Brief Reviews |
From the Department of Pharmacology, The University of Melbourne, Parkville, Victoria, Australia.
Correspondence to Christopher G. Sobey, PhD, Department of Pharmacology, The University of Melbourne, Parkville, Victoria 3010, Australia. E-mail cg.sobey{at}unimelb.edu.au
| Abstract |
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Key Words: hypertension depolarization endothelium-derived hyperpolarizing factor hypercholesterolemia hyperpolarization
| Introduction |
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The physiological roles and properties of K+ channels in arterial smooth muscle have recently been comprehensively reviewed.1 2 3 4 5 6 This Brief Review will first provide a short description of the functional characteristics of the 4 main types of vascular K+ channels and the likely physiological importance of these channels, as well as the phenomenon of K+ channelmediated, endothelium-dependent vascular hyperpolarization. The majority of this review will then examine the evidence for altered K+ channel function in blood vessels in 3 major cardiovascular disease states.
While molecular biological studies are revealing a large diversity in the subtypes of K+ channels that are normally expressed in vascular muscle,7 it is noteworthy that there is still very little information available at the molecular level regarding regulation of K+ channel expression and function in vascular disease. Hence, our current knowledge of the effects of disease on vascular K+ channel expression is somewhat indirect and almost exclusively relies on interpretation of functional or electrophysiological data (eg, recordings of vessel tone or diameter, vascular muscle cell Em, or whole-cell or single-channel currents in isolated myocytes under voltage-clamp conditions) obtained in the presence of pharmacological modulators of K+ channels.
| Calcium-Activated K+ Channels |
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1 mmol/L),
charybdotoxin, and iberiotoxin. Based on the constrictor responses
elicited by these inhibitors, it is thought that
BKCa channel activity may be greater in large
arteries versus microvessels under normal resting
conditions.6 | Voltage-Dependent (Delayed Rectifier) K+ Channels |
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| ATP-Sensitive K+ Channels |
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| Inwardly Rectifying K+ Channels |
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100 µmol/L barium ion
(Ba2+), and because this
inhibitor causes vascular depolarization and
constriction,26 28 29 31
it is thought that vascular KIR channels may be
active under resting conditions. Recent findings in gene-targeted mice
indicate that Ba2+-sensitive,
K+-induced vasorelaxation is mediated by
activation of the KIR2.1
channel30 (see
below). | Endothelium-Dependent Hyperpolarization |
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In addition, in many normal vascular preparations, a
component of agonist-induced, endothelium-dependent
relaxation appears to be mediated by a non-NO, nonprostanoid,
hyperpolarization-related mechanism that involves
activation of K+
channels32
(Figure 2
). The chemical nature of this mediator(s), termed
endothelium-derived
hyperpolarization factor (EDHF), has still not been
definitively identified, nor has the particular type(s) of
K+ channel(s) activated by EDHF, but
inhibition of its action appears to require coapplication of
charybdotoxin and apamin, which may implicate a role for small
conductance KCa, intermediate conductance
KCa, and/or BKCa
channels.33 This particular
combination of inhibitors may be necessary to block release
of EDHF from endothelial cells, rather than to block
the action of EDHF on vascular smooth
muscle.34 EDHF may play a
greater role in the smaller resistance arteries of
animals35 36 37
and humans38 39
and might therefore normally modulate systemic arterial
pressure. It has been suggested that the vascular activity of EDHF is
normally inhibited by NO, such that when NO synthesis is impaired in
cardiovascular disease, EDHF production and/or
function may
increase40 41
(Figure 2
). However, there is also evidence against this
proposal in hypertension and diabetes (see the following
sections).
| Use of Gene Targeting to Study Vascular K+ Channels |
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| K+ Channels in Vascular Diseases |
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Very few published studies have so far examined the impact of disease states on the biophysical characteristics of K+ channels or channel subtypes. By contrast, as mentioned above, most of our knowledge of the effects of diseases on vascular K+ channel expression remains indirect and dependent on interpretation of the experimental data obtained by using K+ channel modulators that are thought to be relatively selective pharmacological agents. The following sections will review current evidence for the effects of 3 major cardiovascular diseases on the expression and function of K+ channels in blood vessels.
Chronic Hypertension
Chronic hypertension has been the most extensively
studied cardiovascular disease state in terms of its
effects on vascular K+ channel function, and
there is now evidence for abnormal functioning of each of the 4 major
K+ channel types during hypertension
(Figure 3
).
