T R E N D S I N CA R D I OVA S C U L A R ME D I C I N E 23 (2013) 59–65

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Review article

Acid–base transporters modulate cell migration, growth

and proliferation: Implications for structure development
and remodeling of resistance arteries?

Ebbe Boedtkjern, and Christian Aalkjaer

Department of Biomedicine, Aarhus University, Denmark

artic le info abstract

Article history: Disturbed acid–base transport across the plasma membrane affects intracellular pH
Received 31 July 2012 control and has been shown—primarily based on studies with non-vascular cells—to
Received in revised form interfere with a number of fundamental cell functions including cell migration, growth
29 August 2012 and proliferation. Here, we evaluate the effects of acid–base transport and intracellular pH
Accepted 30 August 2012 on the morphology of the resistance artery wall, which is altered in a number of
Available online 21 December 2012 physiological and pathological conditions and is an independent predictor of cardiovas-
cular risk. The current evidence supports that disturbed function and/or expression of
acid–base transporters can alter resistance artery morphology—and potentially
atherosclerosis-prone conduit arteries—and hence should be considered as possible
mechanistic components and targets for treatment in cardiovascular disease. More
experimental evidence is required, however, to evaluate the cell biological effects of
acid–base transport in vascular cells, the roles of specific acid–base transporters in artery
remodeling, the relative mechanistic importance of acid–base transporters in the vascular
wall compared to other organs, and the therapeutic potential of modifying acid–base
transport activity pharmacologically or genetically.
& 2012 Elsevier Inc. All rights reserved.

Introduction 2002); and correspondingly, pulmonary artery remodeling is

The structure of resistance arteries (i.e. the media thickness
to lumen diameter ratio) contributes to determining vascular
resistance and is an independent predictor of cardiovascular
risk (Rizzoni et al., 2003; Mathiassen et al., 2007). In the
systemic circulation, morphological changes in the resis-
tance vasculature take place under a number of pathological
conditions including diabetes (Sachidanandam et al., 2007),
hypotension (Li et al., 2002) and hypertension (Mulvany,
associated with pulmonary hypertension (Hales et al., 1983;
Mandegar et al., 2004). Even though the association between
altered intravascular pressure and changes in artery struc-
ture has been described for decades, the temporal and
mechanistic relationships remain to be defined in detail;
and at present, it is unclear to what extent increased media
thickness is a cause or consequence of hypertension.
Vascular smooth muscle cell (VSMC) proliferation, hypertro-
phy and migration are obvious factors to consider when

n
Correspondence to: Department of Biomedicine, Aarhus University, Ole Worms Allé 6, Building 1180, DK-8000 Aarhus C, Denmark.
Tel.: þ45 87167716.
E-mail address: eb@fi.au.dk (E. Boedtkjer).

