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Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, 6, 229-236
229
Sodium Ion Transporters as New Therapeutic Targets in Heart Failure
Antonius Baartscheer1,* and Marcel M.G.J. van Borren2
Departments of Experimental Cardiology1 and Physiology2, Center for Heart Failure Research Academic Medical Center, University
of Amsterdam, Amsterdam The Netherlands
Abstract: Sodium ion transporters in sarcolemma are involved in numerous vital cell functions, such as excitability, excitationcontraction coupling, energy metabolism, pH and volume regulation, development and growth. In a number of cardiac pathologies, the
intracellular sodium concentration ([Na+]i) is elevated. Since [Na+]i and intracellular Ca2+ concentration ([Ca2+]i) are coupled through the
Na+/Ca2+-exchanger, these cardiac pathologies display disturbed calcium handling. For instance, [Na+]i is increased in heart failure (HF)
leading to Na+/Ca2+-exchanger mediated increase in [Ca2+]i, reduced contractility and increased propensity to arrhythmias.
Several studies support the contention that an increase in [Na+]i and [Ca2+]i transduces a signal the nucleus, that triggers development of
cardiac remodelling and hypertrophy. Pharmacological intervention, which favourably interferes with [Na+]i and [Ca2+]i homeostasis,
might prevent hypertrophy, cardiac remodelling, arrhythmias and HF. The most important sodium transport mechanisms that may
underlie increased [Na+]i are: Na+/H+-exchanger (NHE-1), Na+-HCO3- co-transporter (NBC), Na+-K +-Cl- co-transporter (NKCC), Na +channel, Na+/K +-ATPase and Na+/Ca 2+-exchanger (NCX).
Preclinical studies showed that pharmacological interventions, targeted against sarcolemmal sodium ion transporters, proved effective in
ameliorating heart failure. In this respect: 1) NHE-1 inhibition reduces cardiac remodelling, hypertrophy and HF, although, in the patients
following coronary artery bypass graft surgery, it was associated with an increase of stroke. 2) The activity of NBC is up-regulated,
during the development of hypertrophy and may be a therapeutic strategy to prevent the development of hypertrophy and HF. 3) NKCC
is increased in post-infarction HF, and the inhibition of NKCC attenuated post-infarction remodelling. 4) Inactivation of sodium channels
is impaired in HF, which may result, in increased Na+ influx and prolongation of the action potential. 5) Blockade of NCX may be useful
as a part of a combined therapeutic approach. Inhibition of reversed mode, or activation of forward mode NCX reduce Ca2+ overload. 6)
Inhibition of Na+/K+-ATPase (digoxin), is used to increase contractility, however, it enhances progression of HF. Oppositely, new drugs
which increase activity of Na+/K+-ATPase may prevent the development of cardiac remodelling hypertrophy and HF.
In this review we give an overview and discuss the therapeutic relevance of the different sodium ion transport mechanisms in the setting
of heart failure.
INTRODUCTION
The incidence and prevalence of heart failure (HF) have
increased over the last decades. The main reasons for this increase
are the ageing population and an increase in survival rate after
myocardial infarction and other cardiovascular diseases. Although,
pharmacotherapy has significantly improved survival, the prognosis
of HF is still rather poor. Total mortality is high and approximately
half of the deaths are sudden and unexpected. Angiotensin-converting-enzyme (ACE)-inhibitors generally given with diuretics, is the
standard treatment for patients with HF, whereas, beta-adrenergic
receptor antagonists (-blockers) and Na/K-pump inhibitors
(digoxin) are given to respectively prevent arrhythmias and improve
contractility. Despite and improvement in the therapy, mortality in
heart failure (HF) remains high and there is a need for alternative
additional approaches [1, 2]. The major stimulus to initiate HF, is
sustained increased workload of the heart, mostly due to the hypertension and/or myocardial infarction. The increased workload leads
to hypertrophy and cellular and structural remodelling such as
altered calcium handling [3, 4], excitation-contraction coupling [5],
contractility [6], energy metabolism [7], cytoskeleton [8] and extracellular matrix [9]. Dysfunctional Ca2+ (disturbed Ca2+ handling) is
characterized by reduced systolic Ca2+, increased diastolic Ca2+,
elevated decay time of the Ca2+ transients, and decreased
sarcoplasmic reticulum (SR) Ca2+ content [10-12] (see also Fig. 5).