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Effects of Hypertension on
Em
The resting
Em of
vascular smooth muscle cells is reported to be more depolarized in
arteries from hypertensive versus normotensive
animals43 44 45 46 47 48 49
(Figure 3
). Increased vascular depolarization is associated
with enhanced myogenic tone in arteries from hypertensive
animals.50 51 The
effect of hypertension on
Em may
be more profound in smaller resistance vessels, especially in vascular
beds that play a significant role in the regulation of
peripheral
resistance.52
BKCa Channels in
Hypertension
There is strong evidence that the functional role of
BKCa channels is enhanced in vascular muscle
during chronic hypertension. For example, pharmacological
inhibitors of these channels cause augmented depolarization
and constriction of arteries from hypertensive animals. This phenomenon
occurs similarly in vessels from various anatomic regions, including
aorta,53 54 55 56
carotid
artery,57 58 59
and the mesenteric,58
femoral,58 60 and
cerebral61 62
vascular beds. Because increases in both
Ca2+ influx and BKCa
channel activity can be detected even in prehypertensive spontaneously
hypertensive rats (SHRs),60
genetic factors may play at least some role in these changes. However,
increased BKCa channel function may also be a
consequence of elevated blood pressure, as it can be induced over
several weeks by surgical or pharmacological interventions that cause
hypertension,53 61
and it can be reversed by antihypertensive
therapy.54 Therefore,
BKCa channel function may be increased in
arterial smooth muscle cells as a protective mechanism
against progressive increases in blood pressure and may provide
a negative-feedback mechanism that helps to restrict the increased
pressure and vascular tone. Such a mechanism would therefore act to
limit pressure-induced vasoconstriction and to preserve local blood
flow.
Electrophysiological measurements
obtained under voltage-clamp conditions in arterial
myocytes isolated from hypertensive animals have confirmed that the
whole-cell K+ current through
BKCa channels is enhanced in comparison with
currents recorded from normotensive
myocytes.52 53 63
A comprehensive molecular,
electrophysiological, and functional study
in the cerebral circulation of SHRs has provided strong evidence for
greater expression of BKCa channels per myocyte
rather than any change in channel unitary conductance or open
probability.62 Liu et
al62 found that a 2- to
4-fold greater constriction of SHR versus Wistar-Kyoto rat (WKY)
cerebral arteries in vivo in response to iberiotoxin was associated
with a 4.7-fold higher density of BKCa channel
current in SHRs (measured in myocytes by using whole-cell, patch-clamp
techniques) and a 4.1-fold greater expression of the
BKCa channel
-subunit (ie, the pore-forming
part of the channel) in SHRs (determined by Western blot
analysis). Another study has reported that
BKCa channel open probability may be increased
in the renal vasculature owing to higher intracellular
Ca2+ levels during
hypertension.52 Thus,
activity of the BKCa channel appears to be
greater in hypertensive arteries
(Figure 3
), and it may be the primary determinant of resting
K+ efflux and hence, vascular muscle
Em in
hypertension.64
KV Channels in
Hypertension
In contrast to the increased function of
BKCa channels, there is evidence for a decreased
function of arterial KV channels in
hypertension. Voltage-dependent current through
KV channels was found to be substantially lower
in interlobar artery myocytes from both genetic (SHR) and nongenetic
(deoxycorticosterone acetate-salt/nephrectomy regime) models of
hypertension.52 Reduced
function of KV channels in hypertensive myocytes
may seem surprising, given that vascular
Em
appears to be more depolarized (see above), and the activity of
KV channels, like BKCa
channels, is voltage dependent. However, in contrast to the effects on
BKCa channels, a depolarized
Em and a
higher intracellular Ca2+ level in myocytes
from chronically hypertensive
rats52 56 60 65 66
may represent a detrimental positive-feedback mechanism
resulting in decreased vascular KV channel
activity, because (1) intracellular Ca2+
inhibits
KV channel
activity67 and (2)
Ca2+ entry via voltage-activated
Ca2+ channels will be further increased
owing to the depolarizing effect of impaired KV
channel activity. Reduced KV channel activity
could therefore be an important factor underlying the depolarized
Em and
enhanced myogenic vascular tone reported during chronic
hypertension50 51
(Figure 3
). A similar phenomenon may exist in cerebral
arteries after subarachnoid hemorrhage (SAH), a
cerebral vascular disease state that is also associated with vascular
depolarization68 69 70
and increased intracellular Ca2+
levels71 and in which
KV channel function also appears to be
impaired.16