1050-1738/$ - see front matter & 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.tcm.2012.09.001
60 TR E N D S I N CA R D I O VA S C U L A R
evaluating changes in artery structure although their relative
importance depends on the cardiovascular disturbance in
question. There is general agreement that essential hyperten-
sion is associated with eutrophic inward remodeling of resis-
tance arteries (i.e. rearrangement of the same amount of
media material around a smaller lumen diameter (Mulvany,
2002)), while resistance arteries from patients with reno-
vascular hypertension (Rizzoni et al., 2000) and rats chronically
infused with adrenergic receptor agonists (Dao et al., 2001)
are characterized by hypertrophic inward remodeling
(i.e. increased amounts of media material around a smaller
lumen diameter) mainly due to VSMC hypertrophy and hyper-
plasia, respectively. Migration and proliferation of VSMCs are
also key pathogenic factors in atherosclerosis.
Considering the independent predictive value of resistance
artery morphology in cardiovascular risk assessment (Rizzoni
et al., 2003; Mathiassen et al., 2007), treatment strategies that
modify artery structure are desired. The inward remodeling
of arteries from hypertensive patients can be partially
reversed by antihypertensive drugs (Heagerty et al., 1988);
however, in order to develop pharmacological therapies that
target artery structure directly, an in-depth molecular under-
standing of the pathways controlling arterial structure devel-
opment and remodeling is required.
Acid–base disturbances are commonly seen in renal, gastro-
intestinal and pulmonary disease and can be associated with
conditions of altered metabolism, such as in diabetes, cancer
and ischemia. Local changes in pH can also be observed
physiologically during strenuous exercise or high neuronal
activity. Changes in pH affect numerous cellular responses;
and as outlined below (section Importance of acid–base trans-
porters for cell migration and Importance of acid–base trans-
porters for cell proliferation, survival and hypertrophy),
intracellular pH (pHi) is of particular importance for cellular
migration, hypertrophy and proliferation. Although these phe-
nomena have so far primarily been investigated in cultured
cells of non-vascular origin—and further studies are required
to determine the consequences of disturbed pHi regulation in
vascular cells—acid–base transporters should be regarded as
potential new therapeutic targets for modifying the structure
of both conduit and resistance arteries. Here, we evaluate the
current evidence concerning mechanisms of pHi control in
CAII
CO2 + H2O
HCO3-
NBCn1
H2O + CO2 HCO3-
H+
Fig. 1 – Schematic showing the major net acid and base extruders in VSMCs. In addition to the transport of acid–base
equivalents, the transporters also permit uptake of Naþ and Cl and hence contribute to volume regulation. Note that
NBCn1 and NHE1 perform similar net transport functions when the CO2/HCO
pass through the lipid bilayer directly or through gas channels (e.g. aquaporins).
M E D I C I N E 23 (2013) 59–65
VSMCs and the effects of acid–base transporters and disturbed
pHi on structure development and remodeling of resistance
arteries.
Regulation of intracellular pH in the vascular wall
Similar to other cell types, pHi of VSMCs and endothelial cells
(ECs) is primarily influenced by metabolic acid production,
physicochemical buffering and transport of acid–base
equivalents across the cell membrane, see also (Boedtkjer
and Aalkjaer, 2012). Typically, since cell metabolism has the
net effect of adding acid equivalents to the cytosol and the
negative membrane potential favors net influx of Hþ-equiva-
lents, most cells rely on efficient mechanisms of acid extru-
sion to avoid development of intracellular acidification. Net
acid extrusion from VSMCs in mesenteric small arteries is
mediated by the Naþ,HCO 3 -cotransporter NBCn1 (slc4a7)
(Boedtkjer et al., 2006, 2011) and the Naþ/Hþ-exchanger
NHE1 (slc9a1) (Boedtkjer et al., 2012b). Although, the net
effect of both of these secondary active transport mechan-
isms is extrusion of one Hþ-equivalent in exchange for one
Naþ (Fig. 1), they appear to have different roles in pHi control:
NHE1 is predominantly active at low pHi values and plays a
major role for acid extrusion during conditions of severe
intracellular acidification (Boedtkjer et al., 2012b) whereas
NBCn1 is active at both low and near-physiological pHi values
and therefore contributes to acid extrusion during intracel-
lular acidification as well as control of steady-state pHi
(Boedtkjer et al., 2006, 2011). While these disparate roles of
NBCn1 and NHE1 for pHi regulation have been most clearly
defined for mouse mesenteric arteries (Boedtkjer et al., 2006,
2011, 2012b), they also seem to apply to coronary and cerebral
arteries (Boedtkjer et al., 2006) and thus probably are valid for