These alterations translate into functional incompetence of the heart
with reduced fractional shortening, increased diastolic tension,
relaxation abnormalities and arrhythmias. In addition increased
intracellular calcium concentration ([Ca2+]i) can directly accelerate
protein synthesis [13-15] and activate critical hypertrophic
pathways leading to altered gene expression (Fig. 1), such as
*Address correspondence to this author at the Center for Heart Failure
Research, Department of Experimental Cardiology, Academic Medical
Center Room K2-104, University of Amsterdam, Meibergdreef 9 1105 AZ
Amsterdam, The Netherlands; Tel: +31 20 5663265; Fax: +31 20 6975458;
E-mail: [email protected]
1871-5257/08 $55.00+.00
Fig. (1). Calcium Signalling in Cardiac Myocytes.
Cellular signalling modes and effects can be quite complex. This diagram
shows known processes in cardiac myocytes triggered by calcium ions.
Contraction of cardiac cells is driven by Ca2+ that enters through channels in
the cell membrane. Increased diastolic Ca2+ can stimulate a variety of
signalling pathways that have been implicated in the control of gene
transcription and cardiac hypertrophy.
mitogen-activated protein kinase (MAPKs) [16], calcineurin [17],
Ca2+/calmodulin dependent kinase II (CaMKII), erzin radixin
moesin (ERM), phosphoinositide 3 kinase and the serine-threonine
kinas (AKT) [18]. Although hypertrophy of the myocardium is
© 2008 Bentham Science Publishers Ltd.
230 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4
initially an adaptive response, prolonged hypertrophy is associated
with increased sudden cardiac death and progression to HF [19-21].
Ca2+ regulation is closely linked to intracellular sodium handling
([Na+]i), because the route for Ca2+ efflux from myocytes is via the
Na+/Ca2+-exchanger (NCX). NCX utilize the electrochemical Na+
gradient to couple energetically unfavourable Ca2+ efflux from the
myocytes to Na+ transport. NCX functions in the forward mode
(Ca2+ efflux/Na+ influx), thereby reducing diastolic Ca2+ levels by
extruding Ca2+. In addition, NCX can also function in reversed
mode (Ca2+ influx/Na+ efflux) dependent on the sarcolemmal Na+
gradient. In animal models of HF and hypertrophy as well as in
human heart failure, it has been shown that [Na+]i is increased [2230]. When [Na+]i increases, NCX shifts to less forward and more
reversed mode [22, 23] (see also Fig. 8), resulting in an increase of
[Ca2+]i [22]. Changes in Na+ regulation will thus directly affect
[Ca2+]i handling. Therefore, it can be argued that prevention of
increased [Na+]i and the subsequent [Ca2+]i rise, may prove
beneficial in the patients at risk to develop hypertrophy and HF. In
steady state, Na+ homeostasis is the result of the balance between
the influx and efflux of sodium ions. In cardiac myocytes Na+
efflux is primarily regulated by the Na+/K+ ATPases with moderate
contribution of NCX, whereas Na+ influx depends mainly on Na+channel and NHE-1 activity with minor contribution of other
sodium transporters (Fig. 2). All these mechanisms are subject of
regulation [31] and therefore can contribute to abnormal Na+
Baartscheer and van Borren
handling in the failing heart. The feature of this review is to discuss
the therapeutic relevance of these sodium ion transporters in the
treatment of HF.
THE Na+/H+-EXCHANGER
The Na+/H+-exchanger (NHE) is an integral membrane protein
expressed in mammalian cells that becomes activated upon an
intracellular acidosis. NHE expels one H+ from the cytoplasm in
exchange with one extracellular Na+, until a near neutral intracellular pH is reached. At resting pHi values of NHE are still active,
however, perfectly balanced by the sarcolemmal acid loaders. The
small overlap in acid extrusion and acid loading activity causes
background NaCl loading. For this reason NHE has, besides pH i
regulation, also a major role in maintaining intracellular solute
concentrations and cell volume regulation.
