(Circulation. 1995;92:3337-3349.)
© 1995 American Heart Association, Inc.
Articles |
From the Vascular Biology Unit (R.A.C.), Vascular Medicine Section, Robert Dawson Evans Department of Clinical Research, Boston University School of Medicine, Boston, Mass; and Institut de Recherche Servier (P.M.V.), Suresnes, France.
Correspondence to Dr Richard A. Cohen, Vascular Biology Unit, Vascular Medicine Section, Robert Dawson Evans Department of Clinical Research, Boston University School of Medicine, Boston, MA.
Key Words: endothelium-dependent hyperpolarization nitric oxide vascular smooth muscle ion channels membrane potential
| Introduction |
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All is not known regarding the vasodilator function of the endothelium. In the present article, we elaborate that endothelium-dependent vasodilatation can best be explained by the participation of at least two vasodilator substances, nitric oxide and a substance whose identity is unknown. The identification of nitric oxide as an endothelium-derived relaxing factor rests on the similarities in physical, chemical, and physiological characteristics between the endogenous substance and authentic nitric oxide, as well as evidence derived from the use of arginine analogues as competitive inhibitors of nitric oxide synthesis.18 19 Thus, although the precise chemical nature of the nitric oxidelike endothelium-derived vasodilator remains debatable,20 the evidence appears incontrovertible that nitric oxide, in one chemical form or another, participates in endothelium-dependent relaxation. On the other hand, it has long been known that acetylcholine, the prototypical endothelium-dependent vasodilator, causes hyperpolarization of smooth muscle,21 22 23 24 25 and the endothelium dependence of the response was first described by Bolton and colleagues.26 Hyperpolarization of smooth muscle is an action that has not been generally associated with nitric oxide.27 28 29 In addition, in many studies of isolated blood vessels and the intact circulation, the action of endothelium-dependent vasodilators is, at least in part, resistant to inhibitors of nitric oxide.9 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 Although the number of observations in human blood vessels is limited, endothelium-dependent hyperpolarization of human coronary arteries in response to bradykinin also is resistant to nitric oxide synthase inhibitors.43 Therefore, the existence of two endothelium-derived mediators has been proposed to account for endothelium-dependent relaxationone nitric oxide, and the other an endothelium-derived hyperpolarizing factor (EDHF).45 46 47 48 49 50 It is important to note that hyperpolarization is, thus far, a phenomenon that has been measured only in vitro. Thus, the existence of a hyperpolarizing factor in vivo has been deduced to play a role in vasodilatation by the noted failure of nitric oxide synthase inhibitors to completely block endothelium-dependent vasodilation.
Furthermore, the picture is complicated by the fact that at least two different modes of signal transduction may account for endothelium-dependent vasodilation, even for a single endothelium-derived relaxing factor. The first, described for nitric oxide, depends on the stimulation of guanylate cyclase and production of its product, cGMP. Reliance of endothelium-dependent vasodilation on this mechanism is based on the parallel drawn between the increase in cGMP content of arterial tissue caused by endothelium-dependent vasodilators and nitrovasodilators, whose action is based on releasing nitric oxide.51 52 53 54 55 In addition, endothelium-dependent relaxation to nitric oxide may be reduced by hemoglobin or methylene blue, which antagonize the rise in cGMP either by inhibiting guanylate cyclase or by scavenging nitric oxide and preventing its stimulation of the enzyme.53 54 56 57 58 59 60 The cyclic nucleotide causes smooth muscle relaxation chiefly via phosphorylation of, and multiple actions mediated by cGMP-dependent kinase(s), and thus to a decrease in intracellular calcium and a decrease in calcium sensitivity of the contractile apparatus.61 62 63 64 65 66 67
The second mechanism is largely independent of cGMP and may be mediated
by hyperpolarization of the smooth muscle cell
membrane. Having demonstrated efficacious inhibition of the rise in
arterial cGMP by arginine analogue inhibitors
of nitric oxide synthesis or by methylene blue or hemoglobin, potent
relaxation30 32 44 and
hyperpolarization37 68 to bradykinin
or acetylcholine persist in the porcine coronary
artery,30 44 the carotid artery and abdominal aorta
of the
rabbit,32 and the aorta and pulmonary artery of
the rat.37 These observations attest to cGMP-independent
mechanisms of endothelium-dependent relaxation. A
cGMP-independent mechanism of relaxation may also apply to nitric oxide
and nitrovasodilators.69 70 Thus, there is evidence
for
more than one endothelium-derived mediator, one or
all of which may mediate relaxation by more than one mechanism. It is
also possible that the two mediators are interrelated, either by
sharing common mechanisms or by reinforcing or otherwise modulating the
action of the other (Figs 1
and 2
). The
purpose of this review is to summarize the current understanding, gaps
in knowledge, and potential directions for research on
endothelium-dependent vasodilation as it relates to
the question of the existence, identification, and mode of action of a
second, as-yet-unidentified mediator that behaves principally
as an EDHF.
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| Mechanism of Endothelium-Dependent Hyperpolarization |
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Electrical Conduction
An important issue that remains
unresolved is a potential
electrical conduction of hyperpolarization between
endothelial and smooth muscle cells,84 85
which might explain the inability to assay a soluble EDHF in arteries
such as the porcine coronary artery.86 87 Although
simultaneous hyperpolarization of
endothelial and smooth muscle cells occurs in the
porcine coronary artery in response to bradykinin, it could not
be demonstrated by current injections that the two cell types are
electrically connected or by lucifer yellow injections that gap
junctions exist between the two cell
types.85 88 89 These
studies likely exclude, at least in this artery, the possibility that
hyperpolarization is conducted between the
endothelial and smooth muscle cells. The possibility of
electrical coupling between endothelial and smooth
muscle cells may be more likely in the microcirculation, where contacts
between the two cell types are much more
intimate.90 91
Vasoconstrictors such as phenylephrine, U46619, and endothelin have been reported to depolarize the overlying endothelial cells.92 Hyperpolarization by acetylcholine reduces the endothelial depolarization induced by these vasoconstrictors. The depolarization of the endothelial cell by the contractile agonist does not occur if the endothelium is separated from the smooth muscle, even if the smooth muscle and endothelium are reapposed, suggesting electrical transmission or an extremely short-lived mediator.92 Direct electrical signaling between endothelial and smooth muscle cells, if it is shown to occur in some arteries, could explain the difficulty in identifying a distinct diffusable EDHF.