resistance arteries in general.
Obviously, the requirement for cellular acid extrusion
differs under various physiological and pathological condi-
tions. As illustrated in Fig. 2, it has been suggested that
mechanical stimuli (e.g. shear stress (Ziegelstein et al., 1992)),
neurohumoral factors (e.g. insulin (Boedtkjer and Aalkjaer,
2009) and norepinephrine (Aalkjaer and Cragoe, 1988)) and
metabolic disturbances (e.g. during hypoxia (Foy et al., 1997))
Cl-
AE2
HCO3-
HCO3- + H+
H+
NHE1
Na+ Na+
3 buffer system is in equilibrium. CO2 may
 TR E N D S I N CA R D I OVA S C U L A R
Fig. 2 – Diagram of the proposed role of acid–base transporters in modulating vascular structure and function. Note that the
specified enzymes are only examples of mechanistic pathways involved in modifying artery structure; see the main text for
additional details.
affect acid–base transport activity in the vascular wall or in
isolated vascular cells but the signaling pathways have yet to
be defined in detail, see also (Boedtkjer and Aalkjaer, 2012;
Boedtkjer et al., 2012a).
Implications of low intracellular pH for vasomotor
function
Artery remodeling has been proposed to be wall-stress-sensitive
and depend on VSMC activation (Jacobsen et al., 2008). Hence, it
is relevant to consider the effects of disturbed acid–base trans-
port and pHi on the vasomotor function of resistance arteries;
see also (Boedtkjer and Aalkjaer, 2012) for further details. As
illustrated in Fig. 3, acute intracellular acidification of VSMCs
(induced within tens of seconds) causes a marked increase in
intracellular [Ca2þ] and an associated vasoconstriction (see
(Boedtkjer and Aalkjaer, 2012)) whereas prolonged intracellular
acidification of VSMCs (lasting several minutes to hours) attenu-
ates rho-kinase-dependent Ca2þ-sensitivity (Boedtkjer et al.,
2011, 2012b). The inhibition of rho-kinase-dependent signaling
seems—at least in part—attributable to a moderate intrinsic pH-
sensitivity of the rho-kinase, which is inhibited at pHi levels
both below and above normal physiological values (Boedtkjer
et al., 2011). The reduced Ca2þ-sensitivity of VSMCs with low pHi
tends to attenuate agonist-induced vasocontractile responses
(Boedtkjer et al., 2006, 2011, 2012b); however, in endothelium-
intact arteries from global knockout mice, where EC pHi is also
low, the expected vasocontractile dysfunction is masked by a
reduced vasodilatory function caused by a pHi-mediated inhibi-
tion of NO-synthase activity in the ECs (Boedtkjer et al., 2011,
2012b), see Fig. 3. It is relevant that both the rho-kinase and the
NO-synthase pathway have complex effects on VSMC prolifera-
tion and migration which are independent of contractility
(Chang et al., 2002; Wirth, 2010).
Disturbed cellular acid–base regulation also has cardiovas-
cular implications in vivo as illustrated by the disturbed blood
M E D I C I N E 23 (2013) 59–65 61
Fig. 3 – Diagram of the predominant effects of acute and
long-term changes in pHi on tone development of
resistance arteries. Intracellular pH affects a number of
targets including Ca2þ buffers, ion channels, intracellular
enzymes and possibly cellular receptors or sensors. During
acute intracellular acidification (induced within tens of
seconds), an increase in [Ca2þ] is evident causing
vasoconstriction. During sustained intracellular
acidification (lasting several minutes to hours), modulation
of enzyme activity is prominent and both vasocontractile
(e.g. due to reduced rho-kinase signaling) and vasodilatory
(e.g. due to reduced NO-synthase activity) responses are
inhibited. See section Implications of low intracellular pH
for vasomotor function for further details.
pressure regulation in NBCn1 knockout mice (Boedtkjer et al.,
2011). These mice are mildly hypertensive at rest and show
attenuated blood pressure responses to NO-synthase inhibi-
tion (by L-NAME ingestion) and to stimulation (by angioten-
sin II infusion) or inhibition (by Y-27632 injection) of
rho-kinase-dependent signaling (Boedtkjer et al., 2011).
These rather complex perturbations of blood pressure prob-
ably reflect that the net impact of NBCn1 knockout is a
62 TR E N D S I N CA R D I O VA S C U L A R
composite of effects on multiple signaling cascades and
determined among others by the relative activities in the
rho-kinase- and NO-dependent signaling pathways.
Importance of acid–base transporters for cell
migration
In both eutrophic and hypertrophic resistance artery remo-
deling and in atherosclerosis, cell migration is required for
the reorganization of the media material. Studies have shown
that the overlap between adjacent VSMCs increases within a
few hours of stimulation with vascular agonists (Martinez-
Lemus et al., 2004) suggesting that VSMCs are indeed highly
mobile cells allowing for great structural plasticity. This likely
plays an important physiological role by minimizing energy
expenditure during prolonged vasoconstriction (Martinez-
