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REVIEW
ARTICLE
Potassium channels in vascular smooth
muscle: a pathophysiological and
pharmacological perspective
Muhammed Fatih Dogan
a
, Oguzhan Yildiz
b
*, Seyfullah Oktay
Arslan
a
, Kemal Gokhan Ulusoy
b
a
Department of Pharmacology, Ankara Yildirim Beyazit University, Bilkent, Ankara 06010, Turkey
b
Department of Pharmacology, Gulhane Faculty of Medicine, University of Health Sciences, Etlik, Ankara 06170,
Turkey
Keywords
hypertension,
potassium channels,
vascular diseases,
vascular smooth muscle
cells
Received 14 August 2018;
revised 28 February 2019;
accepted 7 March 2019
*Correspondence and reprints:
oguzhany01@gmail.com
ABSTRACT
Potassium (K
+
) ion channel activity is an important determinant of vascular tone
by regulating cell membrane potential (MP). Activation of K
+
channels leads to
membrane hyperpolarization and subsequently vasodilatation, while inhibition of
the channels causes membrane depolarization and then vasoconstriction. So far
five distinct types of K
+
channels have been identified in vascular smooth muscle
cells (VSMCs): Ca
+2
-activated K
+
channels (BK
Ca
), voltage-dependent K
+
channels
(K
V
), ATP-sensitive K
+
channels (K
ATP
), inward rectifier K
+
channels (K
ir
), and tan-
dem two-pore K
+
channels (K
2
P). The activity and expression of vascular K
+
chan-
nels are changed during major vascular diseases such as hypertension, pulmonary
hypertension, hypercholesterolemia, atherosclerosis, and diabetes mellitus. The
defective function of K
+
channels is commonly associated with impaired vascular
responses and is likely to become as a result of changes in K
+
channels during vas-
cular diseases. Increased K
+
channel function and expression may also help to
compensate for increased abnormal vascular tone. There are many pharmacologi-
cal and genotypic studies which were carried out on the subtypes of K
+
channels
expressed in variable amounts in different vascular beds. Modulation of K
+
channel
activity by molecular approaches and selective drug development may be a novel
treatment modality for vascular dysfunction in the future. This review presents the
basic properties, physiological functions, pathophysiological, and pharmacological
roles of the five major classes of K
+
channels that have been determined in VSMCs.
INTRODUCTION
Vascular smooth muscle cells (VSMCs) are contractile
and relaxative cells of all the vessels in the body. They
determine the diameter of the arteries and veins and
regulate tissue perfusion and venous drainage. Periph-
eral vascular resistance and blood pressure are deter-
mined by the vascular smooth muscle (VSM) tone of
the arteries and arterioles [1,2]. K
+
channels in VSMCs
have important roles in regulation of vascular tone,
but their functions have not yet been fully understood
[3,4]. The current knowledge in the literature clearly
shows that changing the equilibrium between internal
and external K
+
currents in VSMCs has a decisive effect
on MP, Ca
+2
influx, and VSM contraction [5,6]. Thus,
K
+
channels play a crucial role in the regulation of
vasomotor function in pathological conditions and they
are the potential targets of many new drugs for several
cardiovascular diseases [3,7].
The depolarization of cell MP and the continuously
elevated intracellular calcium concentrations ([Ca
+2
]
i
)
are both physiologically and pathologically important
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doi: 10.1111/fcp.12461
factors in the induction of cell proliferation as well as
in the contraction of VSMCs [8,9]. Because of the repo-
larizing effects of VSMCs, changes in the expression or
activity of the K
+
channels often translate into an
abnormal resting membrane potential (MP) associated
with abnormal vascular tone in arterial VSMCs.
Changes in the structure and function of the K
+
chan-
nels contribute to the pathophysiological conditions of
some vascular diseases, including hypertension, pul-
monary hypertension, hypercholesterolemia, and
atherosclerosis [10,11]. Increased vascular tone in
these diseases is often associated with depolarizing
changes in the resting MP of VSMCs, which may cause
abnormal vascular tone and hypersensitivity to vaso-
constrictor substances. Because impaired K
+
channel
activity is associated with vascular diseases, K
+
chan-
nels represent potential targets for the design of novel
therapeutic drugs that regulate abnormal vascular
activity [8,12].
Recently many pharmacological and genotypical
studies have been carried out on the subtypes of K
+
channels in VSMCs. Hence, novel specific drugs modu-
lating these subtypes are being developed from day to
day. In the near future, targeting the K
+
channels
modulation as a promising alternative to treat vascular
diseases may be considered a novel pharmacologic
approach. In this review, the basic pharmacological,
physiological, and pathophysiological properties of K
+
channels in VSMCs are presented.
BASIC PROPERTIES OF POTASSIUM
CHANNELS
Extensive evidence indicates that K
+
conductance is
mainly responsible for modulating cellular excitability
in VSMCs [2]. K
+
channels are a largest family of inte-
gral membrane proteins that form aqueous pores in cell
membranes through which K
+
can flow [13,14]. Func-
tionally, five different types of K
+
channels are
expressed in the vasculature: big conductance Ca
+2
-
activated (BK
Ca
), voltage-activate (K
V
), ATP-sensitive
(K
ATP
), inward rectifier (K
ir
), and two-pore domain
(K
2P
)K
+
channels [4,15,16]. Considering their struc-
tural electrophysiological and pharmacological proper-
ties, they are also classified into three main groups
according to the transmembrane (TM) spanning
domain number of each of the a-subunits forming the
channel: 2 TM, 4 TM, and 6 TM. The first 2 TM
groups consist of K
+
channels with two TM domains in
each of the a-subunits, also known as K
ir
and K
ATP
channels. Those with 6 TM are the largest K
+
channel
class and are divided into two types: K
Ca
and K
V
[16,17]. Unlike the 2 TM and 6 TM families, 4 TM
channels have two rather one pore-forming domains
per subunit [6].
The different subunits (aand b) of the K
+
channels
are encoded by different genes. The a-subunit consti-
tutes the pore structure that comprises the gating
apparatus and selective filter and interacts with auxil-
iary subunits that modulate the effects from different
signaling pathways. The b-subunit accessory part,
which increases sensitivity to Ca
+2
, modulates channel
activation and inhibition and reduces sensitivity to K
+
channels inhibitors, such as iberiotoxin (IbTx) and
tetraethylammonium (TEA) [18–20].
K
+
channels activity, an important determinant of
MP in VSMCs, is a major regulator of vessel diameter
and vascular tone. The opening of these channels
induces MP hyperpolarization with K
+
efflux, which
inhibits Ca
+2
entry by the closure of L-type voltage-
activated calcium channels (LVCC), and reduced Ca
+2
entry results in vasodilation [21–23]. Closure of K
+
channels leads to MP depolarization, opening of LVCC,
increased [Ca
+2
]
i
, eventually led vasoconstriction.