Endothelial Cell Membrane Potential
Membrane potential is as
important a determinant of
endothelial cell function as it is for smooth muscle
cells. Endothelial cells also are hyperpolarized by
agents that cause endothelium-dependent
hyperpolarization,85 92 93 94
an event
that has been attributed to the opening of calcium-dependent
potassium channels on the endothelial cell membrane in
response to the increase in cell
calcium.95 96 97 98 99 100 101 102 103 104
Because
the endothelial cell lacks typical
voltage-dependent calcium
channels,97 105 106 the
influx of calcium into the hyperpolarized cell is dependent on and
enhanced by the greater electrochemical gradient for the
cation107 (Fig 1
). Although it is not known
if shear stress regulates EDHF release, shear stressinduced
release of nitric oxide from endothelial cells is
inhibited by calcium-dependent potassium channel blockers,
emphasizing the importance of these potassium channels102
to the release mechanism. Thus, endothelial cell
hyperpolarization may enhance release of all
endothelial cell autacoids whose liberation depends on
calcium, including EDHF.93 108 109
Because
endothelial cells release bradykinin,110
adenine nucleotides,111 112 and
endothelin,113 these autocoids could be involved in
autocrine regulation of nitric oxide and EDHF release. It is even
possible that EDHF acts in an autocrine fashion, hyperpolarizing the
endothelial cell, and that a significant
physiological role of EDHF is to modulate the
release of nitric oxide and other autacoids, such as
prostaglandins. This might occur by potassium channel or
calcium channel activation. For example, an endothelial
cell cytochrome P-450 product that is a potential EDHF,
5,6-epoxyeicosatrienoic acid, increases endothelial
cell calcium influx.114 Cytochrome P-450
inhibitors diminish the sustained
endothelial cell calcium rise caused by histamine,
suggesting that endogenous epoxyeicosatrienoic acids
synthesized by endothelial cells promote calcium influx
and therefore stimulate autacoid release.114
Response of Smooth Muscle Cells to EDHF
How Does
Hyperpolarization of the Smooth
Muscle Occur?
The hyperpolarization of the smooth muscle
membrane mediated by the endothelium has been
attributed to an increase in conductance to potassium ions. The
evidence for this rests on the facts that (1) the cell membrane
conductance of smooth muscle measured electrically during
hyperpolarization is
increased24 26 71 ; (2) the magnitude of
endothelium-dependent
hyperpolarization is decreased in a
concentration-dependent manner by extracellular
potassium71 ; (3) radioactive rubidium efflux is increased
during hyperpolarization37 115 ; (4)
the endothelium-dependent
hyperpolarizations in certain cases have been
prevented by potassium channel
blockers27 80 116 ; and (5)
many parallels can be drawn between the action of EDHF and
pharmacological potassium channel openers, which cause relaxation
primarily by causing
hyperpolarization.117
The role of potassium channels has been proposed also because these channels, particularly large conductance calcium-dependent potassium channels, account for the passage of large amounts of ion current across the membrane, far greater than, for example, the Na+,K+-ATPase, and because the membrane potassium gradient accounts to the greatest extent for the resting membrane potential.118 It has been estimated that only a small increase in the opening rate of large conductance potassium channels is required to nearly maximally hyperpolarize the cell membrane.118 Nevertheless, other potential explanations exist that could contribute to endothelium-dependent hyperpolarization, including activation of the Na+,K+-ATPase79 or inactivation of chloride channels.119 120 For example, taking the latter as a hypothetical example, vasoconstrictors increase smooth muscle cell intracellular calcium, which can lead to depolarization, in part due to the activation of calcium-activated chloride channels. Nitric oxide released from the endothelium decreases intracellular calcium in the smooth muscle.121 Thus, the decrease in calcium caused by nitric oxide could deactivate chloride channels and account for the hyperpolarizing effects of nitric oxide. This example points out that reduction in intracellular calcium induced by nitric oxide, or by another EDHF, could cause secondary changes in membrane potential that may contribute to the regulation of contractile tone. Thus, although experiments with nitric oxide synthase inhibitors suggest that endothelial factors other than nitric oxide can cause hyperpolarization, it is difficult to exclude membrane potential changes due to endothelium-derived nitric oxide when its synthesis is not blocked.
There are several important additional caveats of which to be aware when considering a potential regulation of membrane potential in mediating endothelium-dependent relaxation. First, there is only a certain range of membrane potentials over which an EDHF that operates by opening potassium channels might be expected to contribute significantly to the regulation of membrane potential. On the one hand, very negative membrane potentials are close to the equilibrium potential for potassium, and therefore opening of potassium channels would have little further effect. On the other hand, at depolarized potentials the conductance for potassium is already high, so the effect of further increasing the opening of channels may be negligible. Thus, just as changes in intracellular calcium could cause secondary changes in membrane potential, differences in resting membrane potential could explain differences in experimental results that have otherwise been attributed to the altered release or the absence of EDHF.
Second, caution must be exercised in interpreting experiments in which inhibitors of hyperpolarizing mechanisms are used, such as ouabain to block the Na+,K+-ATPase, glibenclamide to inhibit ATP-dependent potassium channels, or tetraethylammonium and charybdotoxin to block calcium-dependent potassium channels. Although these inhibitors may very well inhibit their intended target, they also may, simply by depolarizing the membrane, nonspecifically inhibit a response initiated by the mechanism that is the actual target of EDHF in the smooth muscle. In addition, many of the inhibitors have been used in concentrations that greatly exceed the range over which they are considered specific. For example, studies have been performed using glibenclamide to inhibit ATP-dependent potassium channels at concentrations exceeding the micromolar range that is more than 10 000 times higher than the concentration that inhibits the ATP-dependent channels in pancreatic ß cells.122 At micromolar concentrations, glibenclamide can inhibit responses mediated by calcium-activated potassium channels.123 124 Another factor that complicates interpretation of experiments is that both endothelial cells and smooth muscle cells possess a large complement of ion channels. None of the inhibitors are specific for one cell type or the other, making it difficult to determine if a pharmacological agent is affecting EDHF release from endothelial cells, its action on endothelial cells, or its action on the smooth muscle.
Third, contractile agents can have various independent effects on membrane potential or intracellular calcium, both of which can influence the response to an EDHF. To avoid movement of the preparation during contraction and the associated difficulty in maintaining cell impalements, many measurements of membrane potential in response to endothelium-dependent agonists have been made in the absence of contractile agents. Different membrane potential responses to endothelium-dependent agents have been recorded in the presence and absence of contractile agents,125 126 so caution is necessary in extrapolating data obtained in resting vascular smooth muscle as to how it relates to the mechanisms by which contracted smooth muscle relaxes. These factors emphasize the importance of future studies to determine the role of EDHF in vivo independent of exogenous contractile agents and at physiological membrane potentials.
How Does
Hyperpolarization Cause
Relaxation?
The mechanism by which hyperpolarization
causes relaxation is controversial. The most direct and obvious
explanation is that hyperpolarization of the smooth
muscle cell membrane inhibits the opening of voltage-dependent
calcium channels, allows calcium sequestration and removal mechanisms
to lower intracellular calcium, and leads to
relaxation.127 Although this mechanism may operate in some
blood vessels under some conditions, it does not fully explain the
mechanism of relaxation. As has been pointed out
previously,117 the isolated rabbit thoracic aorta is not
depolarized during contractions induced by norepinephrine,
and those contractions are poorly inhibited by blockers of
voltage-dependent calcium channels such as nifedipine.