Lemus et al., 2004) and contributes to the pathological artery
remodeling seen among others during hypertension. There is
consistent evidence (Schwab et al., 2005; Stock and Schwab,
2006) that NHE1 is important for migration of cultured cells
and pharmacological inhibition of NHE1 has been reported to
inhibit migration velocity as much as 70%. Also for pulmonary
artery VSMCs, down-regulation of NHE1 has been shown to
attenuate migration (Yu and Hales, 2011).
Multiple mechanisms likely contribute to the effects of NHE1
on cell migration and these can be roughly categorized into
some that depend on ion translocation and others that depend
on NHE1 as a scaffold interacting physically with intra- and
extracellular components. The transport-dependent mechan-
isms support directed locomotion by inducing local volume
changes (by coupled Naþ/Hþ-exchange, Cl/HCO 3 -exchange
and water transport) and modifying local pHi-mediated reg-
ulation of actin polymerization (Stock and Schwab, 2006), see
Fig. 2. Important in these respects is the uneven distribution of
NHE1 on the plasma membrane with particularly high expres-
sion levels at the leading edge of lamellipodia (Grinstein et al.,
1993). The uneven distribution of NHE1 is also crucial for the
generation and maintenance of a longitudinal pH gradient,
which accompanies cell polarity (Stock et al., 2007). The
extracellular acidification associated with increased net acid
extrusion also likely contributes to activation of extracellular
enzymatic activity involved in matrix degradation and hence
allows for migration of cells into tissues (Stock and Schwab,
2006). The transport-independent mechanisms include plas-
malemmal anchoring of actin filaments (e.g. via
ezrin–radixin–moesin proteins), interactions with extracellular
matrix components (e.g. via integrins) and coupling to intra-
cellular signaling cascades altering intracellular kinase activity
or gene expression (Stock and Schwab, 2006). Most of these
mechanisms, however, require verification in VSMCs.
The contribution of Naþ,HCO 3 -cotransporters to cell migra-
tion has so far only been scarcely investigated. Focusing on the
mechanistic pathways described above, the very similar trans-
port functions of Naþ/Hþ-exchangers and Naþ,HCO 3 -cotran-
sporters (Fig. 1) suggest that Naþ,HCO 3 -cotransporters may
substitute for NHE1 at least in aspects requiring ion transloca-
tion. The interaction of NBCn1 and other Naþ,HCO 3 -cotranspor-
ters with the cytoskeleton, extracellular matrix components and
intracellular signaling cascades have not yet been determined in
M E D I C I N E 23 (2013) 59–65
sufficient detail to evaluate whether also in these respects
Naþ,HCO 3 -cotransporters may perform functions similar to
those of NHE1. While the current experimental evidence sug-
gests that another Naþ,HCO 3 -cotransporter NBCe1 (slc4a4)
affects cell migration, the effect is rather modest: in transformed
renal epithelial cells, inhibition of NBCe1 activity reduced
migration velocity after an intracellular acid load and on a short
time scale of 30 min, while—in contrast to NHE1—no effect on
migration was seen after longer observation times (Schwab
et al., 2005). In a recent study using the human breast cancer
cell line MCF-7 stimulated by overexpression of a constitutively
active, amino-truncated ErbB2 receptor, no role for NBCn1 in cell
migration was found (Lauritzen et al., 2012). Studies investigat-
ing the importance of Naþ,HCO 3 -cotransport for cellular migra-
tion have so far been restricted by the lack of specific
pharmacological inhibitors (Boedtkjer et al., 2012a); and clearly,
more information is needed to fully determine its potential role.
Importance of acid–base transporters for cell
proliferation, survival and hypertrophy
In hypertrophic artery remodeling, the amount of media material
increases and hence cell proliferation or hypertrophy is required.
It is generally accepted that an increase in pHi enhances cell
growth and proliferation, which partially appears to be due to
alkaline pHi promoting cell-cycle progression and accelerated
synthesis of protein, RNA and DNA (Pedersen, 2006), see Fig. 2.
NHE1 seems particularly important and, in addition to effects on
pHi, likely promotes an increase in cell volume and uptake of
inorganic ions important for cell growth and division (Pedersen,
2006). In addition, NHE1 may also independently of pHi activate
relevant intracellular signaling cascades (e.g. ERK-activation
and MAPK-signaling) (Pedersen, 2006). Consistent with a role
for Naþ/Hþ-exchange and pHi in cell growth and proliferation,
growth factors have been shown to activate Naþ/Hþ-exchange
activity in fibroblasts and cause intracellular alkalinization
(Moolenaar et al., 1983). Using isolated VSMCs from pulmonary
arteries, previous studies have shown that knockdown of NHE1
or pharmacological inhibition result in a hypotrophic VSMC