Until now 9 isoforms of the exchanger have been identified
[32]. NHE-1 is the most ubiquitously expressed and the predominant
isoform in the plasma membrane of the myocardium [33]. The
activity of NHE-1 is regulated by e.g., stretch and neurohumoral
factors that target membrane bound G-protein coupled receptors,
such as catecholamines, angiotensin II and endothelin I. These
factors, abundantly present in HF, stimulate their receptors and
activate signalling transduction pathways that cause (de)phosphorylation and (un)binding of co-factors from the NHE-1 C-terminus
[33-36].
Fig. (2). [Na+]i regulation in cardiac myocytes.
Upper panel: Electrogenic Na+ influx occurs via sarcolemmal Na+-channels and the forward mode of the NCX, whereas electroneutral Na+ influx is mediated
by the Na+-K+-2Cl--cotransporter (NKCC), Na+/H+-exchanger (NHE), and Na+-HCO-3 cotransporter (NBC). The Na +-dependent acid extruders are stimulated
by a continuous H+ supply via the Cl--dependent acid loaders Cl-/OH--exchanger (CHE) and the Cl-/HCO3--exchanger (anion-exchanger, AE). Lower panel:
Na+ efflux is mediated via the Na+/K +-pump and via reverse mode NCX. Lower panel: Elevated [Na+]i regulates [Ca2+]i, SR-Ca2+-content and SR-Ca2+-release
by its effect on the driving force of NCX.
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Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4
231
In animal models and in the patients with HF, NHE-1 activity is
proved to be significantly increased [24, 25, 37-41] (Fig. 3). It is
expected that hyperactivity of NHE-1 is associated with a more
alkaline pHi and an elevated [Na+]i. However, in HF enhanced acid
extrusion by NHE-1 is perfectly balanced by an equivalent increase
in acid-loading through the Cl-/HCO3--exchanger (anion exchanger,
AE), thereby leaving pHi unchanged under bicarbonate buffered
conditions [42, 43]. Regarding the simultaneous increase in NHE-1
and AE activity at resting pHi values in HF, one can speculates that
the actual [Na+]i under bicarbonate-buffered conditions should be
much higher as always measured under non-bicarbonate-buffered
conditions (Fig. 4). Yet, experimental data on this in HF is lacking.
Evidence exists that a long term increase in NHE-1 activity is
harmful, due to its indirect effect on the [Ca2+]i. Increased NHE-1
activity elevates [Na+]i (Fig. 3) and subsequently causes a Ca2+
overload through NCX, which secondary leads to arrhythmias,
myocardial dysfunction, hypertrophy, apoptosis and HF [44-48].
Fig. (4). Na+-dependent acid extrusion and Cl--dependent acid loading.
Fig. (3). [Na+]i and rate of influx of Na+.
Upper panel: Stimulation rate dependence of [Na+]i, of cardiac myocytes,
stimulated at 2 Hz, isolated from control and from volume and pressure
overload induced HF rabbits. Lower panel: Rate of Na+ influx of cardiac
myocytes isolated from control (with bars) and from volume and pressure
overload induced HF rabbits (grey bars), in the absence (left) or presence
(middle) of 10 mol/l cariporide (inhibitor of NHE-1), after inhibition of
Na+/K+-ATPase with 100 mol/l ouabain. The stimulation rate was 2 Hz.
Difference (right) represents the rate of Na+ influx through NHE-1.
Consequently, inhibition of NHE-1 might be a therapeutic
strategy to prevent the increase in [Na+]i and [Ca2+]i, hypertrophy
and the development of HF. In this respect, it has been shown in
several studies that chronic inhibition of NHE-1 prevents and/or
attenuates hypertrophy and the development of HF [27, 46, 49-56].
