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Effect of ATP-Sensitive Potassium Channel Inhibition on
Coronary Metabolic Vasodilation in Humans
H.M. Omar Farouque, Stephen G. Worthley, Ian T. Meredith
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Objective—Experimental evidence indicates that ATP-sensitive potassium (KATP) channels regulate coronary blood flow
(CBF). However, their contribution to human coronary metabolic vasodilation is unknown.
Methods and Results—Seventeen patients (12 male, age 58⫾10 years) were studied. Coronary hemodynamics were
assessed before and after KATP channel inhibition with subselective intracoronary glibenclamide infused at 40 ␮g/min
in an angiographically smooth coronary artery after successful percutaneous coronary intervention to another vessel.
Metabolic vasodilation was induced by 2 minutes of rapid right ventricular pacing. Coronary blood velocity was
measured with a Doppler guidewire and CBF calculated. The time course of hyperemia was recorded for 2 minutes after
pacing, and hyperemic volume was estimated from the area under the flow-versus-time curve (AUC). Compared with
vehicle infusion (0.9% saline), glibenclamide reduced resting CBF by 9% (P⫽0.04) and increased resting coronary
vascular resistance (CVR) by 15% (P⫽0.03). Glibenclamide reduced pacing-induced peak CBF (50.8⫾6.8 versus
42.0⫾5.4 mL/min, P⫽0.001), peak CBF corrected for baseline flow (25.1⫾4.6 versus 17.6⫾3.1 mL/min, P⫽0.01), and
increased minimum CVR (2.6⫾0.3 versus 3.1⫾0.3 mm Hg/mL per minute, P⫽0.002). Compared with vehicle,
glibenclamide reduced total AUC at 2 minutes (3535⫾397 versus 3027⫾326 mL, P⫽0.001).
Conclusions—Vascular KATP channels appear to be involved in functional coronary hyperemia after metabolic stimulation.
(Arterioscler Thromb Vasc Biol. 2004;24:905-910.)
Key Words: blood flow 䡲 ion channels 䡲 sulfonylurea 䡲 vasoconstriction 䡲 coronary circulation
T
he increase in coronary blood flow (CBF) associated
with increased myocardial metabolism is commonly
referred to as metabolic vasodilation. Several vasodilator
substances produced by the myocardium or from the vascular
endothelium have been proposed as mediators of metabolic
vasodilation including adenosine, nitric oxide, vasodilator
prostanoids, potassium and hydrogen ions, and carbon dioxide.1,2 Despite a growth in knowledge on the factors that
mediate metabolic vasodilation, a precise understanding of
this complex phenomenon is still elusive.
Over the past decade, attention has focused on the contribution of the metabolically regulated ATP-sensitive potassium (KATP) ion channel to the control of coronary vascular
tone.3 These channels are found in the vasculature and may
provide a link between cellular metabolism and vascular tone
through its effect on membrane potential. Studies in animals
suggest that vascular KATP channels are involved in the
regulation of resting CBF, reactive coronary hyperemia, and
metabolic coronary vasodilation.3– 6 We have recently demonstrated a role for KATP channels in the regulation of resting
blood flow in the human coronary circulation.7 However, the
importance of KATP channels in mediating metabolic coronary
vasodilation in humans has not previously been assessed.
Accordingly, we sought to determine the contribution of KATP
channels to pacing-induced metabolic coronary vasodilation
in humans.
Methods
Seventeen patients undergoing elective percutaneous coronary intervention for single-vessel coronary artery disease were studied and
their clinical characteristics are displayed in Table 1. Subjects had at
least 1 angiographically smooth or mildly stenosed (⬍20% diameter
stenosis) major epicardial coronary artery that had not been previously instrumented. Coronary flow studies were performed in vessels
fulfilling these criteria after successful percutaneous intervention to
an unrelated stenotic coronary artery. Patients with unstable angina,
significant valvular heart disease, left ventricular ejection fraction
⬍50%, and renal or hepatic disease were excluded. Thirteen patients
(age 57⫾10 years, 10 male) received intracoronary glibenclamide
and 4 patients (age 62⫾8 years, 2 male) participated in reproducibility experiments. The study was approved by the Southern Health
Human Research Ethics Committee, and written informed consent
was obtained before cardiac catheterization.