phenotype (LaPointe and Batlle, 1994; Yu and Hales, 2011).
In addition to effects on proliferation and growth, NHE1
has been shown to inhibit apoptosis (Pedersen, 2006). NHE1
likely inhibits apoptosis by defending cells against shrinkage
and maintaining pHi more alkaline than the optimum for
endonucleases, caspases and cathepsins critical for induc-
tion of programmed cell death but may also act in part
through a transport-independent scaffolding role (Pedersen,
2006). It should be noted that enhanced NHE1 activity in the
vascular wall may under other circumstances—particularly
during hypoxia/reoxygenation events—contribute to cell
death, in part due to intracellular Naþ- and consequent
Ca2þ-overload (Boedtkjer and Aalkjaer, 2012).
Effects of acid–base transporters on the structure
of systemic small arteries
Although there is strong evidence that disturbed acid–base
transporter function and/or expression affect cell migration,
 TR E N D S I N CA R D I OVA S C U L A R
proliferation, growth and survival, it is difficult to extrapolate
from results based on isolated (and typically non-vascular) cells
to effects on artery morphology seen under in vivo conditions.
Work on spontaneously hypertensive rats supports, however,
that Naþ/Hþ-exchange activity is enhanced and media thickness
increased in this model of hypertension compared to control
Wistar-Kyoto rats (Izzard and Heagerty, 1989), see also (Boedtkjer
and Aalkjaer, 2012) for details. Although this does not necessarily
imply a causative association, the findings are consistent with a
role for acid extrusion in regulation of blood pressure and
resistance artery structure. Further supporting this notion, we
have shown that NHE1 knockout mice are hypotensive; and in
mesenteric arteries from NHE1 knockout mice, the media thick-
ness and the media thickness to lumen diameter ratio are
reduced compared to arteries from wild type mice (Boedtkjer
et al., 2012b). Interestingly, this morphological change was due to
smaller VSMCs while the number of VSMCs per unit artery
length was unchanged (Boedtkjer et al., 2012b). The smaller
volume of the VSMCs was explained by a smaller cross-
sectional area, while cell length was unaffected (Boedtkjer
et al., 2012b). Importantly, in the presence of CO2/HCO 3 when
pHi is similar between VSMCs from NHE1 knockout and wild
type mice, VSMC function was otherwise unaffected by the
absence of NHE1 (Boedtkjer et al., 2012b). The normal (global)
pHi of VSMCs in arteries from NHE1 knockout mice in the
presence of CO2/HCO 3 may suggest that transport-independent
effects of NHE1 (see section Importance of acid–base transporters
for cell migration) could play a major role, although local effects
on pH or volume in intra- or extracellular restricted compart-
ments could also play a role. Nonetheless, the role of pHi for
arterial structure is still controversial; and it seems relevant to
address whether NBCn1 and Naþ,HCO 3 -cotransport, which plays
no obvious role for artery structure under physiological condi-
tions (Boedtkjer et al., 2011), may play a role under stimulated or
pathological conditions.
It remains a particular challenge to determine whether
in vivo inhibition of acid–base transport modifies the mor-
phology of the vascular wall due to direct effects on the
VSMCs or secondary to altered hemodynamic control or
neurohumoral signaling. Tissue-specific knockout mice for
NBCn1 and NHE1 are not available at this time but could
provide important clues to this question. Techniques to
measure pHi in the vascular wall in vivo under various
physiological and pathological conditions and under influ-
ence of e.g. the flowing blood, circulating humoral factors
and transmitters released from perivascular nerves would
also represent an important step forward.
Effects of acid–base transporters on the structure
of pulmonary small arteries
An association between pulmonary hypertension and NHE1
expression and function has been suggested based on
increased NHE1 mRNA and protein expression as well as
enhanced Naþ/Hþ-exchange activity in pulmonary artery
VSMCs from mice with hypoxia-induced pulmonary hyper-
tension (Rios et al., 2005; Shimoda et al., 2006). In line with
this—and consistent with the hypotrophic VSMCs in sys-
temic arteries from NHE1 deficient mice (Boedtkjer et al.,
M E D I C I N E 23 (2013) 59–65 63
2012b) (see section Effects of acid-base transporters on the
structure of systemic small arteries)—NHE1 knockout mice
(Yu et al., 2008) and rats treated with Naþ/Hþ-exchange
inhibitors (Quinn et al., 1998) have been shown to be
unsusceptible to hypoxia-induced pulmonary artery remo-
deling and development of pulmonary hypertension. Later,
the same authors showed that reduced NHE1 expression
inhibits proliferation, hypertrophy and migration of pulmon-
ary artery VSMCs through a mechanism that depends on the
transcription factor E2F1 (Yu and Hales, 2011). Furthermore,