Nevertheless, potassium channel activators, like
chromakalim, whose relaxations are attributed solely to opening of
potassium channels and hyperpolarization, induce
potent relaxations of that preparation. Taken together, these
observations suggest that potassium channel openers may relax by
mechanisms other than inhibition of voltage-dependent calcium
channels.117
This point was made more evident in an investigation of the bradykinin-induced relaxations of the porcine coronary artery that persist in the presence of nitric oxide synthesis inhibitors. The artery was treated with nifedipine before contracting the artery with the thromboxane mimetic, U46619.128 Despite the fact that potassium could no longer contract the artery in the presence of nifedipine (indicating that voltage-dependent calcium channels were blocked), the potassium-induced depolarization inhibited the relaxations to bradykinin. This is consistent with the relaxations being mediated by a hyperpolarizing mechanism. However, in the absence of potassium, the bradykinin-induced relaxations of arteries treated with nifedipine were similar to those observed by others in the absence of nifedipine.30 68 129 This suggests that inhibition of voltage-dependent channels, at least of the L-type blocked by nifedipine, is not important in mediating relaxations associated with hyperpolarization that occur in the presence of nitric oxide synthase inhibitors and makes it likely that EDHF can induce relaxations by other mechanisms.
Potassium channel openers may relax by inhibiting vasoconstrictor-induced, phospholipase Cmediated inositol triphosphate production that would decrease intracellular calcium release.130 131 132 Also, possibly as a result of a reduction in diacylglycerol production by phospholipase C, there is a reduction in calcium sensitivity mediated by protein kinase C.133 134 135 136 These actions of potassium channel openers can all be attributed to hyperpolarization because they are prevented by elevated extracellular potassium and are blocked by glibenclamide.117 There are several lines of additional evidence that the potassium channel openers also may relax by mechanisms independent of the changes in membrane potential that they produce,117 possibly by enhancing the refilling of intracellular calcium stores.137 138 These observations regarding potassium channel openers have important implications for mechanisms attributed to an EDHF. First, relaxations caused by EDHF may differ depending on the mechanism by which the contractile agonist causes contraction. Contractions mediated by agonists that depolarize and activate voltage-dependent calcium channels may be affected differently by a hyperpolarizing stimulus than are those that do not. Thus, rather than indicating that different endothelial factors relax an artery contracted by two different agents, it may be that the difference is explained by the differences in the mechanisms of contraction.139 Second, one should be aware that an EDHF could potentially relax by mechanisms other than those dependent on membrane hyperpolarization, and its effect on membrane potential may be an additional mechanism of relaxation or even an epiphenomenon.
| Nature of EDHF |
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Prostacyclin
Prostacyclin contributes to
endothelium-dependent relaxation of several
isolated blood vessels and vasodilation of perfused
organs.140 141 142 143 144 145 146 147
The vasodilation of the rabbit
coronary circulation by prostacyclin is blocked by
glibenclamide,148 suggesting an underlying opening of
potassium channels as the mechanism. Prostacyclin causes relaxation by
increasing cAMP in smooth muscle cells. Prostacylin has also been shown
to hyperpolarize cultured canine carotid artery smooth muscle
cells,149 and a prostacylin analogue hyperpolarizes the
isolated guinea pig coronary artery.150 In the
latter study, cAMP also hyperpolarized the smooth muscle, suggesting
that hyperpolarization may occur via cyclic
nucleotide-dependent protein kinases, which
are known to modulate potassium channels. Likewise, in the canine
saphenous vein denuded of endothelium, other
activators of adenylate cyclase induce
hyperpolarization by opening ATP-dependent
potassium channels.151
Nitric Oxide
Nitric oxide in solution or nitrovasodilators can hyperpolarize
smooth muscle of several different isolated blood vessels, including
the small mesenteric artery125 and aorta152
of the rat, the uterine126 and coronary artery of
the guinea pig,150 and the basilar artery of the
rabbit.78 Nitric oxide in concentrations exceeding
5x10-7 mol/L hyperpolarized all vessels
studied, including various arteries of rat, rabbit, dog, and guinea
pig.126 In some arteries, nitric oxide caused relaxation
at lower concentrations without hyperpolarization,
but hyperpolarization was always observed at higher
concentrations. In the present study, it was found to be necessary
to depolarize and contract the arteries with phenylephrine
to observe hyperpolarization to nitric oxide.
The failure to observe a hyperpolarizing response to nitric oxide in
resting arteries was attributed to a highly negative resting membrane
potential. Stretching the guinea pig coronary artery was found
to be necessary to observe nitric oxide-induced
hyperpolarizations.150 In contrast,
nitric oxide hyperpolarized the small mesenteric artery of the rat only
in the absence of contractile force.125 These differences
may, as discussed previously, depend on differences in resting membrane
potential in the various preparations or on other experimental
conditions. Although the concentrations of nitric oxide in vivo are not
known, the concentrations that caused
hyperpolarization in several of the above
studies125 126 150 were in the micromolar
range, which is
equal to the concentration of nitric oxide measured in rabbit aortic
medial smooth muscle after stimulation of the
endothelium by acetylcholine.153
It was also demonstrated that the hyperpolarization to acetylcholine in the guinea pig artery was reduced by 41% by a relatively low concentration of NG-monomethyl-L-arginine.126 Another nitric oxide synthase inhibitor, NG-L-arginine methyl ester, as well as NG-monomethyl-L-arginine, had no effect on peak acetylcholine-induced hyperpolarization in the rat aorta but made the response more transient, reducing the more sustained hyperpolarization by about 50%.152 These studies suggest that at least under some circumstances, the release of nitric oxide accounts for part of the hyperpolarizing response to endothelium-dependent vasodilators.
Even in the absence of an effect of inhibitors of nitric oxide on the hyperpolarization stimulated by endothelium-dependent vasodilators, hemoglobin,29 37 methylene blue,71 126 or nitric oxide synthase inhibitors152 154 can depolarize resting arteries. This suggests that nitric oxide tonically released from the endothelium can under certain circumstances hyperpolarize the smooth muscle cell. Despite these findings, removal of the endothelium does not usually depolarize the underlying smooth muscle cells, as one would expect by removing a source of hyperpolarizing factor.27 28 29 43 71 77 80 81 151 This is perhaps due to the physical trauma to the blood vessel associated with removal of the endothelium or to the simultaneous removal of depolarizing factors released by the endothelium.