Intracoronary Doppler Flow Study and
Metabolic Vasodilation
Intracoronary Doppler flow velocimetry was performed as described
previously using a 0.014-inch Doppler guidewire (FloWire; Cardiometrics, EndoSonics).7,8 The study vessel was the left anterior
descending coronary artery in 8 patients, circumflex coronary artery
in 8 patients, and the right coronary artery in 1 patient. Coronary
metabolic vasodilation was achieved by rapid right ventricular
Received February 2, 2004; accepted February 26, 2004.
From the Cardiovascular Research Centre, Monash Medical Centre and Monash University, Melbourne, Australia.
Correspondence to Ian T. Meredith, Cardiovascular Research Centre, Monash Medical Centre, 246 Clayton Road, Clayton, Melbourne, Victoria, 3168,
Australia. E-mail [email protected]
© 2004 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org
905
DOI: 10.1161/01.ATV.0000125701.18648.48
906
TABLE 1.
Arterioscler Thromb Vasc Biol.
May 2004
Patient Characteristics
Total Group
(n⫽17)
Age (y)
58⫾10
Male, n (%)
12 (71)
Risk factors, n (%)
Hypercholesterolemia
Diabetes
Current smoker
Systemic hypertension
Family history of IHD
13 (76)
2 (12)
3 (18)
10 (59)
7 (41)
Body mass index (kg/m2)
28⫾3
N of risk factors per patient*
2.8⫾1.3
Total cholesterol (mmol/L)
4.3⫾1.1
LDL cholesterol (mmol/L)
2.6⫾1.1
Left ventricular ejection fraction (%)
63⫾9
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Data are presented as mean⫾SD.
IHD indicates ischemic heart disease; LDL, low-density lipoprotein.
*Indicates the 5 mentioned risk factors, obesity (body mass index ⬎30kg/
m2), and age ⬎60 years.
pacing at 150 bpm. Pacing was maintained at this rate for 2 minutes
and then ceased abruptly. This method has been shown to induce
reproducible coronary metabolic vasodilation.8 CBF velocity was
recorded for 2 minutes after cessation of pacing, and a flow-versustime curve was constructed to graphically depict the time-course of
pacing-induced hyperemia (Figure I, available online at
http://atvb.ahajournals.org).
Quantitative Coronary Angiography and
Hemodynamic Data
Digital quantitative coronary angiography was performed as previously described using automated edge-detection software (QCACMS version 4.1; MEDIS) by an individual blinded to the study
phase.7 CBF (mL/min) was calculated using the formula, ␲⫻average peak velocity⫻0.125⫻coronary diameter2.9 Coronary vascular
resistance (CVR) (mm Hg/mL per minute) was calculated by dividing mean arterial blood pressure by CBF. Rate-pressure product
(bpm⫻mm Hg), an index of myocardial workload, was computed by
multiplying heart rate and systolic blood pressure. The hyperemic
volume at 2 minutes after cessation of pacing was determined by
calculating the area under the flow-versus-time curve (AUC).
Study Drugs
Glibenclamide lyophilisate (HB 419; Aventis Pharma Deutschland
GmbH, Germany) was used as an inhibitor of vascular KATP
channels. This agent is known to be a specific inhibitor of KATP
channels4,10 and has been used extensively in experimental studies to
examine the role of KATP channels in regulating vascular tone.3–
6,11–16 Glibenclamide was dissolved in 0.9% saline (vehicle) and
infused at 40 ␮g/min into the study vessel through a 2.8-French
infusion catheter (Tracker; Target Therapeutics, Boston Scientific)
by syringe pump at 0.8 mL/min. Assuming a resting CBF rate of 25
to 30 mL/min, this dosing regime would result in an intracoronary
blood glibenclamide concentration of approximately 3 ␮mol/L,
which would be expected to result in unbound drug levels within the
range described to inhibit KATP channel currents in vascular tissue.17
In a previous study, a similar dosing regime induced a significant
reduction of resting CBF.7
Experimental Protocol
The study design is outlined in Figure 1. Vasoactive medication was
discontinued at least 12 hours before the procedure. All patients
Figure 1. The study protocol and the timing of measurements
are illustrated schematically in this diagram. Glib indicates glibenclamide; QCA, quantitative coronary angiography.
received oral doses of aspirin (300 mg) and clopidogrel (300 mg)
before percutaneous coronary intervention, and studies were conducted in a quiet environment with the lights dimmed. Coronary flow
velocity was allowed to return to a stable baseline between vehicle
and glibenclamide infusions. Systemic venous blood samples were
taken before and after glibenclamide infusion for measurement of
plasma glucose, insulin, and C-peptide. Reproducibility of the pacing
protocol was assessed in 4 subjects who underwent 2 separate
periods of ventricular pacing but received vehicle infusion only.
