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Department of Pharmacology and Clinical Pharmacology, St. George's Hospital Medical School, London SW17 ORE, United Kingdom
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We have investigated the
involvement of Cl
in regulating vascular tone in rat
isolated coronary arteries mounted on a small vessel myograph.
Mechanical removal of the endothelium or inhibition of nitric oxide
(NO) synthase with
N
-nitro-L-arginine methyl ester
(L-NAME, 104 M) led to contraction of rat
coronary arteries, and these contractions were sensitive to nicardipine
(106 M). This suggests that release of NO tonically
inhibits a contractile mechanism that involves voltage-dependent
Ca2+ channels. In arteries contracted with
L-NAME, switching the bathing solution to physiological
saline solution with a reduced Cl concentration
potentiated the contraction. DIDS (5 × 106-3 × 104 M) caused relaxation
of L-NAME-induced tension (IC50 = 55 ± 10 µM), providing evidence for a role of Cl. SITS
(105-5 × 104 M) did not affect
L-NAME-induced tension, suggesting that DIDS is not acting
by inhibition of anion exchange. Mechanical removal of the endothelium
led to contraction of arteries, which was sensitive to DIDS
(IC50 = 50 ± 8 µM) and was not affected by
SITS. This study suggests that, in rat coronary arteries, NO tonically
suppresses a contractile mechanism that involves a Cl conductance.
chloride channel; vascular smooth muscle
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE ENDOTHELIUM plays an important role in regulating vascular tone in many vascular beds, including the coronary circulation. In pressurized rat isolated small coronary arteries, nitric oxide (NO) modulates myogenic tone induced by increases in intravascular pressure (10). In the human coronary vascular bed, endothelium-derived NO contributes to metabolic vasodilation of large epicardial arteries (6), and mechanical removal of the endothelium increases intrinsic tone in the rat isolated coronary artery (23). This is of particular interest, inasmuch as removal of the endothelium or inhibition of NO synthase in arteries mounted as ring preparations from many other vascular beds produces little or no increase in basal tension (12, 16, 22, 28), although the effects of contractile agonists are potentiated (12, 16). This suggests that the mechanism producing contraction of coronary arteries in response to removal of the endothelium may not be present in the systemic circulation and is therefore a potential therapeutic target for a selective coronary vasodilator.
The potential importance of this observation is underlined by the well-documented finding that endothelial dysfunction is a feature of cardiovascular disease, including hypertension (7), diabetes (26), and atherosclerosis (19), all of which are risk factors for coronary artery disease. The association of endothelial dysfunction with increased risk of coronary artery disease suggests that coronary vasoconstriction due to reduction in tonic endothelium-derived NO may contribute to impaired myocardial perfusion.
Recent studies have suggested that the endothelium may regulate
vascular tone via an effect on vascular smooth muscle Cl
channels (16). In these studies, norepinephrine-induced
contractions of rat aorta were potentiated by reducing the
Cl concentration of the bathing solution, which suggests
that outward movement of Cl plays an important role in
the contraction. This effect was potentiated in arteries treated with
an NO synthase inhibitor or with the endothelium removed. In addition,
low-Cl solution also initiated contraction in
unstimulated arteries without endothelium but did not cause contraction
in arteries with an intact endothelium. These results are consistent
with a role for membrane Cl conductances as depolarizing
mechanisms in vascular smooth muscle (18). Moreover, the
above data suggest that an intrinsic Cl mechanism is
suppressed by NO.
