(Circulation. 1999;99:3132-3138.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Human Coronary Arteriolar Dilation to Bradykinin Depends on Membrane Hyperpolarization
Contribution of Nitric Oxide and Ca2+-Activated K+ Channels
From the Veterans Administration Medical Center, the Department of Internal Medicine, and Cardiovascular Center, University of Iowa College of Medicine (H.M.), Iowa City, Iowa, and the VA Medical Center, Cardiovascular Research Center and Department of Internal Medicine, Medical College of Wisconsin (Y.L., D.D.G.), Milwaukee.
Correspondence to David D. Gutterman, MD, Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI 53226. E-mail dgutt{at}mcw.edu
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Abstract |
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Background—K+ channel activation in vascular smooth muscle cells (VSMCs) plays a key role in regulating vascular tone. It has been proposed that endothelium-derived hyperpolarizing factor (EDHF) contributes to microvascular dilation more than nitric oxide (NO) does. Whether hyperpolarization is important for coronary arteriolar dilation in humans is not known. Bradykinin (BK), an endogenous vasoactive substance, is released from ischemic myocardium and regulates coronary resistance. Therefore, we tested the effects of inhibiting NO synthase, cyclooxygenase, and K+ channels on the changes in diameter and membrane potential (Em) in response to BK in isolated human coronary microvessels.
Methods and Results—Arterioles (97±4 µm; n=120) dissected
from human right atrial appendages (n=78) were cannulated at a
distending pressure of 60 mm Hg and zero flow. Changes in vessel
diameter (video microscopy) and VSMC Em (glass microelectrodes) were
measured simultaneously. In vessels constricted and
depolarized (Em; -50±3 to -28±2 mV) with endothelin-1 (ET),
dilation to BK was associated with greater membrane
hyperpolarization (-48±3 mV at 10-6
mol/L) than dilation to sodium nitroprusside (SNP) (-34±2 mV at
10-4 mol/L) for similar degrees of dilation. Treatment
with N
-nitro-L-arginine
methyl ester (L-NAME; 10-4 mol/L), an NO synthase
inhibitor, partially decreased dilation to BK (maximum
dilation 61±10% versus control 92±4%; P<0.05).
Charybdotoxin (CTX; 10-8 mol/L), a large-conductance
Ca2+-activated K+ channel blocker, or
apamin (10-7 mol/L), a small-conductance
Ca2+-activated K+ channel blocker,
inhibited both dilation (CTX 22±6% and apamin 45±10% versus control
69±6%; P<0.05) and membrane
hyperpolarization (CTX -31±2 mV and apamin
-37±2 mV versus control –44±2 mV; P<0.05) to BK,
whereas glibenclamide (10-6 mol/L), an ATP-sensitive
K+ channel blocker, was without effect.
Conclusions—Vasodilation of human coronary arterioles to BK is largely dependent on membrane hyperpolarization by Ca2+-activated K+ channel activation, with apparently less of a role for endothelium-derived NO. This suggests a role for K+ channel activation in regulating human coronary arteriolar tone.
Key Words: bradykinin • nitric oxide • endothelin • vasodilation • potassium
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Bradykinin (BK) is a potent endogenous vasodilator that stimulates endothelial B2 receptors, leading to release of a variety of vasoactive substances.1 2 Studies in vivo in humans suggest that BK contributes to basal and flow-mediated vasomotor responses in the coronary circulation.3 BK may also mediate vasodilation of resistance arteries to ischemia in the canine heart.4 Thus, BK may play an important role in regulation of the coronary microcirculation in both physiological and diseased states. However, the mechanism of vasodilation to BK in humans is not understood.
Endothelial cells contribute to regulation of vascular
tone by releasing 
3 vasoactive compounds: nitric oxide (NO),
prostacyclin (PGI2), and
endothelium-derived hyperpolarizing factor
(EDHF).5 6 7 Although NO is often responsible for conduit
artery dilation in some species and vascular beds, EDHF
predominates in smaller arterioles.8
Hyperpolarization and BK-induced vasorelaxation
have been shown in human conduit arteries.9 However, the
relative role of NO and EDHF in dilation of human coronary
resistance vessels is not known.