Therefore, as an important regulator of MP, K
+
chan-
nel activity is an essential determinant of vessel diame-
ter and vascular tone [24,25]. Effects of drugs,
endogenous, or exogenous substances on K
+
channels
in VSMCs are summarized in Table I.
Calcium-activated K
+
channels (K
Ca
)
These channels are expressed virtually in all excitable
tissues and can be classified as three subfamilies: large-
conductance Ca
+2
-activated K
+
channels (BK
Ca
), inter-
mediate-conductance K
+
channels (IK
Ca
), and small-
conductance K
+
channels (SK
Ca
) [51,52]. In general,
vascular endothelial cells express SK
Ca
and IK
Ca
chan-
nels. The single-channel conductivity of BK
Ca
is
between 200 and 250 pS and is significantly different
from the values of SK
Ca
(5–10 pS) and IK
Ca
(20–
40 pS). In the VSM, the most commonly described cur-
rent is a large conductivity (>200 pS). BK
Ca
is known
by pharmacological properties such as apamin (SK
Ca
inhibitor) and clotrimazole (IK
Ca
inhibitor) [53] insensi-
tivity with IbTx high sensitivity, which does not block
IK
Ca
or SK
Ca
[20,54,55].
BK
Ca
, such as K
V
, is voltage-dependent and mem-
brane depolarization activates these channels. BK
Ca
is
specifically activated by Ca
+2
release from the sar-
coplasmic reticulum into the VSMCs [56–59].
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Ryanodine-sensitive Ca
+2
-release channels (ryanodine
receptors [RyRs]) have a very important function in
controlling arterial tone and diameter through regula-
tion of BK
Ca
. RyRs in sarcoplasmic reticulum and BK
Ca
operate as a functional unit to regulate [Ca
+2
]
i
and
arterial tone through changes in MP and Ca
+2
influx.
The RyRs found in the sarcoplasmic reticulum and
BK
Ca
act as a functional unit regulating arterial tone
and [Ca
+2
]
i
with MP changes [60–62]. Hence, BK
Ca
is
target for a number of pharmacological agents that
may have a role in the prevention or reversal of
VSMCs depolarization, contraction, and maintenance of
the resting tone [63,64].
BK
Ca
has been described in almost all VSMCs types
studied so far and play a crucial role in the regulation
of the vascular tone [11,23]. The activation of BK
Ca
causes in a marked K
+
efflux leading to hyperpolariza-
tion in the VSMCs, resulting in LVCC closure and
vasodilation [65–67]. Each subunit provides different
pharmacological properties to BK
Ca
, which consists of
the pore-forming asubunit and the accessory bsub-
unit that modulate a-subunit Ca
+2
sensitivity and
channel activity [68,69]. Four b-subunits have been
determined in VSMCs, but the predominant is the b1-
subunit, which enhances the Ca
+2
and voltage sensitiv-
ity of BK
Ca
[16,70]. Many studies have shown
increased myogenic tone and contractility in the
absence or less expression of the b1 subunit. Moreover,
Yang et al. [71] showed that higher ratio of b1 sub-
unit: a-subunit in cerebral VSMCs related to that in
skeletal muscle may lead to higher Ca
+2
sensitivity of
BK
Ca
current in cerebral arteries. It is well known that
BK
Ca
is primarily activated either by an elevation of
the [Ca
+2
]i or by membrane depolarization and main-
tain MP and vascular myogenic tone through negative
feedback modulation [22,72–74]. Hence, BK
Ca
affects
as a relaxing negative feedback mechanism after ago-
nist-induced membrane depolarization and extracellular
Table I Effects of drug, endogenous or exogenous substances on K
+
channels in VSMCs.
Substance K
+
Channel Species Vascular bed Conclusion References
Taurine BK
Ca
Human Internal mammary artery Channel activation [26]
Taurine BK
Ca
Human Radial artery Channel activation [27]
Testosteron BK
Ca
Human Internal spermatic vein Channel activation [28]
Testosteron BK
Ca
Human Internal mammary artery Channel activation [29]
Propofol BK
Ca
Human Umbilical artery and vein Channel activation [30]
Propofol BK
Ca
Human Internal mammary artery Channel activation [31]
Hydrochlorothiazide BK
Ca
Human Umbilical artery VSMCs Channel activation [32]
Bupivacaine BK
Ca
Human Umbilical artery VSMCs Channel activation [33]
Epicatechin BK
Ca
,K
ATP
,K
V
Human Internal mammary artery Channel activation [34]
Levosimendan BK
Ca
,K
ATP
Human Umbilical artery Channel activation [35]
Propofol BK
Ca
Human Omental artery and vein Channel activation [36]
ACPA BK
Ca
Rat Mesenteric artery Channel activation [37]
Glabridin BK
Ca
Rat Mesenteric artery Channel activation [38]
Taurine BK
Ca
Rat Mesenteric artery
Renal artery
Channel activation [39]
Propofol BK
Ca
Rat Mesenteric artery Channel activation [40]
Propofol BK
Ca
K
ATP
Rat Mesenteric artery and vein Channel activation [41]
Taurine BK
Ca
K
ATP
Rat Aorta Channel activation [42]
Procyanidin B2 BK
Ca
K
ATP
Human Internal mammary artery Channel activation [43]
YM155 K
V
1.5, K
V
2.1 Human PASMCs Channel activation [44]
Levosimendan K
ATP
Human Internal mammary artery Channel activation [45]
Levosimendan K
ATP
Human PASMCs Channel activation [46]
Propofol K
ATP
Rat Aorta Channel activation [47]
High Salt Diet K
ATP
Rat Mesenteric artery Channel disfunction [21]
Thiopental, Propofol K
ATP
Rat Rat Aorta Decrease in K
ATP
-mediated relaxation [48]
Thiopental, Propofol K
ATP
Dog Pulmonary Vein Decrease in K
ATP
-mediated relaxation [49]
Nitric Oxide K
ATP
Rabbit Mesenteric artery Channel activation [50]
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Pharmacological perspective of potassium channels 3
Ca
+2
entry in most isolated arteries obtained from ani-
mals and humans [75,76]. Pharmacologically, external
TEA, charybdotoxin, IbTx, ethylene glycol tetraacetic
acid, and Ni
+2
inhibit channel activity [77–79]. IbTX
(10–100 nM) [80,81] is a potent inhibitor of BK
Ca
that
selectively binds to a specific region on the outside of
the channel and blocks the flow of ions [82,83].