One mechanism by which nitric oxide could hyperpolarize smooth muscle is by increasing cGMP, which in turn causes protein kinasedependent activation of calcium-dependent potassium channels.67 155 156 In addition, ATP-dependent potassium channels appear to be activated by nitric oxide, through a cGMP-dependent mechanism.157 All endothelium-dependent relaxations and hyperpolarizations have been attributed to cGMP-dependent effects on potassium channels.158 This is clearly not the case, as demonstrated by endothelium-dependent relaxations that persist after blocking the rise in cGMP.30 32 37 Some investigators have relied on the ability of methylene blue to block cGMP,27 28 71 74 126 158 159 without accounting for its ability to scavenge nitric oxide,57 as well as to inhibit nitric oxide synthesis by the endothelium.160
Nitric oxide in concentrations from 5x10-7 to 10-5 mol/L increases the activity of single calcium-dependent potassium channels in isolated membrane patches of rabbit aortic smooth muscle cells.70 Because the membrane patches in these experiments were devoid of all nucleotides and cofactors necessary for cGMP generation, this observation provides a mechanism whereby nitric oxide could hyperpolarize smooth muscle cells independent of cGMP. Relaxations to nitric oxide of the rabbit aorta were incompletely blocked by methylene blue, which effectively prevented the increase in cGMP, and the residual relaxations were blocked by charybdotoxin.70 This suggests that cGMP-independent potassium channel activation by nitric oxide can cause relaxation. These effects of exogenous nitric oxide were reproduced by native EDRF. In this case, the effluent of a perfused rabbit aorta whose intact endothelium was stimulated with acetylcholine also was shown to activate single potassium channels in a membrane patch.70 The cGMP-independent activation of potassium channels was apparently dependent on a chemical reaction of nitric oxide with protein sulfhydryl groups, because blockade of these constituents prevented the channel activation. This mechanism provides a molecular mechanism independent of cGMP for nitric oxide to act as an EDHF.70
Tetraethylammonium or charybdotoxin depolarizes and constricts cerebral microvessels of the rabbit.161 Because the constrictions are blocked by calcium channel blockers or by lowering intravascular pressure, hyperpolarization mediated by calcium-dependent potassium channels may provide an important physiological brake to pressure-induced, calcium-dependent myogenic tone. It is possible that nitric oxide released tonically from the endothelium can regulate membrane potential via a potassium channeldependent mechanism and account for these observations.
Another potential hyperpolarizing action of nitric oxide is its ability to stimulate the Na+,K+-ATPase pump. In the rabbit aorta, removal of the endothelium or inhibition of nitric oxide synthesis decreased ouabain-sensitive radioactive rubidium influx used as a marker of pump activity,162 and sodium nitroprusside stimulates pump activity.163 The stimulation of pump activity by sodium nitroprusside appears to be independent of cGMP and attributable to Na+/H+ exchange.163 An endothelium-dependent increase in Na+,K+-ATPase activity might help to explain the depolarizing effects of inhibitors of nitric oxide under resting conditions. In addition, the sodium pump inhibitor ouabain decreases endothelium-dependent hyperpolarization caused by acetylcholine in the coronary artery of the dog79 and the middle cerebral artery of the cat.74
Nonprostanoid, NonNitric Oxide
Endothelium-Derived Hyperpolarizing and Relaxing
Factor(s)
Despite the above discussion of the potential role of
prostacyclin
and nitric oxide as EDHFs, the evidence that another nonprostanoid,
nonnitric oxide factor is an EDHF is overwhelming. In many
arteries, blockade of prostaglandin synthesis with, for
example, indomethacin has little effect on
endothelium-dependent relaxation or
hyperpolarization.37 74 79 80
In
addition, inhibition of the L-argininenitric oxide
pathway with arginine analogues or with hemoglobin or methylene blue
has no or only minimal inhibitory effects on
endothelium-dependent relaxations in many blood
vessels, including the pig coronary
artery30 42 68 128 129 ;
rat small mesenteric
artery125 164 ; guinea pig uterine126 and
coronary artery150 ; dog mesenteric28
and coronary artery38 ; cat middle cerebral
artery74 ; rabbit femoral artery,29 carotid
artery, and abdominal aorta32 ; and dog femoral
vein.159 Also, in several of the
studies,30 32 38 relaxations were
resistant to
combined inhibition of prostaglandins and nitric oxide,
excluding participation by one factor in the absence of the other.
Endothelium-dependent relaxations under these
conditions are associated with hyperpolarization
as indicated by changes in membrane
potential28 29 68 71 74 78 80 125 126 152 164
and rubidium
efflux.37 115 In the porcine coronary
artery30 128 and rabbit carotid artery and abdominal
aorta,32 relaxations resistant to prostanoid and
nitric oxide inhibitors are prevented by elevated
extracellular potassium, and in the rabbit arteries,32 but
not in the pig coronary artery,42 128 blockade by
charybdotoxin implicates the role of calcium-dependent potassium
channels. Tetraethylammonium, a less
specific inhibitor of calcium-dependent potassium
channels, but not the ATP-dependent channel antagonist
glibenclamide, inhibits endothelium-dependent
hyperpolarization to acetylcholine of the rat
aorta165 and guinea pig coronary
artery.80 It should be noted that
tetraethylammonium has been reported to be
a muscarinic receptor antagonist and could block the action
of acetylcholine by that mechanism.166 Glibenclamide, at a
concentration of 3x10-6 mol/L, inhibits
the endothelium-dependent
hyperpolarization to acetylcholine in the rabbit
cerebral artery, and the antagonism is accentuated by blockade of
nitric oxide with methylene blue.27 In the isolated,
perfused rat mesentery, apamin, an inhibitor of small
conductance potassium channels, blocks vasodilation after treatment
with a nitric oxide synthase inhibitor.41
These studies all indicate that a nonprostaglandin,
nonnitric oxide mediator of relaxation and
hyperpolarization exists in some isolated arteries
whose effects are inhibited by either elevated extracellular potassium
or potassium channel blockers. Regardless of the identity of the
mediator in these studies of isolated arteries or vascular beds, its
importance is suggested by vasodilator responses in in vivo human and
animal studies that are resistant to the inhibitors
of both nitric oxide and
prostacyclin.9 33 34 41
Possible Identities of Nonprostanoid, NonNitric Oxide EDHFs
Hydrogen peroxide relaxes arterial smooth muscle by a
cGMP-dependent
mechanism,167 168 169 170
activates
potassium channels,171 172 and causes
hyperpolarization.173 Beny and
vonderWeid173 showed that catalase that effectively
blocked the hyperpolarization to hydrogen peroxide
does not inhibit the endothelium-dependent
hyperpolarization of the porcine coronary
artery to bradykinin, excluding a role for hydrogen peroxide in the
response. However, hydrogen peroxide has been shown to be a product
of nitric oxide synthase when arginine utilization by the enzyme is
prevented174 and therefore remains a candidate EDHF,
perhaps in pathological states, where arginine availability is limited
or blocked.175 Superoxide anion is also generated by
endothelial cells, may be another product of nitric
oxide synthase,176 and, in distinction to its role as an
inactivator of nitric oxide, has been implicated in
causing endothelium-dependent
relaxation.177 Although this action is unlikely to occur
directly, superoxide anion can react with nitric oxide to form
peroxynitrite,178 which can relax smooth muscle, or,
alternatively, superoxide anion chemically degenerates to hydrogen
peroxide, which could be the active agent.
Nonprostanoid products of the metabolism of arachidonic acid remain particularly appealing candidates as EDHFs because as products of phospholipase A2 they would be expected to be released in response to elevated endothelial cell calcium levels. Phospholipase A2 inhibitors such as mepacrine and lipoxygenase inhibitors such as nordihydroguaiaretic acid and BW755c were some of the earliest recognized inhibitors of endothelium-dependent relaxations.1 142 179 180 181 182 183 184 185 These actions have been attributed to nonspecific actions of the drugs in some cases186 ; however, lipoxygenase products are made in abundance by endothelial cells,187 188 189 and some can activate potassium channels,190 191 maintaining their candidacy as EDHFs.