Paracrine influences potentially underlying altered K+ channel activity in hypertension have not yet been extensively explored and could be numerous. One recent report suggested that parathyroid hypertensive factor, a circulating substance originating in the parathyroid gland and associated with some forms of experimental and human hypertension, inhibits KV channels and causes depolarization of myocytes from rat tail artery.72 Parathyroid hypertensive factor is thought to increase Ca2+ influx into vascular muscle cells via L-type, voltage-activated Ca2+ channels (probably due to KV channel inhibition) and consequently to enhance vascular responses to depolarizing and constrictor stimuli in vitro73 and in vivo.74 In an analogous manner, decreased KV channel function in the pulmonary circulation is reported to cause depolarization and vasoconstriction in patients with primary pulmonary hypertension.75 Because NO may activate KV channels in some arteries,15 19 76 77 impaired bioavailability of endothelium-derived NO in hypertension and other cardiovascular disease states could lead to vascular depolarization and contraction that are partly due to inhibition or closure of KV channels. Thus, increased knowledge of mediators that modulate KV channel function could provide important insight into the mechanisms of increased vascular tone during chronic hypertension and may reveal novel targets for pharmacological prevention of vascular dysfunction.
KATP Channels in
Hypertension
Findings from several studies suggest that the function
of vascular KATP channels is impaired during
hypertension. Synthetic KATP channel
activators are less potent dilators in vivo in both
large78 79 and
small80 cerebral vessels of
chronically hypertensive rats. This alteration seems likely to involve
an impaired membrane hyperpolarization response to
these agents, as analogous findings from patch-clamp studies indicate
that a glibenclamide-sensitive K+ current
activated by levcromakalim is decreased in mesenteric artery
smooth muscle cells of chronically hypertensive
animals.81
Cromakalim-induced relaxation of isolated mesenteric artery is
similarly impaired in hypertension induced by chronic NO synthase
inhibition.82 Because
vascular KATP channels are thought to be
inactive under most normal basal
conditions,1 3
increased vascular tone during chronic hypertension is unlikely to be
related to impaired KATP channel
function.78 By contrast, 1
study reported evidence for enhanced KATP
channel function in chronic hypertension, finding an increased
vasodilator effect of cromakalim and greater contraction by
glibenclamide in carotid arteries from stroke-prone SHRs versus
normotensive WKY
rats.83
The vasodilator response associated with cerebral blood flow autoregulation during systemic hypotension, which is mediated by KATP channel activation,84 85 86 is impaired in chronically hypertensive rats.87 Thus, although most studies of vascular KATP channel function during hypertension have examined the effects of synthetic channel openers, these findings86 87 suggest that the KATP channel dysfunction may also interfere with vascular responsiveness to endogenous vasodilator stimuli.
Impaired KATP channelmediated
vascular effects may not necessarily occur for all
endogenous KATP channel
activators, however, because responses to some vasodilators
that increase intracellular cAMP levels (ie, forskolin and
norepinephrine) are preserved in the basilar artery of
hypertensive rats.78 Thus, a
defect in only a particular aspect of KATP
channel function could account for the abnormal responses during
hypertension. Moreover, increased effects of angiotensin II
and protein kinase C are associated with various forms of chronic
hypertension, and both mediators may inhibit
KATP channel function in vascular smooth
muscle88 89 90 91
(Figure 3
). An important goal of future studies will be to
investigate the molecular basis for KATP channel
dysfunction in hypertension. Importantly, several studies have clearly
demonstrated that impairment of KATP
channelmediated vascular responses can be restored to near-normal
levels by long-term treatment of high blood
pressure.80 81 82 87
These findings emphasize the importance of antihypertensive therapy for
correcting many abnormalities in vascular smooth muscle
function.
There is very little information currently available on the effects of hypertension on KATP channel function in human blood vessels, with data from just 1 study reporting preserved dilator responses of isolated mesenteric arteries to cromakalim.92 Some studies of mesenteric arteries from hypertensive animals have also reported unchanged effects of KATP channel openers.47 93 It will be especially important to clarify whether this phenomenon occurs in humans; if it is restricted to certain vascular beds, this knowledge may then be critical in predicting the viability of using KATP channel openers as a potential new class of antihypertensive therapy.