BK
Ca
activation relaxes VSM, especially in the con-
duit arteries. Several studies demonstrated that testos-
terone and taurine-induced vasodilation may occur via
activation of BK
Ca
in the human radial artery and the
internal mammary artery [26,27,29]. It has been
shown that the vasodilator effect of propofol on the
human umbilical vessels [30] and the internal mam-
mary artery [31] is related to BK
Ca
. Propofol also
relaxed the mesenteric arterioles via BK
Ca
activation in
rat [40]. Levosimendan-induced relaxation in the
umbilical artery has been reported to occur due to
BK
Ca
and K
V
activation [35]. However, inhibition of
BK
Ca
induces vasoconstriction and Mart
ın et al. [33]
demonstrated using the patch-clamp technique that
bupivacaine, a local anesthetic drug, inhibits BK
Ca
cur-
rents in the umbilical artery. BK
Ca
is the target of both
vasoconstrictors and vasodilators [84,85]. Alterations
in BK
Ca
activity might also initiate or aggravate patho-
physiological states such as vasospasm and ischemia
[86]. It was reported that cytoplasmic ATP inhibits
BK
Ca
, and suggested that these channels may underlie
hypoxia-induced vasodilation [87]. The mechanisms by
which BK
Ca
contributes to vascular dysfunction are still
unclear and further investigation is needed to deter-
mine the role of BK
Ca
in vascular diseases [73,88].
Voltage-dependent K
+
channels (K
V
)
K
+
channels have multiple functions in the VSMCs and
K
V
are postulated to be a major determinant of vascu-
lar tone [7,89]. Broad K
V
expression has been identified
in vascular system. In response to the depolarization of
the MP, K
V
are activated and K
+
efflux occurs, result-
ing in repolarization. The depolarization of VSMCs
leads to Ca
+2
flow into the cells from LVCC and con-
tractile mechanisms are activated. This shows that K
V
maintain the resting vascular tone by limiting mem-
brane depolarization [90–92].
K
V
have the widest and most diverse family of 12
subfamilies (K
V
1–K
V
12) among the K
+
channels and
consist of four a-subunits and b-subunits. The asub-
units, which forms the K
+
-selective pore, contain six
TM domains (S1–S6) and P-loop between the S5 and
S6 domains. The S1–S4 region composes the voltage-
sensing domain [55,93,94]. Calcium influx through
LVCC associated with membrane depolarization can
also inhibit K
V
channels, and this may be formed sec-
ondary to [Ca
+2
]
i
release by RyRs. 4-aminopyridine (4-
AP), which is a specific inhibitor, and TEA have an
inhibitory effect against K
V
[29,93,95].
In VSMCs, K
V
have five major subfamilies as K
V
1.0,
K
V
2.0, K
V
3.0, K
V
4.0, and K
V
7; however, the K
V
1.2
and K
V
1.5 are predominantly expressed [12,22,24,96].
The relative abundance of K
V
in rat mesenteric artery
is higher than that in rat tail artery [24,96]. Studies
indicate that K
V
1.3 have positive effects in the prolifer-
ation and cell migration, which can result in neointi-
mal hyperplasia or vascular remodeling. Margatoxin is
a potent, highly selective blocker of human K
V
1.3 and
has no effect on K
Ca
[94,97]. It has been demonstrated
that K
V
current in rat small mesenteric artery myo-
cytes consists of two major parts, K
V
1.2–1.5–b1.2
and K
V
2.1–9.3, along with less functional K
V
7.4 and
K
V
7.5, which were encoded by the KCNQ4 and
KCNQ5, and play a key functional role in regulating
vascular tone [91]. Initially, K
V
7(K
V
7.1–K
V
7.5) identi-
fied in murine portal vein myocytes, aorta, pulmonary,
basilar, cerebral, renal, and mesenteric arteries from
rats, mice, and humans [9,85,98–100]. Hence, K
V
7
mostly expressed in VSMCs may be potential of target-
ing to treat vascular diseases such as hypertension and
pulmonary hypertension [94].
ATP-sensitive K
+
channels (K
ATP
channels)
K
ATP
are the important class of ion channels with
expression in many tissues, especially cardiac and
VSM. These channels function in a variety of physio-
logical processes, such as protection of cardiac cells
against ischemic injuries and regulation of vascular
tone [34,87,101]. The density of K
ATP
is relatively
lower in VSM than cardiac myocytes, and the different
expression of K
ATP
subtypes in vascular beds consti-
tutes variable biophysical and the pharmacological
properties [102]. It has been well known that K
ATP
can
directly affect vascular tone and blood flow as a result
of metabolic changes in various tissues and mediate
the effects of various endogenous and pharmacological
vasodilators [2,103].
K
ATP
in VSMCs are insensitive to ATP, and they are
activated by nucleoside diphosphates and inhibited by
glibenclamide (GLI). K
ATP
inhibited by intracellular ATP
were first identified in cardiac myocytes by Noma [104]
and have subsequently been found in the pancreatic b
cells, neurones, skeletal muscle, and vascular and non
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4M.F. Dogan et al.
VSMs [12,105]. The composition of the K
ATP
channel
structure is clear, made up of four pore-forming K
ir
6 sub-
units (K
ir
6.1 or K
ir
6.2) and four regulatory sulfonylurea
(SUR) receptor subunits. While K
ATP
pore-forming sub-
units were encoded by the KCNJ8 (K
ir
6.1) and KCNJ11
(K
ir
6.2) genes, regulatory subunits of K
ATP
were encoded
by the ABCC8 (SUR1) and ABCC9 (SUR2), which are two
SUR genes. It is known that K
ATP
in VSM is formed of the
K
ir
6.1 and SUR2B subunits [101,106].It have shown
that K
ir
6.1 subunit forms pore and has an crucial role in
the regulation of vascular tone. The overactivity of K
ATP
can cause to decreased vascular tone and blood pressure
[101,107]. K
ir
6.1/SUR2B represent the predominant K
ATP
in VSM, but other subtypes are expressed in specific vascular
beds separately or in combination with K
ir
6.1/SUR2B
[55,102]. K
ATP
activation by drugs and neuropeptides may
be a common mechanism of membrane hyperpolarization
and vasodilation. The opening of K
ATP
results in membrane
hyperpolarization, decreased [Ca
+2
]
i
, and vasodilation
[106,108,109]. K
ATP
have been demonstrated to play a
substantial role in vascular tone regulation by using tradi-
tional pharmacological approaches, including the applica-
tion of K
ATP
openers and K
ATP
blockers. These channels,
which constitute an important component of physiologi-
cal regulation as well as metabolic sensitivity, are opened
vasodilators and are closed by vasoconstrictors. K
ATP
is
opened by some compounds such as lemakalim, minoxi-
dil, cromakalim, pinacidil, and diazoxide. In the treat-
ment of myocardial ischemia, glaucoma, bronchial
asthma, hypertension, and male baldness, K
ATP
openers
exhibit a broad therapeutic effect [110–112].
K
ATP
are specifically blocked by SUR derivates such as
GLI. Since GLI-induced vasoconstriction was due to a
blockade of potassium efflux from the smooth muscle
cells, this suggests that under baseline conditions a potas-
sium efflux was responsible for a certain degree of vasore-
laxation [4,97,113]. K
ATP
inhibitor GLI (10 lM)
significantly inhibited both testosterone-induced relax-
ation in internal spermatic vein and levosimendan-
induced relaxation in internal mammary artery [28,45].