The objectives of the present study were to determine whether human coronary arteriolar vasodilation to BK is dependent on membrane hyperpolarization of vascular smooth muscle cells (VSMCs) and to elucidate the contributions of NO and K+ channels.
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Methods |
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General Preparation
All protocols were approved by The University of Iowa and the Medical College of Wisconsin committees on the use of human subjects in research. Human coronary arterioles were dissected from human right atrial appendage tissue obtained from 78 patients (56±17 years of age; 57 men) undergoing valve replacement (aortic, n=6; mitral, n=1) and/or coronary bypass surgery (n=67). Baseline demographic data are summarized in Table 1
. After surgical removal, tissue
was placed in Krebs buffer solution (4°C) with the following
composition (in mmol/L): NaCl 118, KCl 4.7,
CaCl2 2.5,
KH2PO4 1.2,
MgSO4 1.2, NaHCO3 20,
Na2 EDTA 0.026, and dextrose 11, pH 7.4.
Coronary arterioles (n=120; mean internal diameter, 97±4
µm) were carefully dissected from the endocardial surface of the
appendage and transferred to a 20-mL organ chamber containing Krebs
solution. Each end of the vessel was secured to a separate glass
micropipette filled with Krebs buffer and transferred to the stage of
an inverted microscope (CK2, Olympus) coupled to a CCD camera
(WV-BL200, Panasonic) and video micrometer (VIA-100K,
Boeckeler Instruments, Inc). Internal vascular diameters were measured
throughout the experiment with a manually adjusted video microscope, as
described previously.10 Micropipettes were connected to a
hydrostatic reservoir at 60 mm Hg. The chamber solution was
continuously recirculated at 30 mL/min; aerated with 20%
O2, 5% CO2, and 75%
N2; and maintained at 37°C by an external heat
changer. All pharmacological agents were added to the external bathing
solution.
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After 30 minutes' equilibration, vessels were transiently
constricted with 75 mmol/L KCl. Vessels that failed to constrict
>30% (
15% of experiments) before each dose-response curve were
discarded.
Experimental Protocols
After a 60-minute stabilization period, vessels were
constricted to 30% to 60% of resting diameter with endothelin-1.
Vascular responses to cumulative logarithmic increases in the
concentration of BK (10-14 to
10-6 mol/L) in the external bathing media were
examined in the presence and absence of
N-nitro-L-arginine
methyl ester (L-NAME; 10-4 mol/L), an NO
synthase inhibitor, alone or together with
indomethacin (INDO; 10-5 mol/L),
a cyclooxygenase inhibitor.
To test for the role of potassium channels, some vessels were constricted with KCl (45 mmol/L) instead of endothelin-1 or treated with tetraethylammonium chloride (TEA; 10-3 mol/L), a relatively selective blocker of large-conductance Ca2+-activated K+ channels (BKCa); tetrabutylammonium chloride (TBA; 10-3 mol/L), a distinct and less-selective K+ channel blocker; glibenclamide (10-6 mol/L), a selective blocker of ATP-sensitive K+ channels (KATP); charybdotoxin (CTX; 10-8 mol/L), a selective blocker of BKCa11 ; or apamin (10-7 mol/L), a selective blocker of small-conductance Ca2+-activated K+ channels (SKCa),12 for 30 minutes before application of BK. All studies in this group of experiments, except those in which KCl was substituted for endothelin, were performed in the presence of L-NAME and INDO.
Measurement of Membrane Potential
In separate experiments, we simultaneously
examined steady-state changes in vessel diameter and VSMC membrane
potential (Em) in response to BK and sodium nitroprusside (SNP), as
described previously.10 Em was measured with glass
microelectrodes (impedance of 50 to 100 M
; tip potential 
5 mV)
filled with 3 mol/L KCl and connected to a high-impedance amplifier
(Axo-clamp). The microelectrode was advanced through the adventitial
side of the vessel (manual microdrive) in 0.5-µm increments while tip
potential was monitored.