These studies showed that NHE-1 inhibition improves survival rate,
reduces fibrosis and apoptosis, preserves contractility, and prevents
ionic and electrical remodelling. In accordance, SR calcium
handling and the amplitude of calcium transient are normalized in
pressure-volume overloaded rabbits with HF, that were fed with a
NHE-1 inhibitor “cariporide” containing diet (Fig. 5). From the
prevention of excessive fibrosis, prolongation of action potential
duration, and delayed after depolarizations [57-61], one can
conclude that NHE-1 inhibition is also anti-arrhythmic. This antiarrhythmogenic effect together with maintenance of contractility
Increased overlap in acid extrusion and acid loading at the resting pHi value
increases NaCl loading in HF. A) In healthy hearts, the set-point pHi values,
pHi at which an acid-base transporter is quiescent, of NHE and NBC are only
slightly more alkaline than the set-point pHi values of CHE and AE.
Consequently, the small overlap in Na+-dependent acid extrusion and Cl-dependent acid loading causes a small NaCl influx at the resting pHi. B) In
hypertrophied or failing hearts, set-point pHi values of NHE and AE are
shifted in the opposite direction probably due to neurohumoral modulation.
As a result a large overlap in Na+-dependent acid extrusion and Cl-dependent acid loading occurs which causes an excessive NaCl influx
without changing the resting pHi.
explains why the rate of survival is higher in HF following
inhibition of NHE-1 [46, 49].
In most studies, in which chronic inhibition of NHE-1 has been
applied experimentally, treatment started immediately after the
induction of hypertrophy and HF. From a clinical point of view
however, it is even more relevant to determine whether chronic
inhibition of NHE-1 is capable to reverse signs of hypertrophy and
HF, after it has already been developed. Indeed, NHE-1 inhibition
treatment reduced hypertrophy in rats with myocardial infarction
[50], and reversed hypertrophy and improved contractility in
spontaneously hypertensive rats (SHR) (Fig. 6) [62]. Moreover, in
rabbits with volume and pressure overload inhibition of NHE-1, not
only reversed hypertrophy and reduced signs of HF but also
reversed ionic and electrical remodelling [63] are found.
Unfortunately, in a clinical trial designed to prevent ischemia
and reperfusion injury using cariporide to inhibit NHE-1 activation,
232 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4
Baartscheer and van Borren
expense of Na+ influx. In the still energy-deprived tissue the Na+/K +
ATPase is not fully recovered and cannot compensate this Na+
influx. Consequently, [Na+]i sharply rises and causes a NCXmediated Ca2+ overload at the moment of reperfusion that leads to
hypercontracture and lethal cell injury. Indeed, administration of
anti-hhNBC antibody markedly protects systolic and diastolic
functions of the heart during reperfusion. Yet, the role of NBCn1 in
reperfusion injury remains controversial [43].
Fig. (5). Calcium transients and SR calcium content.
Representative examples of calcium transients (upper panel) and SR calcium
content (lower panel) of 2 Hz stimulated myocytes isolated from control,
volume and pressure overload induced HF and volume and pressure
overload induced HF rabbits chronically treated with cariporide (inhibitor of
NHE-1). Rapid cooling (indicated by arrows) caused release of all calcium
from sarcoplasmic reticulum.
in the patients following coronary artery bypass graft surgery,
adverse effects were demonstrated [64]. In cariporide treated
patients an increase incidence of stroke was found. This halted
further clinical studies on NHE-1 inhibitors as a cardio protective
drug. More studies are required to find out whether different NHE-1
inhibitors or alternative strategies to inhibit NHE-1 activity will be
efficient to treat and prevent the development of hypertrophy and
HF in the patients without these adverse effects.
THE Na+-HCO3- COTRANSPORTER
The Na+-HCO3- cotransporter (NBC) is localized in sarcolemma
and becomes activated upon intracellular acidosis. NBC transports
extracellular Na+ and HCO3- into the cytoplasm, thereby restoring
the acidic pHi to near neutral values. The relative contribution of
NHE-1 and NBC in acid load recovery, is approximately 70% and
30%.