Products of cytochrome P-450 are also produced by endothelial cells192 193 and can activate potassium channels,194 and inhibitors of cytochrome P-450 have been reported to inhibit endothelium-dependent relaxations,195 196 making this third class of products of arachidonic acid candidate EDHFs as well.45 47 Relaxations of isolated bovine and porcine coronary arteries197 and vasodilatation of the coronary circulation of the rat87 in the presence of NG-nitro-L-arginine are prevented by SKF 525a or clortrimazole, inhibitors of cytochrome P-450, and by tetrabutylammonium or apamin. 11,12-Epoxyeicosatetraenoic acid, a cytochrome P-450 metabolite, relaxes the isolated coronary arteries, and these were blocked by tetrabutylammonium, further suggesting that cytochrome P-450 products could serve as EDHFs. However, in these and previous studies,86 a diffusable, bioassayable vasodilator released from endothelial cells could not be demonstrated after blockade of nitric oxide synthesis. This leaves open the question of whether products of cytochrome P-450 are released in sufficient quantity by endothelial cells to account for relaxation and hyperpolarization, which is resistant to nitric oxide synthase inhibitors. Furthermore, inhibitors of cytochrome P-450 are notoriously nonspecific. SKF 525a and its analogues are potent direct inhibitors of calcium-dependent potassium channels, and therefore they could block the actions of another EDHF on endothelial and smooth muscle cells as well as the synthesis of the products of cytochrome P-450.198
| How Important Is Endothelium-Dependent Hyperpolarization to Relaxation Caused by Endothelium-Dependent Vasodilators? |
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| Is the Role of EDHF Altered in Vascular Disease? |
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Hypercholesterolemia
Many studies, including those in
patients, have demonstrated
impaired endothelium-dependent vasodilation due to
hypercholesterolemia.200 201 202 203 208 209
However, in hypercholesterolemic rabbit carotid
arteries, acetylcholine-induced relaxations are
normal.200 This is despite the fact that cGMP accumulation
in response to acetylcholine is absent.200 Possibly as a
result of the interruption in the nitric oxidecGMP signaling
pathway, the acetylcholine-induced relaxations, unlike those in
normal arteries, are inhibited by increased extracellular potassium or
charybdotoxin.200 These observations suggest that
acetylcholine-induced relaxations of
hypercholesterolemic rabbit carotid arteries are
mediated differently than those in normal arteries and are subserved to
a greater degree by a potassium channeldependent hyperpolarizing
mechanism. This does not necessarily indicate that a distinct
hyperpolarizing factor mediates the acetylcholine-induced
relaxation because unlike in normal arteries, nitric oxideinduced
relaxations are also inhibited by charybdotoxin in the
hypercholesterolemic arteries.210
Also, inhibitors of nitric oxide synthesis decrease the
acetylcholine-induced relaxations in the
hypercholesterolemic rabbit arteries to an even
greater extent than in normal arteries,200 suggesting a
role of nitric oxide in the cGMP-independent, potassium
channeldependent, acetylcholine-induced
relaxation.70 These results emphasize the existence of two
primary mechanisms of endothelium-dependent
relaxation: one mediated primarily by cGMP, and the other by a
mediator(s) of smooth muscle hyperpolarization,
which may be of major importance only when the nitric
oxidecGMPdependent pathway of relaxation is impaired, as it
appears to be by hypercholesterolemia. The
alternate pathway may maintain vasodilation despite inhibition of what
is normally the primary mechanism.
Hypertension
Endothelium-dependent relaxation and
hyperpolarization to acetylcholine in the aorta of
two-kidney, one clip renal hypertensive rats is decreased compared
with that of normal rats.165 The resting smooth muscle
cell membrane is also more depolarized in the hypertensive rat aorta.
Tetraethylammonium inhibits the relaxation
and hyperpolarization to acetylcholine in normal
rats but does not inhibit further the relaxation of the hypertensive
artery. Glibenclamide has no effect, suggesting that
tetraethylammonium acts on
calcium-dependent potassium channels. This suggests that a
calcium-dependent potassium channel on endothelial
or smooth muscle cells is important in mediating
endothelium-dependent smooth muscle cell
hyperpolarization and that this mechanism is
impaired in hypertension. A similar decrease in
endothelium-dependent
hyperpolarization has been described in the
mesenteric artery of the spontaneously hypertensive
rat.39
Diabetes Mellitus
Unlike in normal arteries where the
presence of
endothelium causes a twofold increase in
arterial Na+,K+-ATPase
activity, the pump activity in diabetic rabbit aorta and carotid
arteries is the same in the presence and absence of the
endothelium.162 211 The sodium pump
activity measured in diabetic arteries with endothelium
is similar to that of normal arteries treated with nitric oxide
inhibitors or denuded of endothelium. This
suggests that a hyperpolarizing mechanism present in normal
arteries, which is accounted for by an enhancement of sodium pump
activity by endothelium-derived nitric oxide, is
impaired in diabetes.
| Future Directions for Research |
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Received April 10, 1995; revision received June 21, 1995; accepted July 24, 1995.