We have therefore investigated how the coronary endothelium regulates
intrinsic vascular tone in rat isolated small coronary arteries and
explored the role of Cl in mediating the contraction
caused by removal of endothelium-derived NO.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Male Wistar rats (250-350 g) were killed by cervical dislocation, and the heart was removed immediately and placed in cold buffer. Typically, two 1.5- to 2.0-mm sections of the septal artery were dissected from the interior wall of the right ventricle and mounted as ring preparations on a small vessel myograph within 1 h (n = 76, 285 ± 5 µm ID at 100 mmHg). The arteries were maintained at 37°C bubbled with 95% O2-5% CO2 in physiological saline solution (PSS) of the following composition (mM): 119 NaCl, 4.7 KCl, 2.5 CaCl2, 1.17 MgSO4, 25 NaHCO3, 1.18 NaH2PO4, 0.026 EDTA, and 6.0 glucose. Arteries were allowed to equilibrate for 1 h before estimation of the internal circumference that they would have at a passive transmural pressure of 100 mmHg in vivo (22). A series of stretches (4-6) were performed such that the calculated (from the Laplace equation) effective pressure exceeded 100 mmHg on the final stretch. From this, the arteries were set to a normalized diameter of 90% of that which they would have assumed in vivo. After a further 30-min equilibration, a series of three contractions to K-PSS (equimolar substitution of NaCl with KCl) was carried out, with the arteries being exposed to K-PSS for 2 min every 10 min.
Protocols
Effect of NO synthase inhibition and the role of
Na+ and Cl.
To examine the influence of NO on vascular tone, 104 M
N-nitro-L-arginine methyl ester
(L-NAME) was added to the myograph bath, and the tension
was recorded for up to 3 h. The contribution of Cl
and Na+ to the contraction elicited by L-NAME
was investigated by the use of low-Cl and
low-Na+ PSS solutions. After contraction to
L-NAME, the solution in the myograph bath was washed to
either PSS or to low-Cl PSS (equimolar substitution of
NaCl with sodium isothionate) or low-Na+ PSS (equimolar
substitution of NaCl with choline chloride + 106 M
atropine or equimolar substitution of NaCl with
N-methyl-D-glucamine chloride), and the change
in tension was recorded for 5 min in the continued presence of
L-NAME before the solution was washed to PSS and
L-NAME (104 M).
Effect of Cl channel blockers on voltage-dependent
Ca2+ channels.
To examine the effect of Cl channel blockers on
voltage-dependent Ca2+ channels (VDCCs), cumulative
concentration-response curves to Cl channel blockers were
carried out on coronary arteries precontracted with 45 mM
K+. After a stable contraction to K+ was
established, Cl channel blockers were added in increasing
concentrations every 4 min. Drugs that did not affect the
K+ spasm at concentrations at which they had previously
been shown to affect Cl channels in electrophysiological
studies were then tested on the contraction to L-NAME.
Effect of Cl channel blockers on
L-NAME-induced tension.
To investigate the role of Cl channels on the contraction
to L-NAME, cumulative concentration-response curves to
Cl channel blockers were carried out in arteries
contracted with L-NAME. Increasing concentrations of DIDS
and SITS were added every 4 min. Inasmuch as the level of
precontraction can affect the response to vasodilators, only arteries
that contracted >0.5 mN/mm were used to examine the effects of the
stilbene derivatives.
Effect of endothelial removal on vascular tone and the effect of
Cl channel blockers.
Two sections of the same septal artery were mounted and contracted with
U-46619 (107 M) and challenged with ACh
(107-105 M). After washout, the
endothelium was removed from one artery by careful rubbing with a human
forearm hair while the artery was still mounted on the myograph; the
other artery was used as a control. The arteries were then contracted
with U-46619 (107 M) and challenged with ACh, and a
<10% relaxation to ACh was taken as evidence of endothelial removal.
After washout, the arteries were left until they had contracted >0.5
mN/mm. Subsequently, a cumulative concentration response to DIDS
(5 × 106-3 × 104 M) was
carried out, with increasing concentrations of DIDS being added every 4 min.
Effect of Cl transport inhibitors on
L-NAME-induced tension.
The effect of the K+-Na+-2Cl
cotransporter inhibitor bumetanide (105 M) was
investigated on arteries precontracted with L-NAME. After contraction to L-NAME, arteries were exposed for 30 min to
bumetanide, and tension was recorded. SITS (5 × 104
M) was then added in the continued presence of bumetanide, and tension
was recorded after a further 30 min.
