1146
Role of ATP-Sensitive Potassium Channels
in Coronary Microvascular
Autoregulatory Responses
Tatsuya Komaru, Kathryn G. Lamping, Charles L. Eastham, and Kevin C. Dellsperger
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The purpose of the present study was to test the hypothesis that ATP-sensitive potassium channels
mediate autoregulatory vasodilatation of coronary arterioles in vivo. Experiments were performed
in 23 open-chest anesthetized dogs. Coronary arterial microvascular diameters were directly
measured with fluorescence microangiography using an intravital microscope and stroboscopic
epi-illumination synchronized to the cardiac cycle. A mild coronary stenosis (perfusion pressure=60 mm Hg), a critical coronary stenosis (perfusion pressure=40 mm Hg), and complete
coronary artery occlusion were produced with an occluder around the left anterior descending
coronary artery in the presence or absence of glibenclamide (10-` M, topically), which inhibits
ATP-sensitive potassium channels, or of vehicle. During topical application of vehicle (0.01%
dimethyl sulfoxide), there was dilatation of small (<100 gm diameter) arterioles during reductions
in perfusion pressure (percent change in diameter. 6.7±1.5%, 11.7±3.5%, and 10.4±5.1% during
mild stenosis, critical stenosis, and complete occlusion, respectively). In the presence of glibenclamide, arteriolar dilatations during coronary stenoses and occlusions were abolished. Glibenclamide
did not affect responses of arterioles >100 ,um. Glibenclamide did not alter microvascular
responses to nitroprusside. These data suggest that ATP-sensitive potassium channels play an
important role in determining the coronary microvascular response to reductions in perfusion
pressure. (Circulation Research 1991;69:1146-1151)
T he coronary arterial system autoregulates effectively during reductions in perfusion pressure.1'2 Kanatsuka et a13 and Chilian and
Layne4 independently demonstrated dilatation of
small coronary arterioles during hypotension. Acute
occlusion of a coronary artery also produced dilatation of small arterioles.5
Since Noma6 described an ATP-sensitive potassium channel in the cardiac myocyte, this channel has
been identified in pancreatic p3 cells,7 skeletal muscle,8 the central nervous system,9 and vascular
smooth muscle.10 The opening of this channel is
linked to cellular metabolism as the probability of its
opening increases with deceases in intracellular ATP
levels. Furthermore, it is possible that other nucleotides, change in pH, and other metabolic factors
From the Department of Internal Medicine and The Cardiovascular Center, College of Medicine, University of Iowa, Iowa City,
Iowa.
Supported by Coronary SCOR grant HL-32295. K.C.D. is a
recipient of a Clinical Investigator Award (HL-02198). K.G.L. is a
recipient of a FIRST Award (HL-39050).
Address for correspondence: Kevin C. Dellsperger, MD, PhD,
Department of Internal Medicine and The Cardiovascular Center,
College of Medicine, University of Iowa, E 329-1 General Hospital, Iowa City, IA 52242.
Received January 3, 1991; accepted May 20, 1991.
including adenosine may modulate the opening of
this channel.11'2 Opening of ATP-sensitive potassium channels consequently causes hyperpolarization
of tissues because of K+ efflux.1112 Hyperpolarization
in vascular smooth muscle inhibits the Ca2+ influx via
voltage-dependent Ca2+ channels and leads to vasodilatation. Recently, Daut et al13 have described a
role for the ATP-sensitive potassium channels in
hypoxia-induced coronary vasodilatation in the excised heart. The participation of these channels in
coronary microvascular autoregulatory response in
vivo has not been determined.
The purpose of this study was to test the hypothesis that activation of ATP-sensitive potassium channels mediates autoregulatory vasodilatation of coronary microvessels. We observed the effect of
glibenclamide, a potent and selective inhibitor of
ATP-sensitive potassium channels,'4 on the arteriolar response during autoregulation and ischemia by
means of direct observation of coronary microvessels
in an intact beating left ventricle.