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I. T. Udosen, H. Jiang, H. C. Hercule, and A. O. Oyekan Nitric oxide-epoxygenase interactions and arachidonate-induced dilation of rat renal microvessels Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2054 - H2063. [Abstract] [Full Text] [PDF] |
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K. Inokuchi, Y. Hirooka, H. Shimokawa, K. Sakai, T. Kishi, K. Ito, Y. Kimura, and A. Takeshita Role of Endothelium-Derived Hyperpolarizing Factor in Human Forearm Circulation Hypertension, November 1, 2003; 42(5): 919 - 924. [Abstract] [Full Text] [PDF] |
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W. Zou, Q. Yang, A. P. C. Yim, and G.-W. He Impaired endothelium-derived hyperpolarizing factor-mediated relaxation in porcine pulmonary microarteries after cold storage with Euro-Collins and University of Wisconsin solutions J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 208 - 215. [Abstract] [Full Text] [PDF] |
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P. Koobi, J. Kalliovalkama, P. Jolma, J. Rysa, H. Ruskoaho, O. Vuolteenaho, M. Kahonen, I. Tikkanen, M. Fan, P. Ylitalo, et al. AT1 Receptor Blockade Improves Vasorelaxation in Experimental Renal Failure Hypertension, June 1, 2003; 41(6): 1364 - 1371. [Abstract] [Full Text] [PDF] |
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S. Taddei, A. Virdis, L. Ghiadoni, D. Versari, G. Salvetti, A. Magagna, and A. Salvetti Calcium Antagonist Treatment by Lercanidipine Prevents Hyperpolarization in Essential Hypertension Hypertension, April 1, 2003; 41(4): 950 - 955. [Abstract] [Full Text] [PDF] |
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S. Gschwend, R. H. Henning, D. de Zeeuw, and H. Buikema Coronary Myogenic Constriction Antagonizes EDHF-Mediated Dilation: Role of KCa Channels Hypertension, April 1, 2003; 41(4): 912 - 918. [Abstract] [Full Text] [PDF] |
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Y.-J. Chen, H. Jiang, and J. Quilley The Nitric Oxide- and Prostaglandin-Independent Component of the Renal Vasodilator Effect of Thimerosal Is Mediated by Epoxyeicosatrienoic Acids J. Pharmacol. Exp. Ther., March 1, 2003; 304(3): 1292 - 1298. [Abstract] [Full Text] [PDF] |
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H.-Y. Kwan, P.-C. Leung, Y. Huang, and X. Yao Depletion of Intracellular Ca2+ Stores Sensitizes the Flow-Induced Ca2+ Influx in Rat Endothelial Cells Circ. Res., February 21, 2003; 92(3): 286 - 292. [Abstract] [Full Text] [PDF] |
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J. R. Falck, U. M. Krishna, Y. K. Reddy, P. S. Kumar, K. M. Reddy, S. B. Hittner, C. Deeter, K. K. Sharma, K. M. Gauthier, and W. B. Campbell Comparison of vasodilatory properties of 14,15-EET analogs: structural requirements for dilation Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H337 - H349. [Abstract] [Full Text] [PDF] |
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J. L. Aschner, T. K. Smith, N. Kovacs, J. M. B. Pinheiro, and M. Fuloria Mechanisms of bradykinin-mediated dilation in newborn piglet pulmonary conducting and resistance vessels Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L373 - L382. [Abstract] [Full Text] [PDF] |
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W. Zhao and R. Wang H2S-induced vasorelaxation and underlying cellular and molecular mechanisms Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H474 - H480. [Abstract] [Full Text] [PDF] |
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R. Mechoulam, M. Spatz, and E. Shohami Endocannabinoids and Neuroprotection Sci. Signal., April 23, 2002; 2002(129): re5 - re5. [Abstract] [Full Text] [PDF] |
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L. A. Schildmeyer and R. M. Bryan Jr. Effect of NO on EDHF response in rat middle cerebral arteries Am J Physiol Heart Circ Physiol, February 1, 2002; 282(2): H734 - H738. [Abstract] [Full Text] [PDF] |
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R. J. Roman P-450 Metabolites of Arachidonic Acid in the Control of Cardiovascular Function Physiol Rev, January 1, 2002; 82(1): 131 - 185. [Abstract] [Full Text] [PDF] |
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C. L. Oltman, N. L. Kane, J. L. Fudge, N. L. Weintraub, and K. C. Dellsperger Endothelium-derived hyperpolarizing factor in coronary microcirculation: responses to arachidonic acid Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1553 - H1560. [Abstract] [Full Text] [PDF] |
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P. Gilbert, J. Tremblay, and E. Thorin Endothelium-Derived Endothelin-1 Reduces Cerebral Artery Sensitivity to Nitric Oxide by a Protein Kinase C-Independent Pathway Stroke, October 1, 2001; 32(10): 2351 - 2355. [Abstract] [Full Text] [PDF] |
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G.-W. He and Z.-G. Liu Comparison of Nitric Oxide Release and Endothelium-Derived Hyperpolarizing Factor-Mediated Hyperpolarization Between Human Radial and Internal Mammary Arteries Circulation, September 18, 2001; 104 (2009): I-344 - I-349. [Abstract] [Full Text] [PDF] |
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P.J Boels, J Deutsch, B Gao, and S.G Haworth Perinatal development influences mechanisms of bradykinin-induced relaxations in pulmonary resistance and conduit arteries differently Cardiovasc Res, July 1, 2001; 51(1): 140 - 150. [Abstract] [Full Text] [PDF] |
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L.-N. Zhang, L.-F. Zhang, and J. Ma Simulated microgravity enhances vasoconstrictor responsiveness of rat basilar artery J Appl Physiol, June 1, 2001; 90(6): 2296 - 2305. [Abstract] [Full Text] [PDF] |
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W. B. Campbell and D. R. Harder Prologue: EDHF-what is it? Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2413 - H2416. [Full Text] [PDF] |
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R. Rastaldo, N. Paolocci, A. Chiribiri, C. Penna, D. Gattullo, and P. Pagliaro Cytochrome P-450 metabolite of arachidonic acid mediates bradykinin-induced negative inotropic effect Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2823 - H2832. [Abstract] [Full Text] [PDF] |
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B. Vanheel and J. Van de Voorde Regional Differences in Anandamide- and Methanandamide-Induced Membrane Potential Changes in Rat Mesenteric Arteries J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 322 - 328. [Abstract] [Full Text] |
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M. H. Laughlin, J. S. Pollock, J. F. Amann, M. L. Hollis, C. R. Woodman, and E. M. Price Training induces nonuniform increases in eNOS content along the coronary arterial tree J Appl Physiol, February 1, 2001; 90(2): 501 - 510. [Abstract] [Full Text] [PDF] |
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M. H. Zink, C. L. Oltman, T. Lu, P. V. G. Katakam, T. L. Kaduce, H.-C. Lee, K. C. Dellsperger, A. A. Spector, P. R. Myers, and N. L. Weintraub 12-Lipoxygenase in porcine coronary microcirculation: implications for coronary vasoregulation Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H693 - H704. [Abstract] [Full Text] [PDF] |