Surprisingly, KATP channel function is augmented in cerebral vessels after exposure to subarachnoid blood,70 79 94 and this is particularly pronounced in hypertensive animals.79 Furthermore, although responses to many vasodilators are generally impaired in cerebral arteries after SAH, the effects of calcitonin generelated peptide (which activates KATP channels) are preserved or augmented,94 95 96 97 and treatment with calcitonin generelated peptide can prevent development of cerebral vasospasm after experimental SAH.98 99 KATP channel openers may therefore represent a promising therapeutic strategy for treatment of depolarized and spastic cerebral arteries after SAH, which is up to 8 times more likely to occur in the presence of hypertension.100
KIR Channels in
Hypertension
There is indirect evidence that vascular
KIR channel function may be altered during
chronic hypertension. McCarron and
Halpern101 reported that
Ba2+-sensitive vasodilator responses to
>7 mmol/L K+ were impaired in
posterior cerebral arteries isolated from stroke-prone SHRs in
comparison with vessels from WKYs, perhaps suggesting impaired
KIR channel function in the cerebral circulation
during hypertension. Earlier studies reported that
K+-induced vascular relaxation was either
augmented45 102
or impaired103 in several
models of hypertension. Our laboratory has recently found that dilator
responses of the basilar artery to K+ in
vivo, which are largely Ba2+ sensitive in
normotensive rats,31 are
moderately enhanced and Ba2+ insensitive in
SHRs (S. Chrissobolis et al, unpublished observations, 1999). Thus, it
is possible that chronic hypertension leads to decreased expression
and/or function of vascular KIR channels
(Figure 3
) and expression of a compensatory vasodilator
mechanism(s) that is upregulated. KIR
channelmediated dilatation of cerebral arteries is also reported to
be impaired after cerebral ischemia and
reperfusion.104
EDHF in Hypertension
Endothelium-dependent vascular
relaxation is impaired in many animals models of hypertension and in
hypertensive humans, and this is thought to be due, at least in part,
to impaired endothelial NO production or
activity.105 106
Consistent with the idea that EDHF may compensate during
impaired vascular production of NO
(Figure 2
), findings made in endothelial NO
synthasedeficient mice (which are moderately
hypertensive107 ) suggest
that EDHF(s) mediates endothelium-dependent relaxation
of saphenous, mesenteric, and skeletal muscle arterioles, whereas the
same functional responses are mediated by NO in normal
mice.108 109
This phenomenon may be specific to certain vascular beds, however,
because no such compensation by EDHF occurs in aorta or the carotid,
pulmonary, cerebral, or coronary arteries of
endothelial NO synthasemutant
mice107 110 111 112 113
or in cerebral
arterioles114 of normal
mice treated with inhibitors of NO synthase or soluble
guanylate cyclase.
Interestingly, impaired production of EDHF, and not NO, may sometimes contribute to reduced endothelium-dependent vascular relaxation during chronic hypertension, and in some instances, basal NO synthesis may be upregulated.115 There are now several reports that the contribution of EDHF to endothelium-dependent vasorelaxation is greatly reduced, whereas that of NO is preserved or increased, in a number of models of genetic and nongenetic hypertension.47 48 49 93 116 117 118 Thus, more work is clearly needed, not only to clarify the chemical identity of EDHF(s) and the molecular details of its K+ channelmediated mechanism of hyperpolarization, but also to understand the relationship between the bioavailability and function of EDHF and NO in normal and diseased arteries.
Diabetes
There is a 2- to 4-fold increase in the risk of
coronary heart disease, cerebrovascular disease, congestive
heart failure, and other cardiovascular complications
due to
diabetes.119 120 121
Moreover, abnormalities of vascular function are thought to contribute
to the etiology of many diabetic complications, including
neuropathy, retinopathy, and myopathy.
Functional changes occurring in blood vessels during diabetes include
endothelial cell
dysfunction5 but may also
involve altered ion channel function in vascular smooth
muscle.
