene glycol-bis(Measurement of aiNa and
pHi.
Conventional voltage-sensitive microelectrodes were made from
filamented borosilicate glass tubing and had resistances of 11-22
M when filled with 3 M KCl. Ion-sensitive microelectrodes, based on
liquid sensors, were manufactured from unfilamented borosilicate glass
tubing as described previously (30).
Na+-sensitive microelectrodes were
calibrated using the reciprocal dilutions method (26).
H+-sensitive microelectrodes were
calibrated in solutions containing 150 mM KCl, 10 mM NaCl, and 10 mM
HEPES. The solutions were titrated to a pH of 6.5 or 7.5 with 1 M NaOH
to determine the slope. The slopes of our
Na+- and
H+-sensitive electrodes and the
selectivity of the Na+-sensitive
electrodes against Ca2+ have been
reported previously (14). Calibration of electrodes was performed after
impalements in all experiments. In a subset of experiments, we
calibrated the electrodes both before and after impalements. There was
no difference in their performance.
Reagents and chemicals. TMA-Cl was "purum" grade and was purchased from Fluka. All other chemicals were "analytical" grade and were purchased from BDH. Ouabain and aldosterone (Sigma Chemical, St. Louis, MO) were added to superfusates from a stock solution of ethanol. The final concentration of ethanol in superfusates was <0.1%. The aldosterone receptor in rabbit heart has a dissociation constant of 0.25 nM (18). Unless indicated otherwise, we used aldosterone in a concentration of 10 nM to facilitate fast binding to the receptor. Dihydroouabain (DHO) and potassium canrenoate (Sigma Chemical) were dissolved directly in superfusates. Bumetanide was dissolved in dimethyl sulfoxide (DMSO; BDH). The final concentration of DMSO in the superfusate was 0.5%. In agreement with a previous study on cardiac myocytes (12), DMSO in this concentration had no effect on Ip. Tetrodotoxin (TTX; Sigma Chemical) was dissolved in modified Tyrode solution to achieve a final concentration of 10 µM.
Statistical analysis. Results are expressed as means ± SE. Statistical comparisons were made using unpaired Student's t-test, one-way analysis of variance followed by a Tukey's test, and repeated measures analysis of variance. Differences were regarded as statistically significant when P < 0.05.
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RESULTS |
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Effect of aldosterone on aiNa. In the first series of experiments, we measured aiNa before and immediately after exposure of isolated papillary muscles to aldosterone. Papillary muscles were initially superfused with aldosterone-free Tyrode solution. We identified stable, satisfactory recordings of both voltage-sensitive and ion-sensitive electrodes according to previously published criteria (14). We then switched to a superfusate that contained 10 nM aldosterone. We did not observe any detectable change in aiNa over the initial 10-min period after the onset of superfusion of aldosterone. We next examined the rate of rise in aiNa on blockade of Na+ extrusion via the Na+-K+ pump. Control papillary muscles and papillary muscles exposed to aldosterone were superfused with 500 µM DHO. We exposed the tissue to aldosterone for ~20 min to ensure binding before we superfused DHO. Figure 1 shows electrode recordings during superfusion of DHO in a representative experiment. The papillary muscle used in this experiment was not exposed to aldosterone. The aiNa recorded immediately before exposure to DHO was 9.9 ± 0.7 mM in seven papillary muscles exposed to aldosterone while aiNa in seven controls was 7.7 ± 0.7 mM. The difference was statistically significant. Figure 2 summarizes the DHO-induced rise in aiNa in control papillary musles and in papillary muscles exposed to aldosterone. The rate of increase in aiNa upon exposure to DHO was significantly greater for papillary muscles exposed to aldosterone than for controls.