Drugs
DIDS, SITS, tamoxifen, 9,11-dideoxy-11
,9-epoxymethanoprostaglandin F2
(U-46619), ACh hydrochloride, niflumic acid, 5-nitro-2-(3-phenylpropylamino)benzoic acid, L-NAME, and
nicardipine were obtained from Sigma Chemical (Poole, UK). IAA-94 was
obtained from Research Biochemicals (Natick, MA).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effect of Inhibition of NO Synthase on Tension of Rat Septal Arteries
Incubation with the NO synthase inhibitor L-NAME caused contraction of >0.50 mN/mm in 70% of arteries and some contraction in all arteries. A representative trace of the effect of L-NAME is shown in Fig. 1A, and the contraction to L-NAME was well maintained for up to 3 h. In 44 arteries, L-NAME induced a contraction of 1.10 ± 0.12 mN/mm. The contraction to L-NAME was unaffected by 0.1-0.5% DMSO, which was used as a vehicle for drugs, but was greatly attenuated (95 ± 3%, n = 5) by the voltage-gated Ca2+ channel blocker nicardipine (106 M). In three arteries, removal of the endothelium
caused contraction of 0.76 ± 0.11 mN/mm, and this contraction was
abolished by nicardipine (106 M). A representative trace
of the effect of nicardipine is shown in Fig. 1B. These data
suggest that inhibition of NO synthase and removal of the endothelium
initiate contraction by a mechanism that involves Ca2+
entry through VDCCs.
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Effect of Low-Cl Solution on Basal and
L-NAME-Induced Tone
and influx of Na+. Replacing the
Cl with a less-permeant anion (isethionate) will increase
the outward electrochemical gradient for Cl and thus
potentiate contraction if it is dependent on the outward movement of
Cl. In six arteries, washout to low-Cl PSS
had only a small effect on tension on unstimulated arteries compared
with washout to normal PSS (Fig.
2A). In contrast, in the same
six arteries, when contraction had been induced by L-NAME (contraction = 0.99 ± 0.17 mN/mm), substitution of PSS by
low-Cl PSS led to a potentiation of the contraction (Fig.
2B). These data are consistent with the proposal that the
contraction induced by L-NAME involves the outward movement
of Cl.
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Effect of Low-Na+ Solutions on L-NAME-Induced Tone
Depolarization of vascular smooth muscle can also occur by the opening of nonspecific cation channels and subsequent Na+ influx (3). Replacement of the Na+ by a relatively impermeant cation in the bathing solution should cause relaxation of the vascular smooth muscle if this mechanism is involved in the contraction to L-NAME. In four arteries treated with L-NAME (contraction = 1.25 ± 0.30 mN/mm), replacement of PSS by low-Na+ PSS (N-methyl-D-glucamine chloride substitution) gave an initial relaxation that was not significantly different from wash to normal PSS (Fig. 3), and this was followed by a substantial contraction. In four separate arteries treated with L-NAME (contraction = 0.88 ± 0.20 mN/mm), wash to low-Na+ PSS (choline chloride substitution) also led to an immediate and profound contraction (Fig. 3). We are uncertain as to the mechanism of the contraction in low-Na+ PSS, but these data clearly suggest that influx of Na+ is not responsible for the contraction to L-NAME.
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Effect of Cl Current Inhibitors on
K+-Induced Tone
conductances in electrophysiological experiments. Drugs that have been
shown to inhibit Cl channels in electrophysiological
experiments can have other effects that would also lead to vasodilation
in functional studies, namely, inhibition of VDCCs and opening of
K+ channels (5, 13). To investigate the
effects of Cl channel blockers on VDCCs, we examined
their effects on the nicardipine-sensitive contraction induced by 45 mM
K-PSS in arteries with an intact endothelium. The stilbene derivatives
DIDS and SITS did not cause relaxation of tension induced by 45 mM
K-PSS and, therefore, did not block VDCCs in this preparation. Tension
remaining after exposure of arteries precontracted with 45 mM
K+ to DIDS (3 × 104 M) was 101 ± 7% (n = 4). A representative trace of the effects of
DIDS is shown in Fig. 4A. In
contrast, all the other Cl channel blockers tested caused
relaxation of 45 mM K-PSS-induced tension and included tamoxifen
(105 M, 78 ± 10%, n = 3),
5-nitro-2-(3-phenylpropylamino)benzoic acid (3 × 106 M, 61 ± 12%, n = 4), IAA-94
(104 M, 58 ± 11%, n = 4), and
niflumic acid (2 × 104 M, 40 ± 9%,
n = 4). Therefore, we tested the stilbene derivatives DIDS and SITS against the contraction produced by L-NAME or
endothelial removal.