Statistical Analysis
Clinical characteristics are expressed as mean⫾SD. Other values are
reported as mean⫾SEM. Hemodynamic and biochemical data were
analyzed using the 2-tailed paired Student t test. Paired data that did
not conform to a normal distribution were analyzed using the
Wilcoxon signed-rank test. Two-way repeated measures analysis of
variance was used to analyze pacing-induced changes in CBF from
baseline before and during glibenclamide. During both saline and
glibenclamide infusions, pacing-related hemodynamic parameters
were compared with the resting state immediately before initiation of
pacing. Peak hyperemic CBF (peak CBF) and hyperemic volume
induced by pacing (AUC) were corrected for changes in baseline
flow immediately before pacing by subtracting the latter value;
P⬍0.05 was considered statistically significant.
Results
Pacing Reproducibility
Four subjects underwent 2 periods of pacing to assess
reproducibility of the pacing protocol. Pacing induced reproducible hyperemic responses (Table I, available online at
http://atvb.ahajournals.org).
Effect of Glibenclamide on Resting Coronary Tone
Intracoronary glibenclamide infusion at 40 ␮g/min was not
associated with changes in heart rate (69⫾3 versus 68⫾3
bpm, P⫽NS), mean arterial pressure (109⫾5 versus
108⫾5 mm Hg, P⫽NS), or rate-pressure product (9808⫾665
versus 9898⫾658 bpm䡠mm Hg, P⫽NS) compared with vehicle infusion. A small vasoconstrictor effect was noted with a
4% reduction in conduit coronary artery diameter compared
with baseline (2.23⫾0.09 versus 2.15⫾0.09 mm; P⫽0.04;
Figure 2). Glibenclamide did not significantly alter resting
CBF velocity (22.8⫾2.4 versus 21.9⫾2.5 cm/second;
P⫽0.20; Figure 2). Compared with vehicle, glibenclamide
reduced resting CBF by 9% (P⫽0.035; Figure 2) and increased coronary vascular resistance by 15% (P⫽0.028;
Figure 2).
Farouque et al
KATP Channels and Metabolic Coronary Vasodilation
907
Figure 2. Effect of vehicle and glibenclamide infusions on resting coronary
hemodynamics: epicardial diameter (A);
coronary blood flow velocity (B); basal
coronary blood flow (C); and basal coronary vascular resistance (D). *P⬍0.05
versus vehicle.
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Effect of Glibenclamide on
Pacing-Induced Hyperemia
Rapid ventricular pacing during vehicle infusion did not alter
coronary artery diameter measured at 2 minutes after cessation of pacing compared with baseline (2.23⫾0.09 to
2.23⫾0.10 mm). However, pacing during glibenclamide infusion resulted in a trend to epicardial vasoconstriction
(2.15⫾0.09 to 2.09⫾0.09 mm, P⫽0.06). Glibenclamide also
resulted in a trend to reduction of peak CBF velocity
compared with vehicle (42.8⫾4.4 versus 40.6⫾4.2 cm/second; P⫽0.12). Pacing increased CBF by 100% during vehicle
infusion, from 25.4⫾3.8 to 50.8⫾6.8 mL/min. Notably,
glibenclamide attenuated the increase in CBF induced by
pacing to 74% from 24.2⫾3.6 to 42.0⫾5.4 mL/min (P⫽0.03;
analysis of variance; Figure II, available online at http://
atvb.ahajournals.org). Peak CBF was 17% less during glibenclamide infusion compared with vehicle infusion
(P⫽0.001; Table 2). Compared with vehicle infusion, the
functional hyperemic volume induced by pacing at 2 minutes
was reduced by glibenclamide (3535⫾397 versus 3027⫾326
mL; P⫽0.001, Table 2). When corrected for changes in
baseline coronary flow before the initiation of pacing, the
differences in peak CBF and hyperemic volume remained
significant (Table 2). Coronary vascular resistance decreased
by 49% from 5.2⫾2.6 to 2.6⫾0.3 mm Hg/mL per minute
during pacing with vehicle (P⬍0.001). During glibenclamide
infusion, the reduction in CVR was attenuated to a 43%
decrease, from 5.5⫾0.7 to 3.1⫾0.3 mm Hg/mL per minute.