In addition, the vasodilation induced by levosimendan
may partially be due to a lowering of [Ca
+2
]
i
, and opening
of K
ATP
[114]. Conversely, Clapp et al. [78] demonstrated
that in guinea-pig aorta, BK
Ca
but not K
ATP
, play a major
role in vasorelaxation induced by the prostanoid agonists,
iloprost and cicaprost.
Inward rectifier K
+
channels (K
ir
)
K
ir
are present in some arterial smooth muscle cells
and in various excitable and nonexcitable cells. The
name of this channel comes from the fact that K
+
ion
current into the cell during changes in MP are larger
than the outward currents. K
ir
are more active at neg-
ative MP and therefore open for regulation the MP in
arteries in the absence of extrinsic depolarizing influ-
ences such as pressure or vasoconstrictors. In contrast
to K
ir
,K
V
and BK
Ca
are inactivated by membrane
hyperpolarization while being activated by membrane
depolarization [2,115].
K
ir
comprise of tetramers where each a-subunit has
two TM domains. The elevation of extracellular K
+
concentration also activates K
ir
and thereby causes
membrane hyperpolarization toward the K
+
equilib-
rium potential [55,77]. Of the large gene family of K
ir
subfamilies (K
ir
1.x to K
ir
7.x), the most relevant K
ir
expressed in the vasculature belong to the K
ir
2.x
(strong inward rectifier), and K
ir
6.x (weakly inward
rectifier) subfamilies. In VSMCs, K
ir
2.1 expression pre-
dominates, particularly in mice cerebral and coronary
arteries, and K
ir
2.1, K
ir
4.1, K
ir
6.x expression predomi-
nates mice mesenteric arteries [4,115,116]. Gollasch
et al. indicated that K
ir
are not functional in VSMCs of
human large epicardial coronary arteries [23].
K
ir
are specifically inhibited by Ba
+2
and Cs
+
,
whereas some of the other K
+
channel inhibitors such
as 4-AP or TEA have little effect on K
ir
. In small-resis-
tance arteries, such as the brain and coronary arteries,
K
ir
is activated by an increase of 15 mMin the extra-
cellular concentration [108,117,118].
Two-pore domain K
+
channels (K
2P
)
K
2P
are the smallest of the K
+
channels and are con-
structed by four TM domains and two pore structures.
They are considered as responsible for background leak
K
+
channels and are open at resting MP therefore
involved in controlling and stabilizing MP [88,119].
Structurally distinct from other vascular K
+
channels,
two pore-forming P loops (P1–P2) arrange in tandem,
one between the first and second TM domain and the
other between the third and fourth TM domain. TWIK-
2 (Tandem of P-domains in a weakly inward rectifying
K
+
channel, K
2P
6.1), TREK-1 (TWIK-related K
+
chan-
nel), and TASK-1 (TWIK-related acid-sensitive K
+
channel, K
2P
3.1) from the 15 known members of the
K
2P
family show the largest expression levels for K
2P
in
VSMCs [6,16,120]. Unlike most other K
2P
, TWIK-2 is
highly expressed in all blood vessels studied to date
including resistance sized vessels. Thus, K
2P
6.1 is a
prime candidate for physiological regulation in the vas-
cular system and also regulates systemic blood pressure
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Pharmacological perspective of potassium channels 5
[16,121]. In addition, TASK-1 channels play a physio-
logical role in regulating basal MP and tone in rat
mesenteric, pulmonary, and rabbit pulmonary arteries.
The contribution of these channels to the regulation of
vascular tone and blood pressure is not fully under-
stood and further research is needed [6,122,123].
The physiological and pathological functions of these
channels are investigated by using animal models
[120,124–126]. K
2P
are very weakly sensitive or
insensitive to the classical K
+
channel blockers, such as
TEA, Ba
+2
,Cs
+
, and 4-AP. These channels are sensitive
to pH and are inhibited by acidification of the extracel-
lular fluid [127,128].
As mentioned above, there are currently several
members of K
+
channels and numerous substances
effect their functions. The list of known external block-
ers and openers of K
+
channels in arterial smooth mus-
cle are given in Tables II and III, respectively.
PATHOPHYSIOLOGICAL ROLES OF
POTASSIUM CHANNELS
The activity and expression of vascular K
+
channels are
changed during major vascular diseases such as
Table II External blockers of K
+
channels in arterial smooth muscle.
K
+
channel Blocker Concentration References
K
V
GLY %50 inhibition, 0.2–1.1 mM[2]
4-AP 1 mM[29]
TEA
+
5–10 mM[81]
Ba
+2
%50 inhibition >1mM[2]
K
V
1.3 Margatoxin %50 inhibition, 10 nM[22]
Charybdotoxin 0.1 lM[129]
K
V
1.5 Diphenyl phosphine oxide-1 %50 inhibition, 0.31 lM[130]
Kv7 Linopirdine 10 lM[85,99,131]
XE991 10 lM
K
V
7.1 HMR1556 10 lM[100]
K
Ca
TEA %50 inhibition, 0.2 mM[2]
4-AP %50 inhibition >5m
M[132]
Ba
+2
Little effect at 10 mM[2]
BK
Ca
IbTx 0.1–100 nM[76,133]
Charybdotoxin 10 nM[100]
Paxilline 1 lM[54,72]
K
ir
Ba
+2
100 lM[134]
4-AP 10% inhibition at 1 mM[2]
TASK-1 Anandamide 10 lM[123]
Zn
+2
100 lM[123,128]
K
ATP
GLY 10 lM[134]
4-AP %50 inhibition, 1 mM[2]
Table III K
+
channel openers in VSMCs.
K
+
Channel Openers References
BK
Ca
NS1619 [83]
NS1608 [20]
Dehydroepiandrosterone [135]
Dehydrosoyasaponin-I [136]
Resveratrol [20]
MaxiKdiol [137]
L-735,334 [137]
NS 004, NS 169 [118]
K
ATP
Nicorandil [137]
Cromakalim [21]
Pinacidil [115]
Minoxidil sulfate [2]
Aprikalim [5]
Diazoxide [112]
PACAP-27 [23]
Lemakalim [87]
K
V
1.1 Acetazolamide [18]
Carbamazepine [18]
K
V
7 Retigabine [138]
Flupirtine [7]
K
ir
Mg
+2
[117]
TASK-1 Halothane [123]
ONO-RS-082 [139]
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6M.F. Dogan et al.
hypertension, pulmonary hypertension, hypercholes-
terolemia, atherosclerosis, and diabetes mellitus.
Changes in K
+
channels in vascular diseases and differ-
ences among species are summarized in Table IV.