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H. Tomioka, Y. Hattori, M. Fukao, H. Watanabe, Y. Akaishi, A. Sato, T. Q. Kim, I. Sakuma, A. Kitabatake, and M. Kanno Role of endothelial Ni2+-sensitive Ca2+ entry pathway in regulation of EDHF in porcine coronary artery Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H730 - H737. [Abstract] [Full Text] [PDF] |
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C. G. Sobey Potassium Channel Function in Vascular Disease Arterioscler. Thromb. Vasc. Biol., January 1, 2001; 21(1): 28 - 38. [Abstract] [Full Text] [PDF] |
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C. J. Hanke and W. B. Campbell Endothelial cell nitric oxide inhibits aldosterone synthesis in zona glomerulosa cells: modulation by oxygen Am J Physiol Endocrinol Metab, October 1, 2000; 279(4): E846 - E854. [Abstract] [Full Text] [PDF] |
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R. W. Jeremy and H. McCarron Effect of hypercholesterolemia on Ca2+-dependent K+ channel-mediated vasodilatation in vivo Am J Physiol Heart Circ Physiol, October 1, 2000; 279(4): H1600 - H1608. [Abstract] [Full Text] [PDF] |
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K. Goto, K. Fujii, U. Onaka, I. Abe, and M. Fujishima Renin-Angiotensin System Blockade Improves Endothelial Dysfunction in Hypertension Hypertension, October 1, 2000; 36(4): 575 - 580. [Abstract] [Full Text] [PDF] |
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K. Goto, K. Fujii, U. Onaka, I. Abe, and M. Fujishima Angiotensin-Converting Enzyme Inhibitor Prevents Age-Related Endothelial Dysfunction Hypertension, October 1, 2000; 36(4): 581 - 587. [Abstract] [Full Text] [PDF] |
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J.-Z. Yu, D. X. Zhang, A.-P. Zou, W. B. Campbell, and P.-L. Li Nitric oxide inhibits Ca2+ mobilization through cADP-ribose signaling in coronary arterial smooth muscle cells Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H873 - H881. [Abstract] [Full Text] [PDF] |
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P. Jolma, J. Kalliovalkama, J.-P. Tolvanen, P. Koobi, M. Kahonen, N. Hutri-Kahonen, X. Wu, and I. Porsti High-calcium diet enhances vasorelaxation in nitric oxide-deficient hypertension Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1036 - H1043. [Abstract] [Full Text] [PDF] |
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Y. Chen, R. M. McCarron, Y. Ohara, J. Bembry, N. Azzam, F. A. Lenz, E. Shohami, R. Mechoulam, and M. Spatz Human Brain Capillary Endothelium : 2-Arachidonoglycerol (Endocannabinoid) Interacts With Endothelin-1 Circ. Res., August 18, 2000; 87(4): 323 - 327. [Abstract] [Full Text] [PDF] |
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R. P. Brandes, F.-H. Schmitz-Winnenthal, M. Feletou, A. Godecke, P. L. Huang, P. M. Vanhoutte, I. Fleming, and R. Busse An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice PNAS, August 15, 2000; 97(17): 9747 - 9752. [Abstract] [Full Text] [PDF] |
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Y. Nishikawa, D. W. Stepp, and W. M. Chilian Nitric oxide exerts feedback inhibition on EDHF-induced coronary arteriolar dilation in vivo Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H459 - H465. [Abstract] [Full Text] [PDF] |
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M. L. H. Honing, P. Smits, P. J. Morrison, and T. J. Rabelink Bradykinin-Induced Vasodilation of Human Forearm Resistance Vessels Is Primarily Mediated by Endothelium-Dependent Hyperpolarization Hypertension, June 1, 2000; 35(6): 1314 - 1318. [Abstract] [Full Text] [PDF] |
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X. YAO, H. Y. KWAN, F. L. CHAN, N. W. K. CHAN, and Y. HUANG A protein kinase G-sensitive channel mediates flow-induced Ca2+ entry into vascular endothelial cells FASEB J, May 1, 2000; 14(7): 932 - 938. [Abstract] [Full Text] |
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V. Schachinger, M. B. Britten, and A. M. Zeiher Prognostic Impact of Coronary Vasodilator Dysfunction on Adverse Long-Term Outcome of Coronary Heart Disease Circulation, April 25, 2000; 101(16): 1899 - 1906. [Abstract] [Full Text] [PDF] |
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F. A. C. le Noble, K. Ruijtenbeek, S. Gommers, J. G. R. de Mey, and C. E. Blanco Contractile and relaxing reactivity in carotid and femoral arteries of chicken embryos Am J Physiol Heart Circ Physiol, April 1, 2000; 278(4): H1261 - H1268. [Abstract] [Full Text] [PDF] |
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L. P. Perrault, F. Mahlberg, C. Breugnot, J.-P. Bidouard, N. Villeneuve, J.-P. Vilaine, and P. M. Vanhoutte Hypercholesterolemia Increases Coronary Endothelial Dysfunction, Lipid Content, and Accelerated Atherosclerosis After Heart Transplantation Arterioscler. Thromb. Vasc. Biol., March 1, 2000; 20(3): 728 - 736. [Abstract] [Full Text] [PDF] |
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M. Hecker Endothelium-Derived Hyperpolarizing Factor--Fact or Fiction? Physiology, February 1, 2000; 15(1): 1 - 5. [Abstract] [Full Text] [PDF] |
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D. J. Blackman, J. A. Morris-Thurgood, J. J. Atherton, G. R. Ellis, R. A. Anderson, J. R. Cockcroft, and M. P. Frenneaux Endothelium-Derived Nitric Oxide Contributes to the Regulation of Venous Tone in Humans Circulation, January 18, 2000; 101(2): 165 - 170. [Abstract] [Full Text] [PDF] |
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K. Goto, K. Fujii, I. Abe, and M. Fujishima Sympathetic Control of Arterial Membrane Potential by ATP-Sensitive K+-Channels Hypertension, January 1, 2000; 35(1): 379 - 384. [Abstract] [Full Text] [PDF] |
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M. Alonso-Galicia, A. G. Hudetz, H. Shen, D. R. Harder, R. J. Roman, and H. A. Kontos Contribution of 20-HETE to Vasodilator Actions of Nitric Oxide in the Cerebral Microcirculation • Editorial Comment Stroke, December 1, 1999; 30(12): 2727 - 2734. [Abstract] [Full Text] [PDF] |
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S. Shimizu and R. J. Paul Hypoxia and Alkalinization Inhibit Endothelium-Derived Nitric Oxide But Not Endothelium-Derived Hyperpolarizing Factor Responses in Porcine Coronary Artery J. Pharmacol. Exp. Ther., October 1, 1999; 291(1): 335 - 344. [Abstract] [Full Text] |
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J. Kalliovalkama, P. Jolma, J.-P. Tolvanen, M. Kahonen, N. Hutri-Kahonen, H. Saha, S. Tuorila, E. Moilanen, and I. Porsti Potassium channel-mediated vasorelaxation is impaired in experimental renal failure Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1622 - H1629. [Abstract] [Full Text] [PDF] |
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S. Taddei, L. Ghiadoni, A. Virdis, S. Buralli, and A. Salvetti Vasodilation to Bradykinin Is Mediated by an Ouabain-Sensitive Pathway as a Compensatory Mechanism for Impaired Nitric Oxide Availability in Essential Hypertensive Patients Circulation, September 28, 1999; 100(13): 1400 - 1405. [Abstract] [Full Text] [PDF] |
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J. You, T. D. Johnson, S. P. Marrelli, and R. M. Bryan Jr. Functional heterogeneity of endothelial P2 purinoceptors in the cerebrovascular tree of the rat Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H893 - H900. [Abstract] [Full Text] [PDF] |