Materials and Methods
General Preparation
Mongrel dogs of either sex (n=23, body weight of
6.5+0.3 kg) were sedated with ketamine (10 mg/kg
Komaru et al ATP-Sensitive K' Channels in Coronary Arterioles
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i.m.) and acepromazine (0.2 mg/kg) and anesthetized
with a-chloralose (75 mg/kg i.v.). Additional doses of
a-chloralose were given as needed to maintain a surgical depth of anesthesia. A catheter (1.7 mm o.d.) was
inserted into the descending thoracic aorta through the
femoral artery for measurement of aortic pressure and
withdrawal of arterial blood for measurement of myocardial perfusion by the radioactive microsphere technique. Another catheter (1.7 mm o.d.) was inserted into
the femoral vein for infusion of fluids.
A cuffed endotracheal tube was inserted into the
trachea. To minimize respiration-induced cardiac
motion, high-frequency jet ventilation synchronized
to cardiac cycles was used, as previously described in
detail.3,5,15,16 Positive end-expiratory pressure was
applied to prevent atelectasis.
A left thoracotomy was performed in the fifth
intercostal space, and the heart was suspended in a
pericardial cradle. A catheter was inserted into the
left atrium through the left appendage for administration of fluorescent dye and radiolabeled microspheres.
A 5F catheter (Millar Instruments, Inc., Houston,
Tex.) was inserted into the left ventricle through the
left atrial appendage for measurement of left ventricular pressure and dP/dt. Heart rate was kept constant
during the experiment by left atrial pacing (152+1
beats/min) after suppression of sinus node activity
with injection of 7% formaldehyde into the region of
the sinus node. Snares were placed around the descending aorta and the inferior vena cava to maintain
systemic pressure at control levels during the experiment. The left anterior descending coronary artery
(LAD) was carefully dissected, and a screw occluder
was placed around the vessel to produce reductions in
perfusion pressure. A 24-gauge catheter was inserted
into a distal branch of the LAD to monitor distal
coronary arterial pressure. The surface of the heart
was kept moist by dripping warmed Krebs' solution
containing (mM) NaCl 118.3, KCl 4.7, CaCl2 2.5,
MgSO4 1.2, NaHCO3 25.0, and KH2P04 1.2 bubbled
with 20% 02, 5% C02, and 75% N2 at the rate of 2
ml/min. Body temperature was maintained with a
servocontrolled thermal blanket.
Microscope and Video System
For direct observation of the coronary microvessels
in the beating left ventricle, we used an intravital
microscope (Zeiss, FRG) equipped with a computerized strobe (Chadwick Helmuth, El Monte, Calif.),
which epi-illuminated the cardiac surface at a single
point in mid diastole during each cardiac cycle. Details
have been described previously.35,15"56 With this system,
fluorescence coronary microangiography was performed. Fluorescein isothiocyanate-dextran (molecular
weight 487,000, Sigma Chemical Co., St. Louis, Mo.)
was injected into the left atrium as a constrast medium.
A x6.3 objective (n.a. 0.2, Zeiss) was used.
Microvascular fluorescent images were transmitted
to a silicon-intensified tube video camera (General
Electric, Owensboro, Ky.) via x 1 or x 6.3 relay lens
and were digitized and displayed on a high resolution
1147
monitor (Panasonic, Japan). Spatial resolution was 8
,um (x 1 relay lens) or 5 ,um (x 6.3 relay lens). Edges
of the enhanced arterioles were traced with a digitizing tablet (Summa Graphics, Cambridge, Mass.), and
their internal diameters were calculated. When arterioles < 100 ,um were observed, we used a x 6.3 relay
lens. Each vessel was measured three times using
different images of the same vessel.
Measurement of Myocardial Blood Flow
Myocardial blood flow was measured with the radioactive microsphere technique, as previously reported.3'5"5"16 Reference blood was collected from the femoral artery at the rate of 1.91 ml/min with a Harvard
pump (Dover, Mass.). At the end of the experiment,
the heart was excised, and tissue samples were cut from
the ischemic area (LAD perfusion area). Radioactivity
of tissue samples and reference samples was counted
with a germanium crystal gamma counter17 (Canberra
Industries Inc., Meriden, Conn.), and myocardial blood
flow (MBF, ml/min/100 g) was calculated using the
following equation:
MBF=(CmxWRx 100)/Cr
where Cm is radioactivity per weight (g) of tissues,
WR is withdrawal rate of the reference blood sample
(ml/min), and Cr is total radioactivity of the reference blood sample.