Mammalian hearts posses at least two different Na+ dependent
bicarbonate co-transporters, an electroneutral (1Na:1HCO3-) and an
electrogenic NBC (1Na:2HCO3-) [45]. The human heart NBC
(hhNBC) represents the electrogenic NBC (NBCe1) [65] whereas,
NBCn1 is the cardiac electroneutral isoform [66]. The only function
ascribed to NBC is its role in pHi regulation; however, since it transports Na+ into the cytoplasm it may also be important in cardiac
Na+ and Ca2+ homeostasis. In addition, activation of the electrogenic
hhNBC may also affect the action potential configuration. Although,
intracellular proton accumulation is possibly a major stimuli for the
activation of NBC, the abundance of modulation sites on NBC also
suggests a strong regulation of its activity by several intracellular
signalling pathways [45]. Peptide hormones and catecholamines
that act on the G-protein coupled receptors modulate NBC by
shifting its set-point pHi (pHi at which an acid-base transporter is
virtually quiescent) [47].
There are reports that NBCe1 plays a role in the development of
ischemia/reperfusion injury in the heart [65]. Following reperfusion
intracellular pHi is quickly restored by NHE-1 and NBC at the
Fig. (6). Effect of NHE-1 inhibition on cardiac hypertrophy in Spontaneous
Hypertensive Rats (SHR).
Cardiac hypertrophy was assessed by heart weight/ body weight ratio in 4
months old untreated SHR (with bar); in 5 months old cariporide-treated
SHR (dashed bar) and in 5 months old untreated SHR (grey bar).
Reproduced with permission from ref 62
Recently, it has been shown in a cardiac hypertrophic rat model
that the activity of both NBCn1 and NBCe1 are up-regulated [67].
In this rat model, it had been suggested that enhanced NBC activity
provides a mechanism for [Na+]i overload in hypertrophied hearts.
In contrast, in a pressure-volume overload rabbit model of HF no
differences were observed in cardiac NBC activity [68]. Thus,
whether or not NBC contributes to elevated [Na+]i may depend on
the species and on the specific pathological condition. In principal
inhibition of NBC could be a new therapeutic strategy to prevent
the increase in [Na+]i. However, it remains unknown whether
inhibition of NBC actually prevents the elevation of [Na+]i and the
development of hypertrophy and HF. A complicating factor for
these studies is the lack of specific NBC inhibitors.
THE Na+-K +-2Cl- COTRANSPORTER
The Na+-K+-Cl- cotransporter (NKCC) is localized in the
sarcolemma and is involved in the cell volume regulation. NKCC
transports extracellular Na+, K+ and Cl- ions into the cytoplasm with
a stoichiometry of 1Na+:1K+:2Cl-, thereby supplying the cell with
solutes that may prevent cell shrinkage.
The NKCC1 is the most ubiquitous expressed isoform and is
present in the heart. It has been demonstrated that NKCC can be
modulated by adrenergic, angiotensin II, and aldosterone receptor
stimulation [69]. Ligands for these receptors are abundantly present
in HF and may increase NKCC activity.
NKCC has been shown to contribute to Na+ loading during
myocardial ischemia and reperfusion. Accordingly, the NKCC
inhibitor bumetanide reduced Na+ loading and attenuated ischemic
injury in diabetic rats [70]. Moreover, recent evidence indicates that
myocardial NKCC is increased in post-infarction HF [71].
Although, in this model of HF, NKCC inhibition attenuated postinfarction remodelling, it remains to be determined whether or not
increased NKCC underlies elevated [Na+]i in HF. If NKCC proves a
major pathway for increased Na+ influx in HF than classical loop
diuretics, bumetanide and furosemide, may be useful therapeutic
tool to prevent the development of hypertrophy and HF. It should
be taken into account that these loop diuretics reduce volume
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Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4
overload by stimulating natriuresis and diuresis, which by itself,
improves hemodynamics and may reduce hypertrophy and HF [72].
THE LATE Na+-CHANNEL CURRENT
Sodium channels (Na+-channels) are activated on the depolarization of sarcolemma. The Na+ current (INa) flowing through these
channels, is responsible for the fast upstroke of the cardiac action
potential (AP) and contributes to the fast conduction during cardiac
excitation. Most of the current rapidly inactivates (INaT) within a
few milliseconds upon depolarization, however, a small fraction of
this current inactivates slowly, the so-called late sodium current
(INaL) [73] (Fig. 7 panel A).