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P. Arvola, X. Wu, M. Kahonen, H. Makynen, A. Riutta, I. Mucha, T. Solakivi, H. Kainulainen, and I. Porsti Exercise enhances vasorelaxation in experimental obesity associated hypertension Cardiovasc Res, September 1, 1999; 43(4): 992 - 1002. [Abstract] [Full Text] [PDF] |
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S. J Duffy, G. New, R. W Harper, and I. T Meredith Metabolic vasodilation in the human forearm is preserved in hypercholesterolemia despite impairment of endothelium-dependent and independent vasodilation Cardiovasc Res, August 15, 1999; 43(3): 721 - 730. [Abstract] [Full Text] [PDF] |
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L. P Perrault, J.-P. Bidouard, P. Janiak, N. Villeneuve, P. Bruneval, J.-P. Vilaine, and P. M Vanhoutte Impairment of G-protein-mediated signal transduction in the porcine coronary endothelium during rejection after heart transplantation Cardiovasc Res, August 1, 1999; 43(2): 457 - 470. [Abstract] [Full Text] [PDF] |
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Z.-D. Ge and G.-W. He ALTERED ENDOTHELIUM-DERIVED HYPERPOLARIZING FACTOR-MEDIATEDENDOTHELIAL FUNCTION IN CORONARY MICROARTERIES BY ST THOMAS' HOSPITAL SOLUTION J. Thorac. Cardiovasc. Surg., July 1, 1999; 118(1): 173 - 180. [Abstract] [Full Text] [PDF] |
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J. Kalliovalkama, P. Jolma, J.-P. Tolvanen, M. Kahonen, N. Hutri-Kahonen, X. Wu, P. Holm, and I. Porsti Arterial function in nitric oxide-deficient hypertension: influence of long-term angiotensin II receptor antagonism Cardiovasc Res, June 1, 1999; 42(3): 773 - 782. [Abstract] [Full Text] [PDF] |
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W. G. Mayhan VEGF increases permeability of the blood-brain barrier via a nitric oxide synthase/cGMP-dependent pathway Am J Physiol Cell Physiol, May 1, 1999; 276(5): C1148 - C1153. [Abstract] [Full Text] [PDF] |
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J. You, T. D. Johnson, S. P. Marrelli, J.-V. Mombouli, R. M. Bryan Jr, and F. M. Faraci P2u Receptor–Mediated Release of Endothelium-Derived Relaxing Factor/Nitric Oxide and Endothelium-Derived Hyperpolarizing Factor From Cerebrovascular Endothelium in Rats • Editorial Comment Stroke, May 1, 1999; 30(5): 1125 - 1133. [Abstract] [Full Text] [PDF] |
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U. Simonsen, R. M Wadsworth, N. H. Buus, and M. J Mulvany In vitro simultaneous measurements of relaxation and nitric oxide concentration in rat superior mesenteric artery J. Physiol., April 1, 1999; 516(1): 271 - 282. [Abstract] [Full Text] [PDF] |
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C. Thollon, J. P. Bidouard, C. Cambarrat, I. Delescluse, N. Villeneuve, P. M. Vanhoutte, and J. P. Vilaine Alteration of Endothelium-Dependent Hyperpolarizations in Porcine Coronary Arteries With Regenerated Endothelium Circ. Res., March 5, 1999; 84(4): 371 - 377. [Abstract] [Full Text] [PDF] |
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W. B. Campbell and D. R. Harder Endothelium-Derived Hyperpolarizing Factors and Vascular Cytochrome P450 Metabolites of Arachidonic Acid in the Regulation of Tone Circ. Res., March 5, 1999; 84(4): 484 - 488. [Full Text] [PDF] |
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M. Kahonen, K. Karjala, N. Hutri-Kahonen, X. Wu, P. Jaatinen, P. Riihioja, A. Hervonen, and I. Porsti Influence of chronic ethanol consumption on arterial tone in young and aged rats Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H464 - H471. [Abstract] [Full Text] [PDF] |
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S. J. Duffy, G. New, B. T. Tran, R. W. Harper, and I. T. Meredith Relative contribution of vasodilator prostanoids and NO to metabolic vasodilation in the human forearm Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H663 - H670. [Abstract] [Full Text] [PDF] |
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X. Yao, P.-S. Leung, H.-Y. Kwan, T.-P. Wong, and M.-W. Fong Rod-type cyclic nucleotide-gated cation channel is expressed in vascular endothelium and vascular smooth muscle cells Cardiovasc Res, January 1, 1999; 41(1): 282 - 290. [Abstract] [Full Text] [PDF] |
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J. B. Su, F. Barbe, R. Houel, T. T. Guyene, B. Crozatier, and L. Hittinger Preserved Vasodilator Effect of Bradykinin in Dogs With Heart Failure Circulation, December 22, 1998; 98(25): 2911 - 2918. [Abstract] [Full Text] [PDF] |
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X. Fang, S. A. Moore, L. L. Stoll, G. Rich, T. L. Kaduce, N. L. Weintraub, and A. A. Spector 14,15-Epoxyeicosatrienoic acid inhibits prostaglandin E2 production in vascular smooth muscle cells Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2113 - H2121. [Abstract] [Full Text] [PDF] |
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C.-W. Sun, M. Alonso-Galicia, M. R. Taheri, J. R. Falck, D. R. Harder, and R. J. Roman Nitric Oxide-20–Hydroxyeicosatetraenoic Acid Interaction in the Regulation of K+ Channel Activity and Vascular Tone in Renal Arterioles Circ. Res., November 30, 1998; 83(11): 1069 - 1079. [Abstract] [Full Text] [PDF] |
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C. L. Oltman, N. L. Weintraub, M. VanRollins, and K. C. Dellsperger Epoxyeicosatrienoic Acids and Dihydroxyeicosatrienoic Acids Are Potent Vasodilators in the Canine Coronary Microcirculation Circ. Res., November 2, 1998; 83(9): 932 - 939. [Abstract] [Full Text] [PDF] |
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R. C. King, V. E. Laubach, R. C. Kanithanon, A. M. Kron, P. E. Parrino, K. S. Shockey, C. G. Tribble, and I. L. Kron Preservation with 8-bromo-cyclic GMP improves pulmonary function after prolonged ischemia Ann. Thorac. Surg., November 1, 1998; 66(5): 1732 - 1738. [Abstract] [Full Text] [PDF] |
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X. Wu, J.-P. Tolvanen, N. Hutri-Kahonen, M. Kahonen, H. Makynen, R. Korpela, H. Ruskoaho, K. Karjala, and I. Porsti Comparison of the effects of supplementation with whey mineral and potassium on arterial tone in experimental hypertension Cardiovasc Res, November 1, 1998; 40(2): 364 - 374. [Abstract] [Full Text] [PDF] |
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P. Hardy, D. Abran, X. Hou, I. Lahaie, K. G. Peri, P. Asselin, D. R. Varma, and S. Chemtob A Major Role for Prostacyclin in Nitric Oxide–Induced Ocular Vasorelaxation in the Piglet Circ. Res., October 5, 1998; 83(7): 721 - 729. [Abstract] [Full Text] [PDF] |
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G.-W. He Potassium-channel opener in cardioplegia may restore coronary endothelial function Ann. Thorac. Surg., October 1, 1998; 66(4): 1318 - 1322. [Abstract] [Full Text] [PDF] |
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M. Alonso-Galicia, C.-W. Sun, J. R. Falck, D. R. Harder, and R. J. Roman Contribution of 20-HETE to the vasodilator actions of nitric oxide in renal arteries Am J Physiol Renal Physiol, September 1, 1998; 275(3): F370 - F378. [Abstract] [Full Text] [PDF] |
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R. O. Cannon III Role of nitric oxide in cardiovascular disease: focus on the endothelium Clin. Chem., August 1, 1998; 44(8): 1809 - 1819. [Abstract] [Full Text] [PDF] |
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