Hypertension
Cardiovascular diseases are the major cause of increas-
ing morbidity in modern societies, and their socio-eco-
nomic consequences are tremendous. Hypertension,
which is caused by diabetes, renal disease, or
unhealthy life style and poor nutrition, is one of, if not,
the major risk factors for myocardial infarction and
stroke [136,164]. Hypertension is generally associated
with increased peripheral resistance in patients with
hypertension and in animal models of hypertension due
in part to enhanced contractile function of VSM
[12,144]. Chronic hypertension is accompanied by a
continuous increase in arterial tone resulting from
coronary artery dysfunction. The increase in the arte-
rial tone is mainly related to depolarization, which may
be due to dysfunction of ion channels responsible for
hyperpolarization of VSMCs [74,165]. The VSM has a
great significance in relation to the pathogenesis of
hypertension [166]. The underlying causes of these
complex pathophysiological processes are probably
VSM remodeling [9]. Abnormal increased vessel tone is
a pathogenic mechanism of hypertension [140]. Both
depolarization and action potential formation are
related to Ca
+2
ion entry into the cell. Increased
[Ca
+2
]
i
in arterial VSMCs during hypertension play a
crucial role in abnormal contraction and phenotypic
changes [167–169].
K
+
conductance plays a pivotal role in the regula-
tion of contractile function in arterial VSM. Disorders
in the functions or activities of the K
+
channels may
be associated with the pathophysiological mechanism
of hypertension leading to vasoconstriction
[73,89,118]. K
+
currents in VSMCs are one of the
most effective factors in preserving membrane stability,
they can suppress the membrane excitability, so less
K
+
current may occur in the hypertension disease
than in the normotensive state [59]. The loss of K
+
efflux causing membrane depolarization results in high
blood pressure in vivo and in vitro in spontaneously
hypertensive rat (SHR) mesenteric arteries [115,169].
It has been shown that humans and animals have an
increase in resting vascular tone in hypertension dis-
ease and that physiological stimulations lead to
increased contractile responses compared to the nor-
motensive control group [77,89].
Alterations of BK
Ca
in VSMCs have been documented
in both physiological (aging, pregnancy) and patho-
physiological conditions (diabetes mellitus) [34,170].
Hyperactivity of the arteries with age progression is the
changes that occur as a result of abnormal expression
and activity of BK
Ca
[141]. Blocking BK
Ca
or RyRs can
cause membrane depolarization, an elevation of
[Ca
+2
]
i
, and vasoconstriction [171]. Although the acti-
vation of the BK
Ca
operates as a negative feedback
mechanism to regulate the level of resting tone [66],
this activation is not enough to abolish the myogenic
tone in the SHRs [52]. Altered activity of the BK
Ca
may also play a role in the increased responsiveness to
TEA and Ba
+2
in SHRs [148]. During the progression
of hypertension, increased expression of BK
Ca
may
occur in order to maintain the resting vascular diame-
ter of arterioles. BK
Ca
current and expression are
increased in the cerebral arteries and aorta of SHRs,
but these increases were not associated with a detect-
able change in mRNA level, suggesting that the
increased expression of BK
Ca
may be mediated primar-
ily by post-transcriptional events [76,147]. The
increased sensitivity to calcium conferred by the b1
subunit is required for the BK
Ca
to translate calcium
sparks to MP hyperpolarization [172]. Impaired b1
subunits inhibited BK
Ca
activation in cerebral arteries
of hypertensive rats, leading to dysfunctional vasodila-
tion [142]. Disruption and knockout of the BK
Ca
-b1
gene (KCNMB1) were associated with elevated blood
pressure in mice, and downregulation of the b1 sub-
unit was been reported in hypertensive rats [72,146].
b1 knockout mice were hypertensive, indicating that
uncoupling BK
Ca
from RyRs by the loss of the b1 sub-
unit alone is sufficient to induce hypertension [145]. It
was demonstrated that b1 knockout mice had higher
systemic blood pressure than control mice (b1-subunit
gene +) [72,173]. It has been also reported that expres-
sion of the pore-forming asubunit of BK
Ca
is increased
in cerebral, mesenteric, and coronary arteries, which
are microcirculatory beds [9].
It has been shown that K
ir
[174] and K
V
currents
decrease in the arterial myocytes of angiotensin II-
induced hypertensive rats [143]. Dilator responses of
the basilar artery to aprikalim, a direct activator of
K
ATP
, are impaired in stroke-prone SHRs in vivo [149].
It has been found that the expression of K
ir
2.1, K
ir
4.1,
K
ir
6.x, and SUR2 mRNA decrease in the isolated
mesenteric arteries of hypertensive mice, and the func-
tional contribution of both K
ir
and K
ATP
decreases in
these mice arteries [115]. There are a significantly
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Pharmacological perspective of potassium channels 7
Table IV Changes in Potassium Channels in Vascular Diseases.
Disease Type of K
+
channel Species Vascular bed Conclusion References
Hypertension BK
Ca
Rat Mesenteric artery Enhancement of the expression and activity of BK
Ca
increases vasorelaxation [140]
Hypertension BK
Ca
Human Mesentery artery SMCs BK
Ca
activity is decreased [141]
Hypertension BK
Ca
Rat Cerebral artery Increased expression of BK
Ca
channels [76]
Hypertension BK
Ca
-b1 Rat Cerebral artery Impaired b1 subunits and BK
Ca
activation [142]
Hypertension BK
Ca
-b1
K
V
1.2, K
V
1.5
Rat Thoracic aorta Kv1.2/Kv1.5 downregulation and BK
Ca
b1-subunit upregulation [24]
Hypertension K
ir
-K
V
Rat Femoral and cerebral
arteries
Decreased K
+
conductance [143]
Hypertension BK
Ca
Rat Mesenteric artery Increased channel expression and current [66]
Hypertension BK
Ca
Human Mesentery artery BK
Ca
activity is decreased [74]
Hypertension K
ir
2.1, K
ir
4.1 K
ir
6.x Rat Mesenteric artery Decrease in the expression and current [115]
Hypertension BK
Ca
K
V
Rat Mesenteric artery SMCs Increased BK
Ca
current and expression, decreased K
V
current and expression [59]
Hypertension BK
Ca
K
V
Rat Mesenteric artery Increased BK
Ca
current, decreased K
V
current [144]
Hypertension BK
Ca
Rat Cerebral arterial VSMCs Increasing the sensitivity of BK
Ca
to Ca
+2
[145]
Hypertension K
V
1.2, K
V
-b1.1 Rat Thoracic aorta, Tail artery,
Mesenteric artery
Increased K
V
current in SHRs [96]
Hypertension BK
Ca
Human b
1
subunit gene (KCNMB1) KCNMB1 gene polymorphisms may be involved in the pathogenesis of hypertension [146]
Hypertension BK
Ca
Rat Femoral artery BK
Ca
channels are highly activated [52]
Hypertension BK
Ca
Rat Aorta Increased BK
Ca
current and expression [147]
Hypertension K
V
SHRs Isolated myocytes from
thoracic aorta
Decreased K
V
activity, increased BK
Ca
activity [89]
Hypertension BK
Ca
Rat Carotid artery Increased BK
Ca
responsiveness to blockers [148]
Hypertension K
ATP
Rat Basilar artery (in vivo) Impaired K
ATP
activity [149]
Hypertension K
V
7.4 SHRs Renal and mesenteric
arteries
K
V
7.4 protein is downregulated in arteries [98]
Pulmonary hypertension K
2P
(TWIK-2) Mice Pulmonary artery The loss of TWIK-2 function [120]
Pulmonary hypertension K
V
1.5, K
V
2.1 Human PASMCs Decreased expression and activation of K
V
1.5 and K
V
2.1 [44]
Pulmonary hypertension K
V
1.7 Rat PASMCs Decreased expression of K
V
1.7 [150]
Pulmonary hypertension K
V
7.4 Rat Pulmonary artery K
V
7.4 activation prevent hypoxia-induced pulmonary hypertension [131]
Pulmonary hypertension BK
Ca
Rat PASMCs Decreased BK
Ca
currents [135]
Pulmonary hypertension K
V
1.2, K
V
1.5,
K
V
2.1, K
V
9.3
Rat PASMCs Increased the expression of K
V
1.2, K
V
1.5, K
V
2.1, and K
V
9.3 [92]
Pulmonary hypertension K
V
Human Pulmonary Artery Dysfunctional K
V
[151]
Pulmonary hypertension BK
Ca
Human PASMCs Inhibition of the BK
Ca
current [75]
Pulmonary hypertension K
2P
(TASK1) Human PASMCs Decreased channel expression and activity [139]
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8M.F. Dogan et al.