233
Initial studies using whole-cell patch-clamp technique configuration, showed no change in INaT in HF [78], although later studies
showed a decrease in current density [79, 80]. In this respect, it
must be realized that reduction of INaT can lead to slowing of the
upstroke of the AP, reduced conduction velocity, unidirectional
block and re-entrant arrhythmias [80]. However, the amount of Na+
influx will not be changed unless the amplitude of the upstroke of
the AP is changed. Similar amplitude of the upstroke, fast or slow,
requires an equal amount of Na+ entry albeit in a longer period of
time. Therefore, reduction of INaT will not necessarily change
[Na+]i. In several studies it has been shown that INaL is increased in
HF [81-84]. In contrast to INaT an increase of INaL results in
prolongation of the AP duration (Fig. 7 panel B) and increased
influx of Na+ ions. For that reason it has been suggested that
increased [Na+]i in HF is caused by an increase of INaL and that
inhibition of INaL can prevent [Ca2+]i overload and may be
beneficial for the development of hypertrophy and HF [83, 85, 86].
Yet, no data are available in which inhibition of INaL proved
beneficial in preventing the development of hypertrophy and HF or
in reducing [Na+]i. On the other hand, it has been shown that
inhibition of INaL can shorten AP duration and decrease the
propensity to evoke EADs related arrhythmias (Fig. 7 panel C) [8286] and improve mechanical efficiency [87]. Whether INaL
inhibition will be an effective treatment for hypertrophy and HF
remains to be investigated.
THE Na+/Ca2+-EXCHANGER
The Na+/Ca2+-exchanger (NCX), a surface membrane antiporter,
is the primary pathway for Ca2+ efflux. The driving force of NCX
depends on the sarcolemmal Na+ and Ca2+ gradient and the membrane potential. NCX catalyzes the electrogenic transport of one
Ca2+ ion across the membrane in exchange for three Na+ ions in a
reversible manner, depending on its direction. By convention NCXmediated transport is called ’forward’ when Na+ is transported
inward and Ca2+ outward and ‘reversed’, when ions are transported
in the opposite directions.
The cardiac specific isoform NCX1 is abundantly present in the
sarcolemma of cardiac myocytes. The large cytoplasmic loop of
NCX is believed to contain the regulatory sites of the protein.
Regulation is achieved by a variety of extracellular and intracellular
factors. However, the exact mechanisms are not completely understood and require further investigation [31, 88-90].
Fig. (7). Sodium current (INa) and increased variability of action potential
duration in HF.
The late INa is associated with slow inactivation component of INa. Panel A
illustrate a normal (left) and an increased late INa (right) due to impaired
inactivation of the sodium current. The enhanced late INa is accompanied by
delayed ventricular repolarization.
Panel B; shows action potential recorded by perforated patch clamp in
representative normal and failing dog ventricular myocytes. Panel C shows
that variability in beat-to-beat action potential duration in failing myocytes
can be rescued by electrical neutralization of the late INa . Panel B and C.
Reproduced with permission from ref 83.
The TTX-resistant Na+-channel Na(v)1.5 is predominantly
expressed in the heart, whereas the minor part of the sodium
channel is composed of the TTX-sensitive sodium channels
Na(v)1.1, 1.2, 1.3, 1.4, 1.6 [74]. Electrophysiological recordings
showed that TTX-resistant and TTX-sensitive Na+ channels,
respectively, accounted for 92% and 8% of the INa, in adult
ventricular cardiomyocytes [75]. The gating and kinetics of the
sodium channel are largely controlled by the membrane voltage,
however the channels can also be regulated by PKA and PKC [76],
calcium, calmodulin and CaMKII [77].