KATP Channels in
Diabetes
Most information currently available regarding vascular
K+ channel function in diabetes concerns
KATP channels. As for chronic hypertension,
there are now several reports of impaired vascular relaxant responses
to synthetic openers of KATP channels in
long-term diabetes. These studies have mostly utilized the
streptozotocin-injected rat model of diabetes and have examined vessels
at 2.5 to 4 months after streptozotocin treatment. In this model in
which plasma glucose levels are increased 3- to 4-fold, impaired
relaxation of the isolated
aorta122 123 124
and mesenteric vascular
bed125 and reduced
dilatation of large126 and
small127 cerebral arteries
in vivo typically develop. These changes are thought to be the result
of a decreased number of vascular KATP channels
and/or reduced sensitivity of these channels to synthetic openers.
Nonspecific cytotoxic effects of streptozotocin seem an unlikely cause
of these changes because, like other manifestations of vascular
dysfunction, abnormal vasodilator responses to
KATP channel openers are prevented by treatments
that prevent or reverse the
hyperglycemia.123
Streptozotocin-induced diabetes may also alter the functional response
of KATP channels in other tissues, including
pancreatic ß-cells128 and
ventricular
myocytes,129 indicating
that hyperglycemia-induced impairment of KATP
channels is not restricted to the vasculature. Because diabetes is
associated with elevated plasma levels of LDL cholesterol
and triglycerides, it is conceivable that some vascular
abnormalities of diabetes are not directly related to hyperglycemia per
se but could instead be a consequence of an altered plasma lipid
profile.130
The period of experimental hyperglycemia appears to be an important determinant of the observed effects of diabetes on vascular KATP channel function because, by contrast, responses to KATP channel activation are reported to be enhanced in the early diabetic state. For example, cromakalim-induced dilatation of large coronary arteries in the dog are augmented 1 week after treatment with alloxan, and responses of the small coronary arteries are unaltered.131 Similarly, only 2 weeks after streptozotocin injection, activators of KATP channels cause enhanced dilator responses of rat isolated renal afferent arterioles.132 Moreover, because glibenclamide may cause marked constriction of those vessels, increased expression and basal activation of KATP channels may both occur in the renal circulation early during diabetes.132 This condition could contribute to the increases in glomerular filtration rate and renal plasma flow (ie, "hyperfiltration"), which occur in early stages of diabetes in both clinical and experimental settings.133 An increased KATP channel activity at this time may therefore reflect a very high metabolic state (ie, low ATP levels) of vascular smooth muscle cells relatively soon after the initiation of hyperglycemia. Increased KATP channel activity in blood vessels during metabolic stress, such as during ischemia, could be beneficial for maintaining tissue perfusion. Hence, tissues could be more susceptible to ischemic damage after extended periods of diabetes owing to impaired function of KATP channels.
On the other hand, mixed effects on
KATP channel function are reported to occur at
4 to 8 weeks after induction of hyperglycemia, presumably in part
reflecting a gradual deterioration of vascular mechanisms during
progression of the disease. For example, Bouchard et
al125 reported that
vasorelaxant responses to lemakalim are impaired in coronary
resistance vessels, but not in the mesenteric vascular bed or the
aorta, after 2 months of hyperglycemia. Likewise, pinacidil-induced
hyperpolarization of the mesenteric artery was
reported to be preserved after 8 to 12
weeks.134 Zimmerman et
al135 reported that dilator
responses to KATP channel openers were impaired
in cerebral arteries from 4- to 8-week-diabetic rats as a consequence
of reduced basal release of endothelium-derived NO.