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Effects of aldosterone on pHi. Because aldosterone has been reported to activate the Na+/H+ exchanger in noncardiac tissue with a short latency, we examined whether exposure to aldosterone can alter pHi. When stable recordings with voltage- and pH-sensitive electrodes were achieved, we switched from an aldosterone-free superfusate to a superfusate containing aldosterone. To facilitate detection of an early change, we used aldosterone in a concentration of 100 nM in these experiments rather than the 10 nM used in all other experiments in the study. Figure 3 shows a recording of pHi during superfusion of aldosterone. We could not detect any change in pHi during ~15 min of exposure to aldosterone of this or four other papillary muscles. In an independent series of experiments, we examined the effect on pHi of a longer duration of exposure to aldosterone. Six papillary muscles were exposed to 100 nM aldosterone before we impaled microelectrodes. By the time pHi was determined, they had been exposed to aldosterone for 47-60 min. The mean pHi was 6.83 ± 0.09. Mean pHi in six controls was 6.95 ± 0.03. The difference was not statistically significant. These results suggest that aldosterone does not activate the Na+/H+ exchanger in cardiac tissue.
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Effect of aldosterone on Ip.
To examine the effect of aldosterone on
Ip, we superfused
isolated myocytes with control Tyrode solution or solution containing 10 nM aldosterone. The myocytes were patch clamped using pipettes containing 10 mM Na+, a
concentration near physiological intracellular levels. The Na+,
K+, and
Cl concentrations of
pipette solutions and superfusates are summarized in Table
1, condition
A. When the whole cell configuration had been
established, we measured the membrane capacitance. We then voltage clamped the myocytes at
40 mV and switched the
superfusate to Tyrode solution containing 1 mM
Ba2+. Superfusion of
Ba2+ induced an inward shift in
membrane current. When a new stable holding current was recorded, we
identified Ip as
the additional shift induced by 50 µM ouabain. Typical recordings of
holding currents in experiments using similar experimental protocols
have been published previously (14, 30). Myocytes were exposed to
aldosterone for 27-90 min or exposed to aldosterone-free Tyrode solution. The duration of exposure to aldosterone was dependent on the
time it took to achieve the whole cell configuration. Mean Ip of myocytes
exposed to aldosterone and mean
Ip of control
myocytes are included in Fig. 4.
Aldosterone induced a significant increase in
Ip.
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Transmembrane ionic gradients, aldosterone, and
Ip.
Aldosterone induced an increase in the rate of rise in
aiNa during exposure to DHO.
This suggests that the increase in
Ip of myocytes
exposed to aldosterone may be due to enhanced transmembrane
Na+ influx and secondary pump
stimulation by a rise in the intracellular Na+ concentration. To examine this
possibility, we manipulated the transmembrane electrochemical gradient
for Na+ in patch-clamped myocytes.
We voltage clamped myocytes at 0 mV using pipettes with filling
solutions that contained 10 mM
Na+. The whole cell configuration
was established in the Tyrode solution that contained 146 mM
Na+. For measurement of
Ip, we then
switched to a superfusate in which the
Na+ concentration had been reduced
to 16 mM by isosmotic substitution of NaCl with TMA-Cl. The
Na+,
K+, and
Cl concentrations of
pipette solutions and superfusates at the time we measured
Ip are summarized
in Table 1, condition B. In initial experiments, myocytes died within a few minutes of switching to the
low-Na+ superfusate. This problem
was eliminated when we used a
low-Na+ superfusate that was
nominally Ca2+ free. Myocytes were
exposed to aldosterone for 21-108 min or exposed to
aldosterone-free solution. The dependence of the aldosterone-induced increase in Ip on
the transsarcolemmal electrochemical gradient for
Na+ is illustrated in Fig. 4. It
is apparent that an aldosterone-induced increase in
Ip is converted
to a decrease when the transmembrane gradient for
Na+ is reduced. This, in turn,
indicates that the aldosterone-induced increase in
Ip is due to
enhanced transsarcolemmal Na+
influx rather than a direct stimulatory effect of aldosterone on the
pump.
Effect of bumetanide on Ip and
aiNa.
The effect of increasing the
Cl concentration in the
patch pipette filling solution on the aldosterone-induced increase in Ip suggests that
aldosterone induces an increase in transsarcolemmal Na+ influx through the
Na+-K+-2Cl
cotransporter. We examined the effect of bumetanide to obtain independent support for this. We voltage clamped myocytes at
40 mV using Na+-free patch pipettes.