In hypertrophy and HF it has been shown that NCX expression,
activity and driving force is altered [23, 24, 91-97] and therefore
could play a role in the impairment of Ca2+ and Na+ handling,
altered contractility and arrhythmogenesis [88, 98-100]. It has to be
realized, because of the steady-state consideration, that NCXmediated Ca2+ efflux is equal to the L-type calcium channel
mediated Ca2+ influx. L-type calcium current in HF proved
unchanged or even reduced [101-107]. Thus regarding steady-state
consideration, the Ca2+ and Na+ flux through NCX in HF is most
likely not different from the ‘normal’ and thus cannot contribute to
enhanced Na+ influx and altered Na+ handling observed in HF. On
the other hand, it is known that the driving force of NCX is shifted
to less forward mode, and increased reversed mode largely caused
by an increase of [Na+]i [23, 24] (Fig. 8). This results in an increase
of cytosolic Ca2+ [24], to compensate for the shift in driving force,
until the Ca2+ efflux through NCX equals the Ca2+ influx.
KB-R7943 and SEA-0400 are inhibitors of NCX [89,107]. KBR7943 largely affects the reverse mode of NCX [107], whereas
SEA-0400 has no preference for forward or reversed mode.
Inhibition of the forward mode reduces Ca2+ efflux and increases
[Ca2+]i, which may ultimately activate hypertrophic signalling
pathways (Fig. 1) and the development of HF. In addition, the
increased [Ca2+]i promotes sarcoplasmic reticulum (SR) Ca2+
loading and SR Ca2+ release, which render the myocytes more
234 Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4
Baartscheer and van Borren
and consequently, a 1.5 mM higher [Na+]i. In rabbit failing myocytes it
has been shown that GATP was ±2 kJ/mole lower compared to
control myocytes [25].
Fig. (8). The dynamic change of the driving force (Gexch.) the Na+/Ca2+exchanger (NCX).
Dynamic change of Gexch in 2 Hz stimulated myocytes isolated from
control rabbits and rabbits with volume and pressure overload induced HF.
Dotted area corresponds to reversed mode operation of NCX.
susceptible to triggered arrhythmias due to spontaneous Ca2+
release from the SR. Inhibition of reversed mode NCX reduces
influx of Ca2+ and may prevent [Ca2+]i overload, which could
reduce activation of the hypertrophic response and DADs related
arrhythmias. Indeed, recent studies have provided evidence that
inhibition of reversed mode by KB-R7943 is effective in reducing
cytosolic Ca2+ overload, cell injury and arrhythmias in different
kinds of preparation and experimental conditions. [107, 108]. Few
data are available regarding HF. In failing myocytes it has been
shown that inhibition of NCX improves excitation-contraction
coupling in HF [109]. So, therapeutic intervention, which inhibits
reversed mode or activates forward mode NCX might reduce Ca2+
overload in HF and as a consequence reduce the hypertrophic
response and DADs related arrhythmias. In addition, the regulatory
mechanisms of the NCX protein, which are achieved by a variety of
extracellular and intracellular factors, are in principle therapeutic
targets to influence the activity of NCX.
THE Na+/K+-ATPase
The Na+/K+-ATPase (Na/K-pump) is found at the plasma
membrane and provides the major route for cellular Na+ extrusion
[110, 111]. The energy derived from the hydrolysis of ATP is used
by the Na/K-pump to extrude three Na+ ions for two K+ ions. A
principal modulator of Na/K-pump activity is [Na+]i [112-114]. In
this way the Na/K-pump keeps [Na+]i low and [K+]i high, thereby
maintaining the asymmetric gradients of these ions across the
sarcolemma.
The myocardium expresses three Na/K-pump -subunit isoforms (1, 2, and 3) and one ß1-subunit isoform. The -subunits
differ in affinity for intracellular Na+ and for the inhibitor ouabain.
In addition, also a Na/K-pump regulatory -subunit, phospholemman
(PLM), is expressed in the heart.