Table IV Continued
Disease Type of K
+
channel Species Vascular bed Conclusion References
Pulmonary hypertension TASK-1 Human PASMCs Endothelin-1 inhibits channel activity [152]
Pulmonary hypertension K
V
Rat Pulmonary artery Decreased K
V
activity in hypoxia-induced pulmonary hypertension [153]
Atherosclerosis BK
Ca
-b1subunit Human Human aortic VSMCs Decreased b1-subunit expression [154]
Atherosclerosis BK
Ca
Human Cultured coronary
artery SMCs
Increased BK
Ca
activity [155]
Atherosclerosis K
ATP
Monkeys Carotid artery Impaired K
ATP
function [156]
Atherosclerosis BK
Ca
Human Aorta There are kinetically different types of channels [11]
Atherosclerosis K
V
BK
Ca
Atherosclerotic
mouse
Aorta Decreased activity of K
V
and increased BK
Ca
activity [157]
Hypercholesterolemia K
ATP
Rabbit (in vivo) Mesenteric Artery K
ATP
is preserved [158]
Hypercholesterolemia K
ATP
BK
Ca
Rabbit Carotid artery 17b-estradiol protect via K
+
channels [159]
Varicocele K
ATP
Human Internal Spermatic
Vein
Testosterone activates K
ATP
[28]
Diabetes mellitus K
ATP
Rat Mesenteric artery KMUP-1 prevents impairment of K
ATP
[160]
Diabetes mellitus K
V
7.1–K
V
7.5 Rat Coronary artery The downregulation of K
V
[138]
Diabetes mellitus K
V
1.1, K
V
1.2, K
V
2.1,
K
V
4.1, K
V
10.1
Rat Mesenteric artery Increased expression of K
+
channels [161]
Diabetes mellitus BK
Ca
Rat Cerebral artery Decreased channel activity and expression [162]
Gestational diabetes K
ATP
Human Umbilical artery Decreased channel expression [163]
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Pharmacological perspective of potassium channels 9
greater expressions of K
V
1.2 and K
V
b-subunit [96]
and increased K
V
activity with decreased BK
Ca
activity
[89] in SHRs arterial smooth muscle cells. Both BK
Ca
and K
V
are the dominant types of K
+
channels
expressed by VSMCs contributing to a negative feed-
back during agonist-induced vasoconstriction. Pin-
terova et al. have suggested that these K
+
channel
types have impaired function in SHRs [67]. K
V
1.2/
K
V
1.5 downregulation and BK
Ca
b1-subunit upregula-
tion have been demonstrated in SHRs thoracic aortas
[24]. Zhang et al. [59] have shown that current and
expression of the K
V
1.2 and K
V
1.5 were decreased in
mesenteric VSMCs, although BK
Ca
current was dramat-
ically greater in SHRs. Increased gene expression in K
V
may be to normalize resting MP and Ca
+2
influx in
response to compensatory responses such as BK
Ca
[96].
K
V
7 in VSMCs and in baroreceptor neurons have been
demonstrated to serve as important regulators of vas-
cular function [85,99,138]. It has been discovered that
K
V
7.4 protein is downregulated in aorta, renal, and
mesenteric arteries in SHRs when compared with nor-
motensive rats [98,100]. Yıldız et al. [132] demon-
strated that testosterone responses in human internal
mammary, radial, and umbilical arteries altered in
patients with cardiovascular risk factors and/or condi-
tions, such as hyperlipidemia, diabetes, hypertension,
smoking, age, gender, body mass index, and vascular
occlusion.
Pulmonary hypertension
Pulmonary hypertension leading to increased vascular
resistance and right heart dysfunction is a complex,
multifactorial, and refractory pathophysiological condi-
tion characterized by an elevated pulmonary arterial
(PA) pressure and pulmonary vascular resistance at
rest or during exercise [8,44]. Pulmonary circulation
relates to K
+
channels, which are the key determinant
of the resting MP in SMCs and regulate [Ca
+2
]
i
in PA
myocytes that in turn regulate pulmonary vascular
tone and remodeling [175]. Reductions or damages in
the activity and expression of the K
+
channels identi-
fied five major classes in PA are associated with the
pulmonary hypertension in both patients and animal
models [88,176].
BK
Ca
and K
V
indicate prominent contributions in the
physiological regulation of conduit PA smooth muscle
cells (PASMCs); however, K
V
function is predominant
[177]. It has been demonstrated that chronic hypoxia
causes membrane depolarization in human PASMCs
in vivo and in vitro, and the hypoxia-induced
membrane depolarization is partly due to inhibition of
the BK
Ca
[75]. Membrane depolarization resulting in a
decrease in K
+
channel activity may lead to PA vaso-
constriction and eventually to the development of
chronic hypoxic pulmonary hypertension [153]. Patho-
logical and pathophysiological conditions are associated
with abnormal vasoconstriction, vascular injury (in-
duced by ischemia and inflammation), and remodeling
(medial and intimal proliferation) [151]. Hypoxic pul-
monary vasoconstriction (HPV) is a physiological mod-
ulator response in the case of alveolar hypoxia that
distributes the blood flow of pulmonary capillary to
regions where the amount of oxygen is greater.
Hypoxia may occur with the disruption of this mecha-
nism. It reduces perfusion in poorly ventilated alveoli
in order to optimize the oxygenation of arterial blood
[131,178]. Activation of the K
+
channels plays an
important role in the inhibition of HPV. Bonnet et al.