Protocols
After the surgical procedure and instrumentation,
at least 30 minutes was allowed for stabilization of
the monitored variables. Microvessels for observation
were selected in the region of cyanosis produced by a
brief coronary occlusion. In 11 dogs, after control
measurements of hemodynamics, microvascular diameter, and myocardial perfusion, glibenclamide (final concentration, 10-5 M) was superfused onto the
surface of the heart via a side port into the suffusion
solution and continued until the end of the experiment (glibenclamide group). Glibenclamide potassium salt (The Upjohn Co., Kalamazoo, Mich.) was
dissolved in Krebs' solution containing dimethyl sulfoxide (final concentration, 0.01 vol%). Twenty minutes after superfusion of glibenclamide, the LAD
screw occluder was tightened to sequentially reduce
perfusion pressure to 60 mm Hg (mild stenosis), 40
mm Hg (severe stenosis), and a complete occlusion.
Complete occlusion usually caused mild systemic
hypotension. Arterial pressure was returned to control levels by tightening the aortic snare. After stabilization at each level of stenosis (minimum of 10
minutes), microvascular images, hemodynamics, and
myocardial perfusion were measured. One dog died
of ventricular fibrillation during complete occlusion.
In another 12 dogs, the effect of vehicle was tested
(vehicle group). The experimental procedures and protocol were the same as above except that vehicle
(0.01% dimethyl sulfoxide solution) was superfused
instead of glibenclamide. In the vehicle group, one dog
1148
Circulation Research Vol 69, No 4 October 1991
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TABLE 1. Transmural Coronary Flow, Coronary Perfusion Pressure, and Blood Gas Analysis at Each Stenosis Level
Mild
Critical
Vehicle/
Control
glibenclamide
stenosis
stenosis
Vehicle group
91±5
Coronary perfusion pressure (mm Hg)
61±1
40±1
89+4
139±22
154±20
83±10*
Ischemic zone flow (ml/min/100 g)
121+12
157±18
152±22
Normal zone flow (ml/min/100 g)
146±14
158±20
7.35±0.01
7.32±0.01
7.33±0.01
7.32±0.01
pH
33±1
32±1
32±1
Pco2 (mm Hg)
32+1
108±6
102±5
105±6
106±7
Po2 (mm Hg)
Glibenclamide group
96±4
99±4
62±2
Coronary perfusion pressure (mm Hg)
41±1
116±14
145±22
136±13
70±10*
Ischemic zone flow (ml/min/100 g)
146±17
147±12
130±10
142±16
Normal zone flow (ml/min/100 g)
7.39±0.01
7.39+0.01
7.38±0.01
7.37±0.02
pH
33±1
31±1
30±1
Pco2 (mm Hg)
30±1
99±5
101+4
P02 (mm Hg)
98±4
98±4
Complete
occlusion
26±2
29±9*
221±35
7.33±0.02
32±2
97±4
27±2
33±10*
193+16
7.36±0.02
30+1
94±4
Values are mean±SEM.
*p<0.05 vs. Control.
died of ventricular fibrillation during the critical stenosis, and three dogs died during complete occlusion.
At the end of the experiment, Evans blue dye
(1.25%) was injected through the distal coronary
catheter to stain the ischemic region. Observed microvessels were located at least 5 mm within the
border of the ischemic area.
In an additional three dogs, the effect of glibenclamide on nitroprusside-induced vasodilatation was
evaluated to exclude a nonspecific inhibitory effect of
glibenclamide on smooth muscle relaxation in arterioles. Nitroprusside (10-` M, Sigma Chemical) was
superfused in the absence and presence of glibenclamide (10-5 M). Changes in diameters produced by
nitroprusside were measured after 10 minutes.