Criteria for successful impalements included an abrupt drop in
potential to a new steady-state value for 10 seconds and a sudden
return to the original baseline when the electrode was pulled from the
VSMC.13 Multiple successful impalements of 3 distinct
VSMCs were averaged to obtain each reported Em
measurement.13
Changes in vascular diameter and Em were measured simultaneously to elucidate the relationship between vasodilation and membrane hyperpolarization. At the end of each experiment, maximal dilation was determined by SNP (10-4 mol/L).
Materials
Endothelin-1 was obtained from Peninsula Laboratories, Inc and
was prepared in saline with 1% BSA. All other reagents were obtained
from Sigma Chemical Co. Glibenclamide was prepared in 100% DMSO and
diluted in saline. INDO was dissolved in saline with 1.0N NaOH, and pH
was adjusted with 0.1N HCl to 7.4. Other agents were prepared in
distilled water. Final molar concentrations in the organ chambers are
reported. The addition of pharmacological agents produced <1% change
in the volume of the circulating bath.
Statistical Analysis
Results are expressed as percent dilation, with 100%
representing the change from constricted diameter with
endothelin-1 or KCl to the diameter in the presence of SNP
(10-4 mol/L). The diameter in the presence
of this dose of SNP was similar to the maximal diameter achieved during
the experiment (pressurized at 60 mm Hg, at a temperature of
20°C, early during incubation). Comparisons of percent vasodilation
under different treatments were performed with 2-factor
repeated-measures ANOVA with proc mixed modules in SAS version
6.2 with autoregressive covariance assumptions. Em values were
compared with a 1-factor repeated-measures ANOVA. Both computations
were followed by a Bonferroni corrected t test when
significant differences were noted. To compare sensitivities of the
agents used, ED50 values (negative logarithm of
the molar concentration of vasodilator that produced 50% of the
maximal dilation to the agonist) were calculated. Percent maximal
dilations and ED50 values were compared by
Student's paired t test. Simple linear regression
analysis was used to evaluate the relationship between
vasodilation and hyperpolarization. Statistical
significance was defined as P<0.05. All data are
presented as mean±SEM; n indicates the number of patients.
Although the design incorporated blinded assignment of vessels to specific treatment protocols, we used stepwise multiple regression analysis to assess whether coronary artery disease (CAD) or risk factors for CAD, age, or sex influenced the vasodilator response. If such a factor were found, our plan was to detect any independent influence using ANCOVA. This approach optimizes our ability to infer whether the models can be generalized to nondiseased human arterioles.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Human right atrial appendages were obtained from 78 patients. One hundred twenty atrial vessels (mean internal diameter of 97±4 µm) were studied at a pressure of 60 mm Hg in Krebs buffer. Patient demographics, including diagnoses, are summarized in Table 1
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Figure 1 shows vasodilator responses to
BK and SNP in human coronary arterioles. Both agents produced
potent concentration-dependent dilations in vessels constricted with
endothelin-1 (maximum dilation: BK 91±2% and SNP 100±0% by
definition).
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Because hyperpolarization may contribute to
vasodilation,8 14 we examined the change in membrane
potential (Em) to both BK and SNP. A typical tracing of Em in response
to BK is shown in Figure 2A. In the
absence of preconstriction, BK (10-6 mol/L)
produced a transient small depolarization (-36 to –30 mV) followed by
a larger and more sustained membrane
hyperpolarization (-30 to –46 mV). In a separate
example, after constriction and depolarization with endothelin-1, BK
(10-6 mol/L) evoked a potent vasodilation (81%)
with an associated decrease in Em (-20 to –45 mV) that was greater in
magnitude than that observed without constriction (Figure 2B).
This type of recording was possible in only a few cases because
of vessel motion with change in diameter. Figure 2C shows a
series of VSMC impalements in the presence of increasing doses of BK in
a single arteriole. BK hyperpolarized and dilated this vessel in a
concentration-dependent manner. The delay from application of BK to the
onset of hyperpolarization approximates the delay
of fluid pumped from the buffer reservoir, where drugs are added, to
the vessel chamber.