[179] showed that dehydroepiandrosterone administra-
tion in hypoxic rats prevented PA remodeling and
decreased pulmonary hypertension via BK
Ca
stimula-
tion and increased expression levels. Hypoxia has been
reported to inhibit K
V
and cause vasoconstriction as a
result of membrane depolarization in PASMCs [2,135].
Exposure to hypoxia has been demonstrated to inhibit
K
V
1.5 and K
V
2.1 opening, in turn, leads to LVCC acti-
vation and PA vasoconstriction [44,153,180]. It has
been also reported that exposure to hypoxia signifi-
cantly increased expression of the K
V
1.2, K
V
1.5, K
V
2.1,
and K
V
9.3 [92,177]. Mitochondrial-hypoxia-inducible
factor-1aactivation suppresses K
V
1.5 in PASMCs of
spontaneously pulmonary hypertensive fawn-hooded
rats which points out that the mitochondria can be
targeted therapeutically [181]. Mutations, which seem
to increase the severity of the disease, are less frequent
in K
V
1.5 (encoded by KCNA5) [182]. In addition, dehy-
droepiandrosterone reduces hypoxia-inducible factor-1a
accumulation under hypoxia in human PA cells [183].
Changes in K
V
function include regulation of cell prolif-
eration and apoptosis eventually leading to pulmonary
vascular remodeling, and the decreased expression and
activity of K
V
may lead to increased PA vasoconstric-
tion, which causes the pulmonary hypertension [184].
It was shown that decreased K
V
1.5 [130] and K
V
1.7
expression contributes to pulmonary hypertension in
rats [150]. K
V
1.5 is an important O
2
-sensitive channel
and potential therapeutic target in pulmonary hyper-
tension. Pozeg et al. [185] demonstrated that K
V
1.5
gene therapy restored HPV and attenuates pulmonary
hypertension of rats. Also, the loss of K
V
7.4 activity,
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10 M.F. Dogan et al.
which plays an important role in the pathogenesis of
pulmonary hypertension, can contribute to enhanced
excitation and vasoreactivity. The protective role for
K
V
7.4 in the pulmonary circulation has been shown to
inhibit hypoxia-induced pulmonary hypertension,
restricting increased vasoreactivity to pressure agents
[131,176,178].
The pathogenesis of idiopathic and hypoxic pul-
monary hypertension is related to the dysfunction of
the K
+
channels. Increased [Ca
+2
]
i
stimulates cellular
proliferation and triggers vasoconstriction. Hypoxia
causes a decrease in whole-cell BK
Ca
currents in
PASMCs [135,186,187]. K
2P
3.1 (TASK-1) and K
2P
6.1
(TWIK-2) subunits involved in pulmonary hyperten-
sion, and the K
2P
3.1- and K
2P
6.1-knockout mice exhib-
ited pulmonary vascular remodeling with increased
vessel diameters, accompanied by enhanced right ven-
tricular pressure indicative of pulmonary hypertension
[188,189]. TASK-1 (encoded by KCNK3) also modu-
lates PA tone. It has been demonstrated that TASK-1
probably play an important role in rabbit PASMCs
mediating pulmonary vascular responses to changes in
pH and might be responsible for the regulatory effects
of pH on HPV [123]. Patch-clamp experiments demon-
strated that mutations in this gene produced reduced
KCNK3 current in PA hypertension [190]. Antigny
et al. [139] reported that KCNK3 expression and func-
tion were reduced in monocrotaline-induced pul-
monary hypertension in rats and in human with
pulmonary hypertension. Moreover, in vivo pharmaco-
logical activation with ONO-RS-082 of KCNK3 signifi-
cantly reversed pulmonary hypertension in rats [139]
and partially restored the function of some KCNK3
mutants channels [190]. KCNK3 mutations may be
associated with certain forms of pulmonary hyperten-
sion, and they may cause worsening of the clinical fea-
tures in homozygous patients [191,192]. Higasa et al.
[191] suggested that rare pathogenic variants in
KCNK3 may also increase the risk of familial PA hyper-
tension. Cunningham et al. [193] showed that the
guanylate cyclase activator, riociguat, a novel treat-
ment for pulmonary hypertension, enhances current
through TASK-1 channels but does not recover current
through mutant TASK-1 channels, seen in pulmonary
hypertension patients. While there is compelling evi-
dence that KCNK3 is involved in the pathogenesis of
pulmonary hypertension in humans [194], KCNK3
does not play a key role in initiating HPV of mice pul-
monary hypertension [189,195], but it may participate
in its maintenance [195]. However, KCNK3/TASK-1
channel did not form a functional channel in mice
which is not a suitable model to study KCNK3 in PA
hypertension [196]. Loss of KCNK3 function and
expression is a hallmark of right ventricle hypertrophy/
dysfunction related to pulmonary hypertension [197].
Lambert et al. [198] reported that KCNK3 function is
severely decreased in right ventricle cardiomyocytes
during the development of right ventricle hypertrophy
in rat models of pulmonary hypertension. Ten different
KCNK3 mutations, which cause damaged channel
activity, described in PA hypertension so far, and novel
candidate drugs to restore KCNK3 function should be
investigated [199]. Moreover, TWIK2 (encoded by
KCNK6) is also involved in pulmonary hypertension
since KCNK6-deficient mice showed increase in right
ventricular pressure [120]. On the other hand, it has
been recently observed that ABCC8 mutations in
patients with pulmonary hypertension decrease K
ATP
function, which is pharmacologically recovered in vitro
by the SUR1 activator, diazoxide [200].
K
+
channel openers have been found to be useful by
inhibiting HPV and also decreasing PA resistance in
models of pulmonary hypertension, which are other-
wise resistant to conventional pharmacotherapy [201].
Hypercholesterolemia and atherosclerosis
Hypercholesterolemia is recognized as one of major
independent risk factor for initiating the complex pro-
cess of atherosclerosis [202]. Hypercholesterolemia and
atherosclerosis are both associated with an impairment
of the endothelium-dependent and K
+
channel-
mediated relaxations in VSMCs. Atherosclerosis is a
chronic inflammatory disease resulting from the accu-
mulation of lipids (such as cholesterol crystals, modified
fatty acids, and lysophospholipids) and fibrous elements
in the coronary artery and aorta. It is known that
VSMCs are closely involved in the development of
atherosclerosis [11,154,203]. This disease is particu-
larly associated with the decreased vascular activity of
endothelium-derived nitric oxide, which is likely to play
an important role in the development of atherosclerosis
with aging. As a result, arteries may exhibit increased
vascular tone under basal conditions and may respond
poorly to endothelium-dependent vasodilator agonists.
In the case of changes in vascular activity, the K
+
channel activity or function may also be abnormal.
The proliferation and migration of VSMCs from arterial
media have been recognized as essential steps in the
development of stenosing atherosclerotic plaques in
humans [25,155,164].