Statistical Analysis
All values are presented as mean±SEM. Leastsquares regression analysis (polynomial) was performed to investigate the relation between control
arteriolar diameter and vascular response. Arterioles
were divided into two groups according to control sizes,
small arterioles (<100 ,um) and large arterioles (>100
,gm). One-way analysis of variance was used to evaluate
the changes in hemodynamic variables, regional coronary blood flow, blood gases, and microvascular diameters. Student's t test for paired samples or nonpaired
samples with Bonferroni correction was used for individual comparisons. Differences were considered significant atp<0.05.
Results
Hemodynamics and Blood Gases
In the vehicle group, systolic, diastolic, and mean
aortic pressures during control conditions were
105+4, 79+5, and 91±5 mm Hg, respectively. In the
glibenclamide group, these values were 111+4, 87+4,
and 97+4 mm Hg, respectively. In both groups, aortic
pressure was constant during the experiments. Po2,
PCO2, and pH were maintained within the physiological range during the experiments (Table 1).
Transmural coronary blood flow and coronary perfusion pressure during each level of stenosis are
shown in Table 1. There were no differences in
coronary perfusion pressure between the glibenclamide and vehicle groups during each experimental
condition (Table 1). Transmural coronary flow during a mild stenosis was not significantly different from
control. Coronary flow was significantly reduced by a
critical stenosis and complete occlusion.
Microvascular Response
Control microvascular diameters were not significantly different between vehicle and glibenclamide
groups in either small or large arterioles. Vehicle
itself did not alter microvascular diameters, as shown
in Figure 1A (small arterioles: 68±5 ,um before and
67±5 gm after vehicle, p=NS; large arterioles:
170±18 gm before and 165±19 ,um after vehicle,
p=NS). In the vehicle group, small arterioles dilated
during a mild stenosis, whereas larger arterioles did
not change (Figure 1B). During a critical stenosis and
complete occlusion, dilatation in small arterioles was
observed (Figures 1C and 1D, respectively). Large
arteriolar diameters decreased during complete occlusion (Figure 1D). Degrees of microvascular responses were significantly correlated to control diameters in all three perfusion pressure levels.
Glibenclamide itself did not cause a significant
change in microvascular diameters, as shown in Figure 2A (small arterioles: 59±5 ,um before and 55±5
,um after glibenclamide, p=NS; large arterioles:
167±14 ,m before and 160±14 ,um after glibenclamide, p=NS). In contrast to vehicle, small arterioles
did not dilate during a mild stenosis or severe stenosis in the presence of glibenclamide (Figures 2 and
3). During a complete occlusion, glibenclamide reversed the vasodilatation to marked vasoconstriction.
Komaru et al ATP-Sensitive K' Channels in Coronary Arterioles
A. Vehicle
B. Vehicle and mild coronary stenosis
C. Vehicle and critical coronary stenosis
D. Vehicle and coronary occlusion
1149
50
Change
In
Diameter (%)
40
30
20
10
0
-10
-20
-30
-0
-5
so
40
a
0tsjX
20
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Change
10
-10
-20
-30
-40
-50
0
0~~~
In
Diameter (%)
r=y_0.474X+1.05 2e X2
~~~44'~8 y-28.2_O.27x.4.89-4X2
~~~.~ r=0.62 pcO.05
100
200
300
100
200
300
(gm)
FIGURE 1. Scatter diagrams showing the arteriolar response (12 dogs) during superfusion of vehicle alone (panel A), during a
mild coronary stenosis with vehicle (panel B, coronary perfusion pressure=61+1 mm Hg), during a critical coronary stenosis with
vehicle (panel C, coronary perfusion pressure=40±1 mm Hg), and during a complete coronary occlusion with vehicle (panel D,
coronary perfusion pressure=26+2 mm Hg). Shaded area, small arterioles; nonshaded area, large arterioles; NS, not significant.
Regression analysis shows that microvascular response to reduction of perfusion pressure was significantly related to control
diameters (panels B, C, and D). The x axis intercept of regression lines was 146, 139, and 105 um during mild stenosis, critical
stenosis, and complete occlusion, respectively.