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The K+ channel opener levcromakalim
(106-105 M) induced relaxation in rat
isolated coronary arteries contracted with 45 mM K-PSS, and the maximum
relaxation to 105 M was 73 ± 3% (n = 5); a representative trace is shown in Fig. 4B.
Levcromakalim did not cause relaxation of tension in arteries contracted with 60 mM K-PSS. These data suggest that levcromakalim is
causing relaxation of arteries contracted by 45 mM K-PSS by opening
K+ channels, and therefore the observation that DIDS did
not cause relaxation of 45 mM K-PSS-induced tension indicates that the
agent is not acting as a K+ channel opener.
Effect of Stilbene Cl Channel Blockers on
L-NAME-Induced Tone
6-3 × 104 M) caused concentration-dependent relaxation of
coronary arteries contracted by addition of L-NAME
(contraction = 1.25 ± 0.28 mN/mm, n = 8); a
representative trace and a summary of the data are shown in Fig.
5. The IC50 for DIDS against
L-NAME was 55 ± 10 µM (n = 8). In
coronary arteries precontracted with U-46619 (contraction = 1.40 ± 0.14 mN/mm, n = 5), DIDS elicited a
relaxation but was markedly less potent than against the
L-NAME-induced contraction (Fig. 5B), and 150 µM DIDS produced 50% relaxation of the contraction to U-46619. In a
separate series of six arteries, L-NAME caused a
contraction of 0.89 ± 0.12 mN/mm, and addition of the stilbene
derivative SITS (105-5 × 104 M)
did not cause relaxation. The percentage of the initial tension remaining after 5 × 104 M SITS was 107 ± 14%.
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Effect of Mechanical Removal of the Endothelium
The maximum relaxation to ACh was 63 ± 5% when the artery was precontracted with U-46619 before mechanical removal of the endothelium, and after the endothelium was removed, the maximum relaxation was reduced to 1 ± 3%. A representative trace showing the contractile effect of endothelial removal and the subsequent relaxation to DIDS (5-300 µM) is shown in Fig. 6A. In this experiment, after washout of DIDS, the artery contracted again, and a single dose of SITS (500 µM) was added that produced only a small relaxation. Inasmuch as SITS would be expected to cause a substantial blockade of the anion exchanger, the above evidence suggests that the DIDS-induced relaxation is not due to inhibition of this mechanism. All five arteries subjected to mechanical removal of the endothelium contracted (mean contraction = 0.64 ± 0.05 mN/mm after 52 ± 5 min; mean contraction in 5 control arteries with intact endothelium = 0.01 ± 0.04 mN/mm). A concentration response to DIDS was carried out, and the mean results are shown in Fig. 6B. DIDS caused a concentration-dependent relaxation in endothelium-denuded arteries, with a maximum relaxation of
0.80 ± 0.11 mN/mm, slightly below
the original baseline. The IC50 for DIDS was 50 ± 8 µM (n = 5). The presence of some intrinsic tone that
was sensitive to DIDS in these experiments was confirmed by the slight
relaxation of arteries with an intact endothelium of 0.10 ± 0.05 mN/mm.
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Effect of Cl Transport Inhibitors on
L-NAME-Induced Tension
cotransporter (bumetanide) and
Cl/HCO3 exchanger (SITS) that
would be expected to reduce the outward Cl gradient.
L-NAME contracted four arteries (0.54 ± 0.05, n = 4), and addition of bumetanide (10 µM) caused a
small contraction that was 16 ± 8% of the initial tension after
5 min (Fig. 7). This was followed by a
relaxation of 25 ± 4% of the initial tension after 30 min. Addition of SITS (500 µM) caused a further relaxation of 78 ± 4% of the initial tension.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The major finding of this study is that, in rat isolated small
coronary arteries, endothelium-derived NO provides a tonic inhibition
of an intrinsic contractile mechanism that involves Cl.