They were superfused with Tyrode solution containing 10 nM aldosterone
and 10 µM bumetanide for 10-70 min before we measured
Ip. The effect of
bumetanide on the aldosterone-induced increase in
Ip is illustrated
in Fig. 5. Bumetanide blocked the aldosterone-induced increase in
Ip.
Effect of potassium canrenoate on Ip.
We performed experiments to examine the effect of blockade of the
mineralocorticoid receptor on the aldosterone-induced increase in
Ip. We superfused
myocytes with Tyrode solution containing 10 nM aldosterone and 1 µM
potassium canrenoate. They were voltage clamped at 40 mV with
Na+-free patch pipettes. The mean
Ip, measured
after 21- to 45-min exposure to aldosterone and potassium canrenoate,
has been included in Fig. 5. Mean
Ip was
significantly smaller than mean
Ip of myocytes exposed to aldosterone only. We conclude that potassium canrenoate blocked the effect of aldosterone on
Ip. We examined
the effect of potassium canrenoate on
Ip in the absence
of aldosterone in an independent series of control experiments. We
exposed myocytes to 1 µM potassium canrenoate. They were voltage
clamped at
40 mV with patch pipettes containing 10 mM
Na+. Mean
Ip of five
myocytes was 0.38 ± 0.06 pA/pF. This is similar to the mean
Ip of 0.32 ± 0.03 pA/pF measured under experimental conditions that were identical
except that the myocytes were not exposed to potassium canrenoate
(included in Fig. 4). We conclude that the effect of 1 µM potassium
canrenoate to abolish the aldosterone-induced increase in
Ip is not due to
direct inhibition of the
Na+-K+
pump by potassium canrenoate.
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DISCUSSION |
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Rationale for experimental model. We used ion-sensitive microelectrodes to demonstrate that aldosterone enhances Na+ influx in isolated papillary muscles. The whole cell patch-clamp technique was then used to explore the mechanism for this effect in single cardiac myocytes. When this technique is used to study the Na+-K+ pump, it is usually a key objective to achieve good control of intracellular ionic concentrations. Although such control to a large extent can be achieved in cardiac myocytes (11, 21), measured pump currents may exhibit some deviation from the current predicted by the Na+ concentration in pipette solutions because a concentration gradient exists between the tip of the patch pipette and the cytoplasm (20) or between the cytoplasm and a diffusion-restricted subsarcolemmal space (5).
When transsarcolemmal Na+ fluxes are large relative to our ability to control the Na+ concentration at intracellular pump sites, the relationship between pipette Na+ concentration and Ip does not accurately reflect Na+ activation of the pump (5, 20). Experimentally, the errors arising from this problem can be minimized by reducing non-pump transsarcolemmal Na+ fluxes with appropriate design of experimental solutions and voltage-clamp protocol (11, 21). The ouabain-sensitive current recorded when using Na+-free patch pipette filling solutions gives an indication of the degree of control of intracellular Na+ that can be achieved. Nakao and Gadsby (21) reported that this current amounts to ~0.04 pA/pF, a value that is only ~3.5% of the current recorded at saturating levels of pipette Na+ concentration. They demonstrated that the current was largely due to electrogenic pumping of Na+ leaked into cells through the sarcolemma. An increase in this leak would be expected to induce an increase in the measured Ip (20). When using Na+-free patch pipettes, we measured an Ip of 0.05 ± 0.01 pA/pF in control myocytes. Exposure to aldosterone induced a large increase in Ip. It is unlikely that a direct effect of aldosterone on the pump induced this increase in Ip, since steady-state aiNa was significantly increased rather than decreased after aldosterone superfusion. In addition, the aldosterone-induced increase in Ip was converted to a decrease when the transmembrane gradient for Na+ was reduced (Fig. 4). Induction of transsarcolemmal influx of Na+ and the development of a concentration gradient between intracellular pump sites and the patch pipette filling solution offers the simplest explanation for the increase in Ip recorded with exposure to aldosterone.Mechanism for aldosterone-induced
Na+ influx.