Control Diameter (gm)
Large arteriolar diameters were not different between the vehicle- and glibenclamide-treated groups
(Figure 3).
In another three dogs, the effect of glibenclamide
on nitroprusside-induced dilatation was investigated.
In large (n=4) or small (n=5) arterioles, the nitroprusside-induced dilatation was not altered by glibenclamide (large arterioles: 9.4+±4.1% before and
16.4±5.8% after glibenclamide, p=NS; small arterioles: 20.9±5.4% before and 25.8±5.7% after glibenclamide, p=NS).
Discussion
The present study provides evidence that ATPsensitive K' channels play an important role in
regulating coronary blood flow. Under control conditions, a reduction in perfusion pressure caused
small arterioles to dilate. This result is consistent
with several previous investigations,3-5 although
Chilian and Layne4 reported that larger arterial
microvessels also participate in the autoregulatory
response. Daut et al'3 suggested that ATP-sensitive
K' channels may mediate ischemia-induced vasodilation in the excised heart as well as hypoxia-induced
coronary vasodilation. In the present study, glibenclamide abolished arteriolar vasodilations in re-
Control Diameter
sponse to reduction in perfusion pressure yet did not
reduce dilator responses to nitroprusside. Because
glibenclamide is a potent and specific inhibitor of
ATP-sensitive K' channels,14 the data indicate that
ATP-sensitive K' channels mediate the arteriolar
responses to reductions in coronary perfusion pressure and suggest that a common mechanism may
mediate vasodilation during autoregulation, critical
stenosis, and complete occlusion.
Methodological Consideration
To produce the reduction of perfusion pressure,
the LAD was dissected, and a snare was placed
around it. Implantation of devices around the LAD
and surgical treatment is known to impair autonomic
tone.18 Furthermore, a-chloralose, which was used in
this study, may also modulate the autonomic tone.
However, the autoregulatory response is basically an
intrinsic phenomenon that can occur in the absence
of extrinsic influences such as neural or humoral
factors. Furthermore, the instrumentation and procedures were applied to both vehicle and glibenclamide groups in the same manner. Accordingly, the
conclusion drawn in the present study cannot be
affected by these factors.
1150
Circulation Research Vol 69, No 4 October 1991
B. Gllbenclamwde
and mild coronary stenosis
A. Gllbenclamide
s0
Change
In
Diameter (%)
r=0.20 NS
40
30
20
10
0
%
0
.10
.20
r=0.39 NS
0
l
.1.0
0
0
-0
.40
-0
C. Glibencamide and critical coronary stenosis
D. Gllbenclanide and coronary occlusion
50
40
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Change
In
Diameter (%)
,ME_
r=0.47 NS
30
20
10
0
-10
|
~~~~~~r=0.21
NS
0
0
.~~~~~
_
0~~~~~~~~~~~
0 0~~~~~~~~
t
0
0
0
0
.20
-0
00
0
0
0
40
.50
0
100
300
200
Control olamwter
")
100
200
Control DIameter
300
(r)
FIGURE 2. Scatter diagrams showing arteriolar response (11 dogs) during superfusion ofglibenclamide (10`5) alone (panel A),
during a mild coronary stenosis with glibenclamide (panel B, coronary perfusion pressure=62+2 mm Hg), during a critical
coronary stenosis with glibenclamide (panel C, coronary perfusion pressure =41+1 mm Hg), and during a complete coronary
occlusion with glibenclamide (panel D, coronary perfusion pressure=28+2 mm Hg). Shaded area, small arterioles; nonshaded
area, large arterioles; NS, not significant. Note that small arteriolar (<100 ,um) dilatation in response to reduction in perfusion
pressure was blocked by glibenclamide.
In our system, spatial resolution is 5 gm, and the
changes in microvascular diameter by reduction in
perfusion pressure were greater than the minimal resolution. These microvascular responses to reduction in
perfusion pressure were reproducible, since other investigators3'5 have reported the similar results.