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Figure 3 summarizes responses to BK and
SNP. Both agents simultaneously dilated and hyperpolarized
vessels, although the magnitude of
hyperpolarization was less with SNP (versus BK,
P<0.05 at highest dose). Vasodilator responses correlated
closely with changes in Em; however, the relationship was steeper for
BK (Figure 4) than for SNP (BK versus
SNP, P=0.0024). These findings indicate that in contrast to
SNP, dilation to BK depends largely on membrane
hyperpolarization, which implies that EDHF plays an
important role in human coronary microvascular responses to BK.
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In the presence of L-NAME (10-4 mol/L),
vasodilation to BK was modestly but significantly decreased (maximum
dilation 61±10% versus control 92±4%, P<0.05;
ED50 9.7±0.8 versus control 9.8±0.4,
P=NS; n=6). Addition of INDO to L-NAME produced no further
reduction in dilation to BK (maximum dilation 77±7% versus control
95±1%; P<0.05 versus no inhibitors) (Figure 5).
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Figure 6 summarizes changes in Em and
diameter to BK in the presence and absence of L-NAME plus INDO.
Although vasodilation was reduced after L-NAME plus INDO (60±5%
versus control 82±7%; P<0.05),
hyperpolarization was not. These results indicate
that a small portion of the dilation to BK is mediated primarily by NO,
although NO does not contribute to the associated membrane
hyperpolarization.
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EDHF-induced dilation typically is mediated by activation of
K+ channels in VSMCs. Extraluminal KCl (45
mmol/L), which prevents membrane hyperpolarization
via flux through K+ channels, diminished
vasodilation to BK (Figure 7; maximum
dilation 33±15% versus control 92±4%; P<0.05). In this
protocol, L-NAME and INDO were not included in the bathing solution.
This result is consistent with an important role for
K+ channels in vasodilation and
hyperpolarization to BK.
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We tested the effect of several K+
channel-blocking agents on dilation to BK (Table 2). In the presence of L-NAME plus INDO,
TEA, a relatively selective blocker of BKCa,
attenuated coronary arteriolar dilation to BK, whereas TBA, a
blocker of both BKCa and
SKCa, reduced dilation even more. Glibenclamide,
a selective blocker of KATP, did not alter
dilation to BK. CTX, a chemically distinct and more selective blocker
of BKCa, markedly reduced dilation to BK. Apamin,
a selective blocker of SKCa, decreased the
ED50 value. In addition to inhibiting the maximal
dilation to BK, combined treatment with CTX and apamin or use of apamin
alone reduced ED50 (Table 2). In vessels
from 6 patients, CTX was administered in the absence of L-NAME and
INDO. As seen in Figure 8, CTX
alone markedly attenuated dilation to BK (P<0.05).
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To link the effects of K+ channel blockers on
diameter with changes in Em, we performed separate studies in which
both were recorded simultaneously (Figure 9). Treatment with L-NAME plus INDO had
no effect on resting Em or vascular tone. BK produced dilation
(69±6%) and membrane hyperpolarization. The
inhibitory effect of CTX (22±6% versus control;
P<0.05) or apamin (45±10% versus control;
P<0.05) on vasodilation to BK was associated with a
parallel reduction in membrane hyperpolarization,
whereas glibenclamide (66±7% vasodilation) did not affect either
parameter. Therefore,
Ca2+-activated K+
channels play a key role in dilation to BK, inducing membrane
hyperpolarization in VSMCs in human
coronary resistance vessels.
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Presence of disease and age and sex of the patients posed no significant influence on vasodilation in these experiments. However, all but 10 patients had CAD, and only 6 had no preexisting conditions. This limits the degree to which external validity regarding the influence of CAD can be imputed from the results.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study is the first to determine the role of vascular smooth muscle hyperpolarization in dilation of human coronary arterioles to BK. The major new findings are 3-fold. First, vasodilation of human coronary arterioles to BK is dependent on membrane hyperpolarization of VSMCs, largely through mechanisms other than activation of NO synthase and cyclooxygenase. Second, activation of both BKCa and SKCa channels contributes to membrane hyperpolarization and relaxation. Third, NO-induced dilation of human coronary arterioles is associated with much less membrane hyperpolarization than is dilation to BK. Taken together, these findings suggest that EDHF plays an important role in regulating human coronary arteriolar tone. These conclusions are confined to atrial arterioles; ventricular vessels may respond by different mechanisms.