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Pharmacological perspective of potassium channels 11
Vascular smooth muscle is dependent on stabilizing
mechanisms for limiting Ca
+2
entry, and these mecha-
nisms may be a decrease in susceptibility to vasoconstric-
tors or an increase in activation of BK
Ca
. The opening of
K
v
in the atherosclerotic mouse aorta is decreased, and it
is susceptible to be depolarized resulting in Ca
+2
entry
[157]. It has been demonstrated that disruption of the
KCNE2 gene, which encodes a K
V
accessory subunit (b
subunit), causes atherosclerosis in mice [204]. K
V
contri-
bution to adenosine-mediated relaxation abolished by
hypercholesterolemia in porcine coronary arterioles
[205]. Recent studies have shown altered function and
expression of the vascular K
ATP
and b1-subunit of BK
Ca
in
experimental hypercholesterolemia and atherosclerotic
patients [154,206]. Hypercholesterolemia is associated
with impairment of BK
Ca
-mediated vasodilatation in
cholesterol-fed rabbits [207]. BK
Ca
activity is modulated
by membrane cholesterol. As both cholesterol levels and
BK
Ca
involved in pathophysiological mechanism in vascu-
lar disease, identifying disruption of BK
Ca
-cholesterol
interaction may provide new approaches for therapeutic
intervention [208]. Low cholesterol levels suppressed
BK
Ca
-b1 subunit-mediated channel inhibition and vascu-
lar constriction in mouse arteries [209]. Faraci et al.
[156] suggested that in addition to impairment of
endothelium-dependent responses, atherosclerosis impairs
relaxation of the carotid artery in response to activation
of K
ATP
. Altered K
ATP
function in the regulation of coro-
nary vascular tone has been reported in experimental
hypercholesterolemia [210]. 17b-estradiol protects the
hypercholesterolemic rabbit carotid arteries by maintain-
ing both endothelium and K
ATP
and BK
Ca
structures
[159]. Loss of this protective mechanism increases the
risk of thrombosis and the effects of vasospasm-related
vasoconstrictor factors on the arterial vessel wall [211].
Also, in animal models of atherosclerosis or hypercholes-
terolemia, damage of acetylcholine-induced relaxation
responses of endothelium has been associated with rela-
tive protection of endothelium-independent vasodilatation
[158]. Two types of BK
Ca
are present in SMC obtained
from the atherosclerotic aorta. Along with L-type chan-
nels, typical of normal adult human aorta, the channels
of S-type with different kinetic properties were also pre-
sent in these cells. Under similar conditions, S-type chan-
nels had about a four-times-shorter opening time and
considerably lower Ca
+2
sensitivity [11].
Diabetes mellitus
Diabetes mellitus is one of the most prevalent diseases
in the world, and vascular dysfunction is one of the
most important complications in diabetic patients.
Diabetes mellitus is closely related to vascular dysfunc-
tion through both endothelium-independent and
endothelium-dependent mechanisms. Vascular function
abnormalities contribute to the etiology of many dia-
betic complications such as neuropathy, retinopathy,
and myopathy [25,161]. K
ATP
in VSMCs are regulated
in decreasing amounts in diseases like diabetes mellitus
and hypertension, and potentially contribute to the
end-organ problems in these diseases [90,212]. K
ATP
are found in pancreatic-b-cells as well as in VSMCs.
K
ATP
play a crucial role in regulation of blood glucose
level by adjusting insulin release from these cells.
Firstly, K
ATP
was discovered in rabbit mesenteric artery
in 1989 [110,112,201]. Recently, it has been demon-
strated that reduction of K
ATP
current and K
ATP
chan-
nel-induced vasorelaxation in human umbilical artery
smooth muscle are due to the decreased expression of
K
ATP
channels in during gestational diabetes mellitus
[163]. Moreover, KMUP-1, a xanthine derivative, regu-
lates K
ATP
activity and prevents impairment of mesen-
teric artery reactivity and vascular dysfunction in
diabetic rats [160]. The reduction in BK
Ca
-b1 expres-
sion in renal arterioles of type I diabetic patients [70]
and in cerebral artery of type II diabetic rats [162] has
been shown to result in an increase in the myogenic
tone. N-3 polyunsaturated fatty acids protect the coro-
nary BK
Ca
function and vasoreactivity in diabetic rats
as a result of not only increasing BK
Ca
-b1 expressions,
but also decreasing artery tension and [Ca
+2
]
i
[213].
Hyperglycemia increases oxygen production both in
humans and in animals, and vascular K
ATP
inhibition
is formed. Continuous inhibition of K
ATP
may cause
deterioration of the relaxation response of the vessels
[4]. Also, the changes in the K
V
current have been
shown in some diabetic vessels [15,214]. Hong and
colleagues reported that the expression and flow of
many subunits of K
V
(such as K
V
1.1, 1.2, 1.4, and
1.5) are increased in early and chronic stages of
diabetes mellitus in the mesenteric artery of type II
diabetic rats [161].
CONCLUSIONS
K
+
channels are the major ion conductance of the
VSM cell membrane, and they dominantly regulate MP
which is a bright tool for processing vascular tone
quickly, efficiently, and precisely. The impressive com-
plexity of the numerous combinations of K
+
channels
allows precise adjustment of vascular response to direct
ª2019 Soci
et
e Franc
ßaise de Pharmacologie et de Th
erapeutique
Fundamental & Clinical Pharmacology
12 M.F. Dogan et al.
environment and provides a steady blood flow to
compensate for pathological conditions by responding
to various physiological situations.
Regarding altered K
+
channels in presented vascular
diseases, several drugs such as riociguat (pulmonary
hypertension) [215], nicorandil (angina pectoris) [216],
minoxidil, diazoxide, and pinacidil (hypertension) [111]
are used clinical practice. Also, promising new-genera-
tion drugs such as dehydroepiandrosterone [217], ipta-
kalim [218], dichloroacetate [219], levcromakalim
[220], and other benzopyran derivatives [221] have
been developed and/or introduced to the market.
There are many opportunities for future research on
vascular tone regulation through K
+
channels [222–
224]. Nonetheless, our understanding is lacking about
the regional heterogeneity in the nature and composi-
tion of K
+
channels in different vascular beds. More-
over, given strong evidence of the critical role of K
+
channels in a variety of vascular pathological condi-
tions including hypertension, PA hypertension,
atherosclerosis, and diabetes mellitus, targeting K
+
channel function represents a novel and promising
strategy for the prevention and treatment of a variety
of diseases [225–229]. However, many complex alter-
ations in vascular K
+
channel functions have been
described in diseases, and the understanding of the reg-
ulation of expression and function of the K
+
channels
in these disease states is also limited, especially since
these diseases relate to different vascular beds through-
out the body.
As further progress is made, along with molecular
and electrophysiological approaches, we will clarify the
expression and function of different sequences of K
+
channels contributing to the regulation of VSM con-
tractility in different cell types and in different segmen-
tal regions. This information is crucial for the
understanding of certain K
+
channel abnormalities and
their causes in specific diseases. The future of therapeu-
tic applications by activation of vascular K
+
channels
would seem to be a very promising in numerous vascu-
lar disease states.
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