Modulation of the Na/K-pump activity can be achieved by
changing expression levels, shifting the -isoform expression, and
changing PLM phosphorylation. PLM phosphorylation by protein
kinase A (PKA) and protein kinase C (PKC), causes dissociation of
PLM from the -subunits thereby increasing the Na+ and K+ affinity
of the Na/K-pump [115]. Further, it should be realized that the
sodium gradient across the sarcolemma largely depends on the
energy that can be transferred to the Na/K-pump by hydrolysis of
ATP (GATP) [116]. A rather small change of ±2 kJ/mole of the
GATP will shift the thermodynamic equilibrium of the Na/K-pump
Several studies have reported a decrease in the activity of the
Na/K-pump in hypertrophy and HF due to downregulation of the
number of pumps and/or due to shift in isoform expression [117125]. However, most studies regarding expression of the Na/Kpump were performed in tissue homogenates and could reflect
changes in non-myocytes [126]. In addition, these experiments
cannot dis-criminate between sarcolemma and intercellular Na/Kpump expression. It is therefore hard to show a clear relationship
between the expression and activity of Na/K-pump. In this respect it
is surprising that there are only a few reports in which Na/K-pump
function activity is actually measured in the setting of HF. In
myocytes from rats with HF, the maximal Na+ efflux rate was
reduced with unchanged [Na+]i-affinity [127]. In contrast, in myocytes from dogs with hypertrophy induced by chronic atrioventricular block, maximal Na/K-pump activity is unchanged but [Na+]iaffinity was reduced [28]. In myocytes from rabbits, with volume
and pressure overload induced HF, neither maximal Na+ efflux rate
nor the affinity of Na/K-pump was reduced [23]. So, it seems that
Na/K-pump expression may be altered in cardiac myocytes without
a change in maximal activity. Moreover, from steady-state
considerations it follows that the Na/K-pump in HF, even if downregulated at the protein level, is capable to balance increased sodium
influx. Thus, the actual activity of Na/K-pump must be higher in
HF. Increased [Na+]i in HF could kinetically compensate for downregulation of the Na/K-pump and increased sodium influx in order to
achieve steady-state. Another reason for the discrepancy between the
expressions and activity of the Na/K-pump might be altered regulation of the pump in HF. However, signalling cascades involved in
hormonal regulation, in particular, are varied and complex.
Alterations in regulation may be the result of posttranslational
modification such as phosphorylation. It remains to be determined
whether and to what extent such modifications affect the Na/Kpump, per se, or some regulatory component [128, 129].
Following the argumentation that prevention of an increased
[Na+]i and the subsequent [Ca2+]i rise may prove beneficial in the
patients at risk to develop hypertrophy and HF. Activation of the
regulation mechanisms and/or direct activation of the Na/K-pump
might be therapeutically beneficial in reducing [Na+]i and [Ca2+]i,
development of hypertrophy and HF and prevent the remodelling.
Whether Na/K-pump activation will be an effective treatment for
hypertrophy and HF remains to be investigated and needs
development of new drugs. Until now inhibition of the Na/K-pump
(digoxin) is used to increase contractility of the heart in the setting
of HF. Inhibition of the pump results in a further increase of [Na+]i
and secondarily to an increase of [Ca2+]i and contractility.
Although, the short term effect of Na/K-pump inhibition is
beneficial in the treatment of HF because of increased contractility.
The long term effect might be detrimental because of the increase
of [Na+]i and [Ca2+]i. In this respect it has been shown that
reduction of Na+ efflux associated with Na+/K+-pump inhibition
promotes cardiac hypertrophy [130, 131].
SUMMARY
The sodium ion transport pathways that regulate [Na+]i maintain
normal Ca2+ handling, contractility and electrical activity of healthy
cardiomyocytes. Under pathophysiological conditions, such as
hypertrophy and HF, [Na+]i is increased due to an unbalanced
increased Na+ influx. The increased Na+ influx in HF may originate
from increased NHE-1, NBC and NKCC activity, and altered
inactivation of the Na+-channels. Increased [Na+]i in HF causes
NCX mediated elevation of [Ca2+]i, which is known to be a
hypertrophic signal. Cardiac hypertrophy is a major risk factor for
cardiac death and commonly precedes the development of HF. The
altered Na+ and Ca2+ handling in HF leads to electrical remodelling
Altered Sodium Handling
Cardiovascular & Hematological Agents in Medicinal Chemistry, 2008, Vol. 6, No. 4
and increased incidence of EADs and DADs, which are known
triggers for arrhythmias. In this respect, it has been shown experimentally that normalizing Na+ and/or Ca2+ handling is beneficial in
the prevention and regression of hypertrophy and HF and related
arrhythmias. These findings may help to find new therapeutic
strategies for the treatment of cardiac hypertrophy and HF.
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