Role of NO and Cyclooxygenase in
Vasodilation to BK
In animal models, activation of endothelial
B2 receptors stimulates NO synthase and
phospholipase A2 to release NO and vasoactive
metabolites of arachidonic acid,
respectively.1 2 15 NO plays a major role in
endothelium-dependent vasodilation in conduit vessels,
whereas factors other than NO contribute more to the microvascular
response in perfused rat hearts, intact canine hearts, and isolated
coronary arterioles.1 2 8 16 17 This is
consistent with reports that endothelial NO
synthase activity is lower in resistance arteries than in conduit
arteries.8 18
NO synthase inhibitors only modestly reduce vasodilation to endothelium-dependent agents in human coronary arteries.19 20 Acetylcholine-induced increases in coronary flow in patients are also independent of NO.21 These findings are consistent with those of the present study suggesting that factors other than NO play a prominent role in endothelium-dependent vasodilation to BK in human coronary arterioles. However, this conclusion is made indirectly, because it is not possible to measure NO release in individual microvessels. Furthermore, the conclusion is based on the efficacy of 10-4 mol/L L-NAME in inhibiting NO synthase. Although higher doses may be necessary in some preparations,22 23 in our laboratory this same dose inhibits human coronary arteriolar dilation to adrenomedullin by >50% (unpublished observations).
In the present study, addition of INDO, a cyclooxygenase inhibitor, to L-NAME did not further reduce vasodilation to BK (data not shown; n=3). This is consistent with reports that cyclooxygenase-derived vasoactive substances such as PGI2 do not contribute to endothelium-dependent vasodilation in coronary arteries from animals and humans.2 8 9 17 20 24
Role of K+ Channel Activity
The portion of the endothelium-dependent
vasodilation resistant to inhibition of NO synthase and
cyclooxygenase is thought to be mediated by an
endothelium-derived substance25 that
activates K+
channels,2 26 27 hyperpolarizes VSMCs,14 and
has been termed EDHF. Kemp and Cocks20 and Ohlmann et
al24 reported a prominent contribution of
K+ channel activation to BK-induced
vasorelaxation in human coronary arteries. In the present
study, inhibition of changes in membrane potential with exogenous KCl
markedly diminished vasodilation to BK in human coronary
resistance arteries, implying that K+ channels
play a critical role.
We demonstrated that TBA, a blocker of BKCa and SKCa,28 reduces vasodilation to BK more than does TEA, which is primarily a blocker of BKCa channels. Furthermore, CTX or apamin decreased sensitivity, whereas their combination reduced both maximal response and sensitivity. However, glibenclamide, a selective blocker of KATP channels, had no effect. These results are consistent with those of Dong et al,29 who demonstrated that vasorelaxation of rabbit carotid artery to acetylcholine is completely inhibited by CTX and is partially inhibited by apamin. A similar role for CTX and apamin-sensitive potassium channels in vasorelaxation to BK and acetylcholine has been demonstrated in a variety of other models.26 30 These findings are consistent with our observations that both BKCa and SKCa K+ channels contribute to BK-induced vasodilation in human coronary arterioles.
Membrane Hyperpolarization and
Vasodilation
EDHF has been defined pharmacologically as
endothelium-dependent vasorelaxation resistant
to inhibition of NO synthase and
cyclooxygenase.2 9 14 25 A limitation
of this definition is the failure to include frank
hyperpolarization in association with vasodilation.
In the present study, we demonstrated that BK-induced changes in
membrane potential correlate with endothelium-dependent
vasodilation in human coronary arterioles, consistent
with a role for EDHF.