The contractile effects of L-NAME and removal of the
endothelium confirm the contribution of NO from the endothelium as a
tonic vasodilator influence. The contraction is mediated by entry of Ca2+ into the vascular smooth muscle via VDCCs, inasmuch as
the contractions are sensitive to nicardipine. This suggests that, in
arteries with a functioning endothelium, NO suppresses an intrinsic
depolarizing mechanism and subsequent removal of NO produces
depolarization of the smooth muscle cells to open VDCCs to cause
contraction. Future studies simultaneously measuring tension by means
of the myograph and membrane potential by microelectrode will be
carried out to confirm the central role of a depolarizing mechanism.
There are three potential depolarizing influences involving ion
channels in vascular smooth muscle: opening of Cl
channels leading to Cl efflux, opening of nonspecific
cation channels leading to Na+ influx, and closing of
K+ channels. The potentiation of the contraction to
L-NAME by reduction of extracellular Cl is
consistent with an outward movement of Cl through a
Cl channel being responsible for the depolarization. If a
nonspecific cation channel were mediating the depolarization, reduction
of extracellular Na+ would be expected to decrease
depolarization and contraction, whereas this procedure produced a
contraction. This suggests that the contraction induced by
L-NAME is not mediated by a nonspecific cation channel.
However, a degree of caution is necessary in interpreting the data from
ion substitution experiments, since we do not have precise information
on the intracellular ion concentrations. In addition, other ion
transport mechanisms may be affected. There is evidence for NO opening
K+ channels to cause hyperpolarization (1, 2),
and we cannot rule out the possibility that removal of a
hyperpolarizing K+ influx could play a role in the
contraction to L-NAME. Nevertheless, the data imply that
when NO is removed, the smooth muscle cells of the rat coronary
circulation depolarize sufficiently to open VDCCs to produce
contraction. This is clearly different from most systemic arteries,
where inhibition of NO synthesis or mechanical removal of the
endothelium does not evoke contraction. A recent report demonstrated
that the endothelium inhibits anion channel-dependent contractions of
rat aortic rings elicited by substitution of the more-permeable anion
I for Cl (17). In contrast to
our study, removal of the endothelium alone in the rat aorta did not
lead to significant contraction, and the endothelial factor involved
was not NO.
Relaxation by DIDS of arteries contracted by L-NAME or
removal of the endothelium is further evidence for a role of
Cl in mediating the contraction. The relaxation to DIDS
is observed in endothelium-denuded vessels and is therefore due to a
direct effect on the vascular smooth muscle. We have demonstrated that DIDS is not acting as a VDCC blocker. We also attempted to examine whether DIDS relaxed the artery by opening of K+ channels.
DIDS did not relax the contraction to 45 mM K+, which was
inhibited by the K+ channel opener levcromakalim.
Levcromakalim did not inhibit the contraction produced by 60 mM
K+. However, without membrane potential measurement, this
conclusion is tentative, inasmuch as K+ equilibrium
potential, and presumably membrane potential, should be around
30 mV, and levcromakalim may not be able to hyperpolarize the smooth
muscle under these conditions.
The most likely explanation for the vasodilator action of DIDS is via
its effects on mechanisms involving Cl. In addition to
blockade of Cl channels, the stilbene derivatives also
block the Cl/HCO3 exchanger mechanism,
which may be involved in maintaining intracellular Cl
concentration. Blockade of this mechanism could induce relaxation by
reducing the Cl electrochemical gradient that is
responsible for the depolarizing influence of opening Cl
channels. However, SITS, which has a potency similar to DIDS on the
Cl/HCO3 exchanger (4, 9),
did not relax coronary arteries when added on its own. However,
bumetanide, an inhibitor of the
Na+-K+-2Cl cotransporter,
produced a relaxation of the L-NAME-induced contraction after 30 min. Subsequent addition of SITS in the continued presence of
bumetanide produced a substantial relaxation. This result suggests that
both Cl transport mechanisms are able to maintain an
outward Cl electrochemical gradient in these arteries and
that the contraction to L-NAME is dependent on this
electrochemical gradient being maintained. The vasodilator action of
DIDS is not likely to be due to inhibition of inward Cl
transport systems.