Transsarcolemmal Na+ influx could
occur through Na+ channels,
through the
Na+/H+
exchanger, or through the
Na+-K+-2Cl
cotransporter. The Na+ channels
are expected to be inactivated at the holding potentials we used
(
40 or 0 mV), and exposure of myocytes to TTX had no effect on
the aldosterone-induced increase in
Ip. In addition, the aldosterone-induced increase in
Ip was converted
to a decrease when the
[Cl
]pip
was increased without any change in the transsarcolemmal electrochemical gradient for Na+
(Fig. 4). These findings indicate that an effect on passive entry of
Na+ through an ion channel cannot
be involved in the aldosterone-induced increase in
Ip.
Aldosterone receptors and the
Na+-K+-2Cl
cotransporter.
A two-step model for the effect of aldosterone on cells has been
proposed (28). According to this model, aldosterone binds to both a
receptor on the surface of cell membranes and to an intracellular
receptor. Binding to the surface receptor is characterized by a short
latency (minutes) of the response and by a lack of sensitivity to
canrenone. The receptor has been linked to changes in electrolyte
transport. In contrast, the response to binding to the intracellular
receptor occurs with long latency (hours) and is blocked by canrenone.
A genomic effect of binding to this receptor is usually invoked. We
found that
Na+-K+-2Cl
cotransport was activated with a relatively short latency, but we were
not able to demonstrate activation within the few minutes of latency
reported for activation of
Na+/H+
exchange in human lymphocytes (28, 29). In our study, the effect of
aldosterone within the first few minutes could only be studied if we
achieved the whole cell configuration before exposure was started.
Intracellular Ca2+ is expected to
be clamped at a low level by the EGTA in the pipette filling solution.
This may have prevented detection of a response to aldosterone, since
release of Ca2+ from intracellular
stores and changes in cytosolic levels of Ca2+ are thought to be involved in
the messenger cascade for nongenomic effects (24). The classical
mineralocorticoid receptor blocker potassium canrenoate abolished the
aldosterone-induced increase in
Ip (Fig. 5).
Within the framework of the two-step model for aldosterone effects,
this suggests an involvement of the intracellular receptor, although
the latency of the response in our study implies a nongenomic
mechanism. A detailed exploration of this possibility was beyond the
scope of the study.
Functional significance of aldosterone-induced
Na+-K+-2Cl
cotransport.
The presence of aldosterone receptors in the heart (17, 18, 23)
suggests that aldosterone plays a role in regulation of cardiac
function. However, this role is poorly understood at present (3). Our
study has demonstrated that aldosterone enhances influx of
Na+ through the cotransporter.
This may reduce extrusion of Ca2+
through the
Na+/Ca2+
exchanger and hence enhance contractility. In support of these speculations, a positive inotropic effect of aldosterone on isolated cat papillary muscles has been reported (25). Diastolic properties of
cardiac muscle might also be altered by
Na+-K+-2Cl
cotransport activation. Activation of the cotransporter increases cardiac myocyte volume, and this may decrease cardiac compliance and
hence impair ventricular filling (8). The sarcolemmal
Na+-K+-2Cl
cotransporter is inhibited by atrial natriuretic factor (8) and, as
demonstrated in this study, activated by aldosterone. Levels of both
hormones are elevated in heart failure (4, 31). If the effects
demonstrated in vitro also occur in vivo, one might speculate that an
adverse effect of aldosterone may be compensated for by release of
atrial natriuretic factor. Such interaction would have important
therapeutic implications.
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ACKNOWLEDGEMENTS |
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This study was supported by National Heart Foundation of Australia Grant G93S3842 and by the North Shore Heart Research Foundation.
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FOOTNOTES |
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Address for reprint requests: H. H. Rasmussen, Dept. of Cardiology, Royal North Shore Hospital, Pacific Highway, St. Leonards, Sydney, NSW 2065, Australia.
Received 31 March 1997; accepted in final form 26 September 1997.
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