NO can activate a variety of K+ channels in VSMCs from conduit arteries of several species.31 32 33 In contrast, no role was seen for NO in the Em change to endothelium-dependent vasodilators in canine and rat mesenteric arteries or in rabbit cerebral arteries.34 35 We demonstrated directly that exogenous NO (SNP) induces minor membrane hyperpolarization despite significant dilation. This is consistent with other reports that high extracellular concentrations of KCl do not change vasodilation to exogenous NO in human coronary conduit arteries.20 24 In the present study, a portion of the dilation to BK was blocked by L-NAME, although no effect on membrane potential was observed. This suggests minimal contribution of membrane hyperpolarization to the vasodilation evoked by NO, although it should be considered that the dose of L-NAME may not have been sufficient to alter membrane potential.
Potential Limitations
Potassium channel blockers may act on the
endothelium as well as vascular smooth muscle,
potentially blocking the release or synthesis of relaxing
factors.36 Ishizaka and Kuo37 showed that
KATP channels in porcine coronary
arteriolar endothelial cells are important in dilation
to hyperosmolarity. However, there are no investigations of the effect
of K+ channel blockers on the
endothelial synthesis or release of EDHF. Increases in
endothelial K+ efflux and
[Ca2+]i to shear stress
are not altered by K+ channel-blocking agents in
endothelial cells of bovine aorta and calf
pulmonary arteries.38 Consistent with
these results, KCl does not alter the release of
PGI2 or NO to BK in endothelial
cells from bovine aorta.39 This finding suggests that
endothelial metabolism of
arachidonic acid or EDHF-mediated vasodilation to BK is
not affected by blocking endothelial
K+ channels. Nevertheless, we have not excluded a
potential role for endothelial
KCa channels in the dilation to BK.
This study found a limited contribution of NO to BK-induced dilation in human coronary arterioles. Because all but 6 patients had CAD or coronary risk factors, we cannot exclude the possibility that the presence of conduit coronary atherosclerosis reduced the contribution by NO to coronary vasomotor response.40 However, inhibition of NO synthase in patients with angiographically normal coronary arteries does not affect basal or stimulated coronary blood flow responses to acetylcholine,41 suggesting an important role for other factors such as EDHF in the normal human coronary microcirculation. Analysis of risk factors for CAD showed no influence of hypertension, hypercholesterolemia, diabetes mellitus, sex, or age on vasodilator or membrane potential responses.
A limitation of the present study is the lack of a true control group, because healthy individuals do not undergo cardiopulmonary bypass. We attempt to deal with this limitation in a statistical fashion, identifying the influence of individual risk factors; however, conclusions are limited to patients with heart disease, and postulations about normal human coronary physiology are inferential.
Clinical Implications
Studies in both animals and humans demonstrate that diabetes
mellitus,42 hypertension,43
hypercholesterolemia,44 and
atherosclerosis45 reduce
endothelium-dependent vasodilation by impairment of
NO-mediated mechanisms. This could be explained by the demonstration
that in disease states, hyperpolarizing mechanisms may be preserved or
even play an enhanced role in regulating vascular
tone.46 47 Thus, the observation of a prominent role for
EDHF in human coronary arteriolar dilation may be a reflection
of normal physiology or a compensatory response to loss of NO.
In summary, vasodilation of human coronary arterioles to BK is largely dependent on membrane hyperpolarization, whereas vasodilation to exogenous NO is less dependent. The vasodilator response to BK is mediated largely by activation of large- and small-conductance Ca2+-activated K+ channels, with a lesser contribution by NO. These findings indicate a prominent role for EDHF in regulating human coronary arteriolar tone.
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Acknowledgments |
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This study was supported by a Fellowship Grant from the American Heart Association, Iowa Affiliate; a grant from the NHLBI (HL-52869); and a merit award from the Veterans Administration. Dr Gutterman is the recipient of an AHA Established Investigator Award. We wish to acknowledge the expert statistical consultation provided by Fausto Loberiza, MD; the technical assistance of Michael Breu; and the secretarial help provided by Kari Beyar.
Received December 31, 1998; revision received April 1, 1999; accepted April 1, 1999.
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