KATP channel function could be restored in those
diabetic vessels by application of an NO donor
drug.135 However, such a
mechanism of endothelial NO-dependent
KATP channel activation may not always occur in
other preparations, as others have found no evidence of a role for NO
in the dilator responses of rat cerebral vessels to
KATP channel openers in
vivo,127 136
and KATP channelmediated relaxant responses
are impaired even in endothelium-denuded vessels after
slightly longer periods of
diabetes.122 124
Other K+ Channels in
Diabetes
Information is still generally lacking regarding the
effects of diabetes on the function of other types of
K+ channels. Diabetes, like several other
vascular diseases, is recognized as a condition in which there is
increased oxidant
stress.137 Hence, with
increased production of reactive oxygen species in the vascular
wall and consequently, a decreased bioavailability of NO (eg, due to
inactivation of NO by superoxide anion), activation of
BKCa or KV channels by
NO/cyclic GMP might be expected to be decreased under resting or
stimulated conditions. Moreover, there is recent evidence that
peroxynitrite, which is formed by the reaction of superoxide anion with
NO, can cause vasoconstriction (and presumably,
Em
depolarization) by inhibition of BKCa channels
in cerebral vascular muscle
cells.138 139
Consistent with this notion, there is evidence that
Em is
more depolarized than normal in cerebral arteries of
genetic140 and
nongenetic135 models of
diabetes, although it is not altered in mesenteric arteries of
streptozotocin-injected
rats.134 A reduced
hyperpolarizing influence of basally released
endothelium-derived NO may contribute to
cerebrovascular depolarization in some
cases.135 In addition,
there is preliminary evidence for an overall decrease in the outward
K+ current in cerebral myocytes from
spontaneously diabetic BB rats, which may involve decreased
BKCa channel function and increased
KV channel
function.140 Finally,
K+-induced relaxation is impaired in
mesenteric arteries from diabetic
rats,130 perhaps reflecting
an altered KIR channel
function.
EDHF in Diabetes
Recent findings suggest that the role of EDHF may be
diminished in diabetic arteries. The component of
endothelium-dependent relaxation that is
resistant to NO synthase inhibition but sensitive to vascular
depolarization is reduced in mesenteric vessels from diabetic rats,
whereas the NO-mediated component is preserved or
augmented.130
Consistent with this finding, direct measurements of
Em in
vascular muscle cells have confirmed that the
endothelium-dependent
hyperpolarization by EDHF is markedly reduced in
mesenteric arteries from diabetic
rats.134 Thus, impaired
production and/or effects of EDHF may account for the
diminished endothelium-dependent relaxant responses of
diabetic mesenteric arteries.
Hypercholesterolemia
and Atherosclerosis
It is well established that vascular dysfunction occurs
in hypercholesterolemia and
atherosclerosis. In particular, this disease is
associated with impairment of endothelial function, and
reduced vascular activity of endothelium-derived NO is
likely to play a major role in the development of
atherosclerosis.141
As a consequence, arteries may exhibit an increased vascular tone under
basal conditions and may respond inadequately to
endothelium-dependent vasodilator agonists. Under such
conditions of altered vascular reactivity,
K+ channel activity or function may also be
abnormal.
BKCa Channels in
Hypercholesterolemia and
Atherosclerosis
Najibi and
colleagues142 143
have reported functional evidence of an enhanced role for
BKCa channels in the vasodilator responses of
carotid arteries from hypercholesterolemic rabbits.
These investigators found that although the magnitude of
endothelium-dependent relaxation was preserved, the
responses of hypercholesterolemic but not of normal
arteries were sensitive to
charybdotoxin.142
Similarly, acetylcholine-induced relaxation is inhibited by
charybdotoxin in aortic rings of atherosclerotic but not of normal
mice.76 Initially, the
findings of Najibi et al were interpreted as being evidence for
upregulation of an EDHF-mediated compensatory component during impaired
NO production in
hypercholesterolemia.142
However, subsequent studies by those workers revealed that the
mechanism of the vasorelaxant response to exogenous NO becomes
charybdotoxin sensitive despite an impaired production of
cyclic GMP after cholesterol
feeding,143 suggesting that
the functional role of BKCa channels in vascular
muscle is markedly increased during
hypercholesterolemia. These observations could
be explained, in part, by a lower level of basal
BKCa channel activity (and hence, increased
BKCa channel availability for opening) under
conditions of impaired activity of endothelium-derived
NO. Analogous evidence for an increased role of
BKCa channels in vasodilator responses to NO has
been reported in cerebral arteries during NO synthase
inhibition136 and after
SAH.144 Interestingly,
recent patch-clamp studies have found that the activity of
BKCa channels is significantly higher in smooth
muscle cells from human coronary atherosclerotic plaques than
in medial smooth muscle cells, possibly suggesting a role for
BKCa channels in the development of human
atherosclerosis.145
KATP Channels in
Hypercholesterolemia and
Atherosclerosis