rho-kinase (ROCK1 and ROCK2) expression was strongly
reduced in pulmonary arteries from NHE1 deficient mice
while a paradoxical increase in phosphorylation of its
immediate downstream target MYPT1 was observed (Yu
et al., 2008). This suggests a complex disturbance of rho-
kinase signaling, which may be important for the reduced
tendency of NHE1 knockout mice to develop pulmonary
hypertension. The involvement of the rho-kinase pathway
in development of pulmonary hypertension is supported by
other studies (Xu et al., 2010; Peng et al., 2012); and recently, it
was shown that sustained hypercapnia inhibits rho-kinase
activity and ameliorates pulmonary hypertension in rats
(Peng et al., 2012). The mechanistic background needs to be
further explored, but since hypercapnia would be expected to
cause intracellular acidification of VSMCs—and no significant
change in rho-kinase expression was seen in pulmonary
arteries from the hypercapnic rats—the reported pH sensi-
tivity of the rho-kinase pathway (Boedtkjer et al., 2011) (see
section Implications of low intracellular pH for vasomotor
function) could play a prominent role.
Conclusions and future directions
The current evidence supports that acid–base transporters
are important for structure development and remodeling of
resistance arteries in both the systemic and the pulmonary
circulation. Hence, acid–base transporters may play a con-
siderable role in development of hypertension and athero-
sclerosis and provide a promising target for new treatment
strategies to improve cardiovascular survival.
Nevertheless, several important questions should be
addressed to substantiate the role of acid–base transporters
for control of resistance artery structure: (1) The link between
acid–base transport and changes in cell migration, prolifera-
tion, growth and survival is well established for cultured non-
vascular cells and supported by initial studies on VSMCs.
More work is required, however, to conclusively determine
the relevance of acid–base transport for cell migration,
proliferation, growth and survival in VSMCs both in culture
and in vivo. (2) Acid–base transporters clearly play a promi-
nent role by controlling pHi but also have pHi-independent
effects due to their function as molecular scaffolds and their
involvement in cellular signaling cascades. It should be
determined to what extent the effects of disturbed
acid–base transporter expression on artery structure are
secondary to an altered pHi regulatory function. (3) In addi-
tion to direct effects on VSMCs, disturbed acid–base transport
function could alter neurohumoral signaling or water and
electrolyte balance—due to or independent of changes in
64 TR E N D S I N CA R D I O VA S C U L A R
pH—and thus cause a secondary change in artery morphology.
The chain of events linking acid–base transport function to
artery morphology and the potential role of disturbed blood
pressure regulation in this response should be further investi-
gated. (4) While the discussion above has focused mainly on
the benefits of inhibiting artery remodeling during pathological
states, it should be kept in mind that artery remodeling is also
an important physiological response to sustained vasoconstric-
tion (Martinez-Lemus et al., 2004). The potential negative
effects of inhibiting this physiological process require further
investigations.
Finally, in order to advance studies on the role of acid–base
transporters in the vascular wall both in vitro and in vivo and
exploit potential therapeutic effects of acid–base transport
inhibition, it is imperative that selective pharmacological
inhibitors of NBCn1 and NHE1 with appropriate pharmaco-
kinetic profiles be developed. A number of Naþ/Hþ-exchange
inhibitors with selectivity towards NHE1 are available and
have been administered clinically although neurological side-
effects have precluded wider clinical use, see also (Boedtkjer
et al., 2012a). Specific pharmacological inhibition of Naþ,
HCO 3 -cotransport is still a major challenge (for an in-depth
discussion, see (Boedtkjer et al., 2012a)) and although the
compound S0859 is a promising non-selective inhibitor of
Naþ,HCO
3 -cotransport (Ch’en et al., 2008; Larsen et al., 2012),
a selective NBCn1 inhibitor is desired to reduce side-effects
due to inhibition of other Naþ,HCO 3 -cotransporters. S0859
furthermore shows strong binding to plasma proteins
restricting its use to isolated cells in saline solutions
(Larsen et al., 2012) and underscoring the need for further
advancements both in terms of pharmacokinetic and phar-
macodynamic properties.
Acknowledgments
Related work in the authors laboratories is supported by the
Danish Council for Independent Research (10-094816 to E.B.
and 271-06-0472 to C.A.), the Danish Heart Foundation (08-10-
R68-A2179-B719-22494 to E.B.) and the Lundbeck Foundation
(R93-A8859 to E.B.).
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