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Departments of Pharmacology and Toxicology and Physiology, Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
ENDOTHELIAL CELLS
regulate vascular tone through the release of soluble mediators such as
prostacyclin, nitric oxide (NO), and endothelium-derived
hyperpolarizing factor (EDHF). This issue of AJP: Heart & Circ
Physiol contains nine research articles covering the topic of
EDHF. These articles consider the identity of EDHF, the mechanism of
action of EDHF, the role of gap junctions in the EDHF response, and the
influence of shear stress and gender on EDHF. The articles include
studies in isolated vessels of humans and experimental animals as well
as a clinical study in humans. These articles do not represent all
aspects or all points of view in this field of investigation, but they
are a snapshot of important original contributions to our understanding
of the physiology of EDHF. As expected, the contributors do not reach a
consensus on the nature of EDHF. However, many of the salient arguments are discussed and several consistent properties of EDHF are defined.
As originally described, acetylcholine caused hyperpolarization of
vascular smooth muscle in arteries with an intact endothelium but not
in the absence of the endothelium (6, 10, 11, 21). The
hyperpolarization by acetylcholine was inhibited by high extracellular potassium concentration and potassium channel blockers and mimicked by
potassium channel agonists. The activity was not affected by inhibitors
of NO synthase or cyclooxygenase. This pioneering research established
the existence of EDHF and indicated that it was distinct from NO or
prostacyclin. Furthermore, these studies implied that EDHF acted to
open smooth muscle cell potassium channels, allowing potassium efflux
along its chemical gradient and resulting in membrane
hyperpolarization. These conclusions have been confirmed by subsequent
investigations including some of the articles in this Special Topic.
Because few laboratories are equipped to measure membrane potential in
smooth muscle cells, another functional definition of EDHF has
subsequently emerged: agonist-induced, endothelium-dependent
relaxations that are not blocked by inhibitors of NO synthase or
cyclooxygenase but are inhibited by potassium channel blockers. These
two definitions are assumed to define the same mediator.
The relative contributions of NO, prostacyclin, and EDHF in regulating
vascular tone have not been clearly defined. However, in vitro studies
with inhibitors of the synthesis of these mediators indicate that the
contribution of NO to vascular tone is greatest in large-diameter
vessels, whereas the contribution of EDHF is greatest in small-diameter
vessels and microvessels (36). This conclusion has been
confirmed in vivo (37, 43). In this regard, the studies by
Coleman et al. (12), Wu et al. (44), Huang et
al. (32), and Zhang et al. (45) in this
Special Topic were all conducted in arterioles and indicate the role of
EDHF to arteriolar tone.
The chemical identity of EDHF is controversial. Several chemical
mediators produced by the endothelium have EDHF activity in some
vascular beds. Studies from a number of laboratories (7, 22, 24,
25, 31, 39) indicate that epoxyeicosatrienoic acids (EETs)
function as EDHF. EETs are cytochrome P-450 metabolites of
arachidonic acid and are produced by the endothelium (39, 40). They are released in response to acetylcholine,
hyperpolarize smooth muscle, open calcium-activated potassium channels,
and relax arteries. Inhibitors of cytochrome P-450 inhibit
acetylcholine-induced hyperpolarization of smooth muscle and
relaxation. Indeed, the EETs are the only endothelial factors that
hyperpolarize vascular smooth muscle that has been identified by
chemical methods (7, 40). In other studies, inhibitors of
cytochrome P-450 failed to affect the EDHF response
(13, 20, 41). In an accompanying article, Halcox et al.
(27) confirm the role of cytochrome P-450 metabolites in regulating vascular tone in human subjects. They report
that acetylcholine and bradykinin dilate the human forearm vasculature
in the presence of NO synthase and cyclooxygenase blockade. Infusion of
potassium chloride blocked the dilation to bradykinin. The cytochrome
P-450 inhibitor miconazole also blocked the
bradykinin-induced vasodilation but not the dilation to acetylcholine.