Relatively few studies have examined the effects of
hypercholesterolemia and
atherosclerosis on the functioning of
non-BKCa K+ channels
in blood vessels, with no
electrophysiological data reported so far
to the authors knowledge. However, available evidence suggests that
there may be regional variations in any associated changes to
KATP channels, perhaps with more marked effects
occurring in the larger vessels, which are also more susceptible to
atherosclerotic lesion development. In carotid arteries from
atherosclerotic monkeys, aprikalim-induced relaxation is impaired (as
is acetylcholine-induced relaxation), whereas relaxant responses to the
NO donor sodium nitroprusside are generally
preserved.146 Similarly,
relaxation of atherosclerotic rabbit aortic rings is impaired in
response to nicorandil, an agent that possesses properties of both
KATP channel openers and NO
donors.147 Because
responses to NO donors are commonly preserved in atherosclerotic
vessels, this finding may reflect an impairment of
KATP channelmediated vasodilatation in the
atherosclerotic aorta. By contrast, dilatation of small
coronary arteries in vivo in response to aprikalim is preserved
in atherosclerotic
monkeys,148 and relaxation
of rabbit carotid and mesenteric arteries in response to
KATP channel openers or hypoxia is
unaffected by hypercholesteremia, whereas responses to acetylcholine
are
attenuated.149 150
Interestingly, unlike the reduction of
endothelium-dependent relaxation, impairment of
KATP channel function in atherosclerotic vessels
may not be readily reversible by dietary
treatment.146
KV Channels in
Hypercholesterolemia and
Atherosclerosis
4-Aminopyridine induces contraction and
rhythmic activity of aortic rings from atherosclerotic but not control
mice.76 Because it is
thought that basal NO release from endothelial cells
may activate KV channels on vascular
smooth
muscle15 19 20
and that NO activity is reduced in atherosclerotic
arteries,141 it was
suggested that the findings were evidence for reduced basal
KV channel activity in atherosclerotic
vessels.76 An alternative
interpretation might be that increased effects of a
KV channel inhibitor reflect an
increased basal influence of
these channels during atherosclerosis, whereby
inhibition of channel activity might be expected to have an increased
influence on vascular muscle
Em and
tone. In another study, 4-aminopyridine was found to
inhibit endothelium-dependent, NO-mediated relaxation
in response to acetylcholine in normal rabbit cerebral arteries, but it
had no effect on the impaired responses to acetylcholine in vessels
from cholesterol-fed
rabbits,77
consistent with a reduced role for KV
channels in the relaxant responses of atherosclerotic
vessels.
EDHF in
Hypercholesterolemia and
Atherosclerosis
Few studies have so far tested the effects of
hypercholesterolemia and
atherosclerosis on EDHF function.
Lysophosphatidylcholine, which is elevated in oxidatively modified LDL,
is reported to inhibit different components of
endothelium-dependent relaxation mediated by either NO
or EDHF,151 suggesting that
responses to both endothelium-derived factors may be
sensitive to hypercholesterolemia. Similarly,
EDHF-mediated relaxation of human isolated gastroepiplopic arteries was
reduced during
hypercholesterolemia.38
By contrast, EDHF-mediated (ie, NO synthase and
cyclooxygenase-independent),
endothelium-dependent relaxation of the rabbit renal
artery was increased during
hypercholesterolemia despite an impaired
endothelium-dependent relaxant response overall in the
absence of inhibitors, consistent with an enhanced
role for EDHF in helping to maintain vascular function during reduced
NO activity152
(Figure 2
).
| Concluding Remarks and Future Directions |
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Only a very modest amount of data currently exists at the molecular level regarding vascular K+ channel function in disease. As further progress is made, particularly through molecular and electrophysiological approaches, in unraveling the relationship between K+ channel structure and function, we will obtain a clearer picture of the ways in which channel expression and function are normally regulated. We can then use this information in seeking to identify specific K+ channel abnormalities and their causes in particular diseases. Increased appreciation of the diversity of vascular cell types present throughout the circulation and the relevance of specific K+ channel functions in different cell types and in different segmental regions may prove very important for understanding vascular K+ channel biology as well as pathology.4 With the development of more selective pharmacological modulators, activation of vascular K+ channels would seem to be a very promising direction for therapy in numerous vascular disease states associated with vascular constriction and depolarization. In particular, the utilization of gene targeting technology in mice will very likely provide major advances in our understanding of the function of vascular K+ channel subtypes in isolated vessel preparations (as in Reference 3030 ) and ultimately, in the intact circulation in vivo in both health and disease.
| Acknowledgments |
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Received September 13, 2000; accepted October 5, 2000.
| References |
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