Potential Mechanisms for Autoregulatory and
Ischemic Vasodilatation in the Coronary Circulation
ATP-sensitive K' channels have been shown to be
linked to intracellular ATP levels.'1 The present
study suggests that autoregulatory microvascular vasodilatation was mediated, at least in part, by an
electrophysiological phenomenon that was modulated by the metabolism of vascular smooth muscle.
The ATP level of microvascular smooth muscle during autoregulation has not yet been determined. In
ischemic myocardium, the level of ATP does not
decrease until later phases of ischemia.19 However,
studies by Jones20 have suggested that intracellular
ATP is compartmentalized and that a gradient of
intracellular ATP concentration exists from mitochondria to the cell membrane. If this is the case in
coronary arteriolar smooth muscle, the ATP concentration in the vicinity of this channel may be low
enough to cause opening of these channels.
The ATP-sensitive K' channel is also known to be
regulated by receptor-operated mechanisms.14 In insulinoma cells, somatostatin and galanin increase the
opening probability of this channel to secrete insulin.14 Recently, Kirsch et a121 have shown that the
A,-adenosine receptor is linked to ATP-sensitive
potassium channels via Gi protein in the cardiocyte.
Protein kinase C has also been suggested to modulate
the opening in insulinoma cells.14 The roles of G
protein or protein kinase C in autoregulation or
ischemic vascular response in coronary arterial system remain undetermined.
Effect of Glibenclamide on Large Coronary Arterioles
In large arterioles (>100 ,um), glibenclamide did
not cause a significant change in vascular response to
reductions in perfusion pressure. Diameters of large
arterioles remained at control level during a mild and
critical stenosis despite reduction in distending pressure, demonstrating there may be some change in
vascular tone in large arterioles as well as small ones.
However, results by others3-5 suggest that, in autoregulatory vasodilatation, the role of large arterioles
is minimal. Therefore, the absence of effect with
glibenclamide during decreases in perfusion pressure
in large arterioles is not surprising. This observation,
however, does not necessarily indicate that ATP-
Komaru et al ATP-Sensitive K' Channels in Coronary Arterioles
technical support of Mr. John Clausen. The authors
also wish to thank The Upjohn Co. for the generous
supply of glibenclamide potassium salt.
A. Small artrioles (< 100 rn)
30
21)
'
b
10
-
glibendaam-de
(
0.05
References
vs vehicle
p 0.05 vs control
~~~~~~t
s
Change in
Diamwter (%)
vehicle
*
*p
t
10
O
c
_
0
-10
-2
-0
*t
,
.
a
.-
a
1
B. Large arterioles (> 100 mn)
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20
40
60
60
100
Perfusion pressure (mmHg)
FIGURE 3. Graphs showing microvascular responses to reductions in perfusion pressure in small (panel A, intemal
diameter <100 ban) and large (panel B, intemal diameter
>100 pm) arterioles (23 dogs). * p<O.OS vs. vehicle; tp< 0.05
vs.
1151
control.
sensitive potassium channels do not exist or function
in large arterioles, because passive collapse produced
by low perfusion pressure may have masked the
vasodilatation via this channel.
In summary, glibenclamide significantly attenuated
the small coronary arteriolar response to a reduction
of perfusion pressure without reducing dilator responses to nitroprusside. These results suggested
that ATP-sensitive potassium channels play a crucial
role in autoregulatory coronary microvascular dilatation. Further studies are required to determine the
mechanisms that modulate ATP-sensitive potassium
channels during coronary autoregulation.
Acknowledgments
The authors thank Drs. Frank Faraci, Donald
Heistad, Andreas Muigge, and Allyn Mark for their
critical review of this manuscript. The authors gratefully acknowledge the secretarial assistance of Mrs.
Maureen Kent in preparing the manuscript and the
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KEY WORDS * coronary arterioles * intravital microscopy
autoregulation * ischemia * glibenclamide * microcirculation
Role of ATP-sensitive potassium channels in coronary microvascular autoregulatory
responses.
T Komaru, K G Lamping, C L Eastham and K C Dellsperger
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Circ Res. 1991;69:1146-1151
doi: 10.1161/01.RES.69.4.1146
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1991 American Heart Association, Inc. All rights reserved.
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