The authors concluded that EDHF is an EET in the human forearm
microvasculature. Similarly, Wu et al. (44) report
flow-induced dilation in the presence of NO synthase and cyclooxygenase
blockade that was blocked by the potassium channel blocker
charybdotoxin. Two inhibitors of cytochrome P-450 also blocked the dilation. These authors concluded that EDHF, a cytochrome P-450 metabolite, preserves flow-induced dilation in female
rats. Finally, Zhang and co-workers (45) compared the
ability of stereoisomers and regioisomers of the EETs as well as EET
analogs with a All of the articles in this Special Topic, and most articles in the
literature, use inhibitors of cytochrome P-450 to define the
role of the EETs as EDHFs. Identification of EETs as EDHF by
pharmacological approaches alone should be viewed with caution. Similarly, a lack of effect of cytochrome P-450 inhibitors
does not establish that EDHF is not a cytochrome P-450
metabolite unless enzyme inhibition is chemically verified because
there are many cytochrome P-450 isozymes with different
affinities for substrates and inhibitors. For example, the cytochrome
P-450 inhibitor 17-octadecynoic acid inhibits the
Of interest, these studies by Halcox et al. (27), Huang et
al. (32), and Wu et al. (44) emphasize a role
for EDHF following inhibition of NO synthase and in NO synthase
knockout mice. Others (3) reported that NO inhibits EDHF
release. Because NO binds heme, it has been suggested that NO binds and
inactivates cytochrome P-450 epoxygenase and blocks EET
synthesis. Alternatively, Dora and co-workers (15)
suggested that NO may inhibit EDHF release by increasing cGMP and
protein kinase G and inhibiting calcium entry into endothelial cells
via a protein kinase G-regulated cation channel.
Potassium causes vasodilation in low concentrations by activation of
the sodium-potassium ATPase (18, 19). In the rat hepatic
artery, acetylcholine promotes the release of potassium from
endothelial cells through potassium channel activation. Potassium causes hyperpolarization and relaxation of smooth muscle in
concentrations <14 mM. However, in concentrations >14 mM, it will
depolarize and contract the smooth muscle. Thus potassium functions as
an EDHF within the concentration window of 4.8-14 mM. The article by Dora and Garland (14) supports this view. However,
other laboratories have concluded that potassium is not EDHF (16, 17, 33, 38). This discrepancy may be attributed to the narrow concentration window in which potassium causes hyperpolarization and
dilation. It has been suggested that EETs mediate the opening of
potassium channels in endothelial cells, and endothelial potassium mediates the hyperpolarization and vasodilation. Another study (38) contradicts this conclusion and indicates that EETs
act on the smooth muscle cells to cause dilation. Coleman et al.
(12) present evidence in guinea pig submucosal arterioles
that substance P promotes endothelium-dependent hyperpolarization of
the smooth muscle cell membrane, whereas potassium chloride promotes
depolarization. These authors conclude that EDHF is not potassium in
the guinea pig arterioles. Instead, these investigators provide
evidence for the electrotonic spread of current from endothelial cells to smooth muscle cells. This idea of electrical coupling of endothelial cells and smooth muscle cells through gap junction is of growing importance. There is a need for additional research on the contribution of endothelial-muscle cell gap junctions and their role in the mechanism of EDHF. Because vascular smooth muscle cells are much larger
than endothelial cells, it is not obvious how hyperpolarization of an
endothelial cell will promote hyperpolarization of an electrically coupled smooth muscle cell. Under normal circumstances, the potential voltage and current density of the larger cell will control the membrane potential of the smaller cell, not vice versa. Additionally, there is not a one-to-one coupling of endothelial cells to smooth muscle cells. These concerns raise the issue of whether the electrical coupling between endothelial cells or between smooth muscle cells is
critical for the EDHF response or the spread of the EDHF effect. Chaytor et al. (9) investigated the contribution of
electrical coupling using synthetic peptides homologous to specific
regions of the connexins that comprise vascular gap junctions. These
"Gap" peptides are specific for connexin40 and -43, which are
present in gap junctions of endothelial cells of the rat hepatic
artery, and specific for connexin37, which is present in smooth muscle cell gap junctions. Inhibition of connexins with these Gap
peptides blocked gap junction formation. Furthermore, a combination of the Gap peptides that block connexin40, -43, and -37 inhibited acetylcholine-induced relaxations in rat hepatic arteries pretreated with inhibitors of NO synthase and cyclooxygenase. These studies emphasize the importance of gap junctions in the transmission and
spread of the EDHF response.