Other potential targets for DIDS are membrane Cl
conductances, which produce depolarization in vascular smooth muscle.
Two Cl currents have been identified in vascular smooth
muscle: the Ca2+-activated Cl current
[ICl(Ca)] and the swell-activated
Cl current
[ICl(swell)]. The IC50
for DIDS against ICl(Ca) is 200-700 µM
(18), similar to the concentration (150 µM) required to
cause 50% relaxation of coronary arteries contracted with U-46619 . Therefore, it is possible that U-46619 activates
ICl(Ca) to produce contraction in this tissue.
Previously, it was suggested that ICl(Ca)
represents a depolarizing mechanism for agonist-induced contraction in
blood vessels (18). DIDS is an effective inhibitor of
ICl(swell), with an IC50 of 21 µM
in rabbit isolated portal vein smooth muscle cells (14),
which is similar to the IC50 of 55 µM estimated for DIDS
against L-NAME-induced contraction, and an IC50
of 50 µM for DIDS against the contraction to endothelial removal in
the present study. In contrast, SITS has been shown to be much less
potent than DIDS against ICl(swell) in canine colonic myocytes (5). It is worth noting that the
inhibitory effect of DIDS against the contraction to L-NAME
was much more rapid than the relaxation induced by bumetanide + SITS. These results are consistent with DIDS acting as a channel
blocker (14) and bumetanide and SITS as transport
inhibitors. Preliminary studies show that NO inhibits
ICl(swell) in rabbit isolated portal vein smooth
muscle cells (8). Consequently, it is possible that ICl(swell) may represent the depolarizing
mechanism that is suppressed by NO in rat isolated coronary arteries.
However, the precise identification of which Cl channels
may be involved will require single-cell electrophysiological studies.
The mechanism underlying the contraction to low Na+ (25 mM)
is interesting and appears to involve depolarization of the vascular smooth muscle, inasmuch as the contraction was sensitive to nicardipine (J. Graves, unpublished observations).
Na+-K+-ATPase has been reported to be inhibited
by low extracellular Na+ (<50 mM), and inhibition of this
electrogenic mechanism would cause depolarization and thus contraction.
The contraction to low Na+ is of interest, inasmuch as it
presents another feature of these coronary arteries that is very
different from that previously reported for systemic arteries. It has
been reported that rat isolated mesenteric resistance arteries do not
contract to low-Na+ solutions unless they are pretreated
with ouabain (20). In addition, low-Na+
solutions potentiate myogenic tone in arteries and veins, although the
low-Na+ solutions used in this study may have had reduced
Cl content (15).
Interestingly, human epicardial arteries also contract when treated
with NO synthase inhibitors (27), and this raises the possibility that a similar mechanism exists in the human coronary circulation. Spontaneous contractile activity of human isolated coronary arteries that is sensitive to Ca2+ channel
antagonists has also been described (25). This intrinsic activity and contraction to disruption of the NO pathway is not seen in
most small systemic arteries. Thus this Cl mechanism, if
present in humans, may provide a potential therapeutic target for
selective vasodilation of coronary arteries. Since this contractile
mechanism may be prominent in arteries with a damaged endothelium,
agents targeting this mechanism may act more potently on diseased
arteries and thus avoid cardiac steal.
Conclusion
We have provided evidence that a mechanism involving Cl, possibly a Cl conductance, is involved
in the contraction of rat coronary arteries produced by removal of
endothelium-derived NO. This mechanism may be of great importance in
cardiovascular disease associated with disturbances in the coronary
circulation and is a novel target for therapy.
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ACKNOWLEDGEMENTS |
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This work was supported by the British Heart Foundation and The Wellcome Trust.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. E. Graves, Dept. of Pharmacology and Clinical Pharmacology, St. George's Hospital Medical School, London SW17 ORE, UK (E-mail: jgraves{at}sghms.ac.uk).
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.
Received 9 May 2000; accepted in final form 4 August 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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