Several reports suggest that hydrogen peroxide functions as EDHF
(5, 35). Other reports document the ability of reactive oxygen species (ROS) to increase potassium channel activity and hyperpolarize smooth muscle (1, 2). There are several
potential sources of superoxide anion in endothelial cells,
including NADPH oxidase, NO synthase, and cytochrome P-450
(4, 23, 42). Superoxide dismutase converts
superoxide to hydrogen peroxide. Thus ROS fit the basic profile of
EDHF; however, it remains to be determined whether ROS play a
physiological role in this regard. Hamilton and co-workers
(28) performed studies in the radial and internal mammary
arteries of humans to determine the role of hydrogen peroxide. These
arteries produce superoxide and contain superoxide dismutase and have
the capacity to produce hydrogen peroxide. However, neither
catalase nor superoxide dismutase inhibited the relaxations to
carbachol in arteries treated with inhibitors of NO synthase and
cyclooxygenase. Whereas human radial and internal mammary arteries
exhibit EDHF-mediated relaxations, these relaxations cannot be
attributed to hydrogen peroxide.
The articles by Wu et al. (26) and Golding et al.
(44) indicate that the contribution by EDHF differs in
females and males, and estrogen may be responsible. These studies,
however, describe opposite results. Wu and co-workers (44)
demonstrate that arterioles of the gracillis muscle dilate in response
to increases in flow. This dilation occurred in both males and females;
however, the response was greater in females. The flow-mediated
dilation was eliminated by inhibition of NO synthase and cyclooxygenase
in males but not in females. Inhibitors of cytochrome P-450
and potassium channels eliminated the response in females. The authors
concluded that EDHF preserved flow-mediated dilation in females but not males. Golding and co-workers (26) reported that middle
cerebral arteries relaxed to ATP in the presence of inhibitors of NO
synthase and cyclooxygenase. These relaxations were less in females and in estrogen-treated, ovariectomized females than in males or
ovariectomized females. These studies by Wu et al. (26)
and Golding et al. (44) were performed in arterioles from
different vascular beds, raising the possibility that gender or
estrogen may have differential effects on the circulation. Obviously,
this important issue requires further study and clarification.
These articles represent the growing interest in EDHF and its role in
the control of regional circulations under normal conditions and in
disease. These studies also indicate the challenge for future research
to define the roles of EETs, hydrogen peroxide, and potassium;
determine the interactions among NO, prostacyclin, and EDHF; and
clarify the participation of gap junctions in mediating and spreading
the EDHF response in the vascular wall.
ARTICLE
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ARTICLE
REFERENCES
17 double bond and with two additional carbons to
relax coronary microvessels and activate calcium-activated potassium
channels in coronary myocytes. These analogs and isomers had similar
activity. There was no apparent regioselectivity or stereoselectivity
in causing relaxation. In addition, the analogs were comparable in potency and activity to the naturally occurring EETs. These articles further emphasize a role for EETs as a mediator of
endothelium-dependent relaxations in the presence of cyclooxygenase and
NO synthase inhibition.
-hydroxylation of arachidonic acid by cytochrome P-450 at
low concentrations and inhibits epoxygenase activity in fivefold higher
concentrations (29). In addition, in the smooth
muscle cells of some vessels, arachidonic acid is metabolized by
cytochrome P-450 to the vasoconstrictor
20-hydroxyeicosatetraenoic acid (20-HETE) (30, 34).
Inhibitors of cytochrome P-450 will block the formation of
both endothelial vasodilator EETs and smooth muscle cell constrictor
20-HETE (8).
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FOOTNOTES |
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This special topic section is a collection of papers accepted under a special call for manuscripts by the Editor. See Journal web site for information about the next call.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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