Minimum CVR after pacing was 19% greater with glibenclamide (P⫽0.002; Table 2). Mean heart rate, arterial pressure, and rate-pressure product were similar during each of
the pacing runs (Table 2).
Humoral Parameters
There were no changes in plasma glucose levels before and
after glibenclamide infusion (5.6⫾0.4 versus 5.6⫾0.4 mmol/L;
P⫽NS). However, there was an increase in plasma insulin
concentrations from 10.3⫾6.1 to 16.4⫾3.9 mU/L (P⫽0.06).
C-peptide levels were also increased from 0.9⫾0.1 to
1.1⫾0.1nmol/L (P⫽0.04), indicating that the increase in insulin
during the study was related to pancreatic insulin secretion.
Discussion
In this study, we confirm that coronary vascular KATP channel
inhibition produces an increase in basal coronary vascular
tone in angiographically smooth coronary arteries of patients
with coronary atherosclerosis. Importantly, we demonstrate
for the first time to our knowledge that coronary vascular
KATP channel inhibition with glibenclamide results in attenuation of the coronary vasodilation induced by pacing
TABLE 2. Effect of Pacing on Systemic and Coronary
Hemodynamic Parameters
Heart rate (bpm)
Mean arterial pressure (mm Hg)
Vehicle
Glibenclamide
P
151⫾1
151⫾1
NS
108⫾5
110⫾5
NS
16658⫾992
16934⫾976
NS
Peak CBF (mL/min)
50.8⫾6.8
42.0⫾5.4
0.001
⌬Peak CBF (mL/min)
25.1⫾4.6
17.6⫾3.1
0.01
Rate-pressure product
(bpm 䡠 mm Hg)
Minimum CVR (mm Hg/mL per min)
AUC (mL)
⌬AUC (mL)
2.6⫾0.3
3.1⫾0.3
0.002
3535⫾397
3027⫾326
0.001
834⫾223
418⫾154
0.02
⌬Peak CBF was calculated by subtracting baseline flow from peak CBF to
account for differences in baseline CBF.
AUC indicates area under the flow–time curve over 2 minutes and is a
reflection of the hyperemic volume induced by pacing.
⌬AUC refers to the hyperemic volume corrected for baseline flow.
P values refer to paired comparisons of the listed variables between vehicle
(saline) and glibenclamide infusions.
908
Arterioscler Thromb Vasc Biol.
May 2004
tachycardia in humans. This was evident as a modest reduction of peak CBF and in the hyperemic volume after rapid
cardiac pacing during glibenclamide infusion. These findings
imply that KATP channels contribute not only to resting
coronary tone but also to metabolic vasodilation in the human
coronary circulation.
KATP Channels and Resting Coronary Tone
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ATP-sensitive potassium channels are involved in mediating
basal coronary vascular tone in animals. In vivo studies in the
canine and porcine coronary circulations indicate that KATP
channel blockade with glibenclamide reduces basal CBF by
7% to 52%.4,11–13,18 The large variation in the magnitude of
reduction in CBF documented in these studies is probably
related to differences in the experimental model used and the
dose and method of administration of glibenclamide. Our
findings of a significant 9% reduction in resting CBF and a
15% increase in CVR are consistent with the body of
published literature from nonhuman species and humans.7
KATP Channels and Coronary
Metabolic Vasodilatation
Rapid cardiac pacing has been used to study metabolic
coronary vasodilation, avoiding the confounding effects of
catecholamine and autonomic influences associated with
exercise. Katsuda et al demonstrated that coronary vascular
KATP channel blockade reduced pacing hyperemia by 21% in
conscious dogs and 8% in anesthetized dogs,5 with estimated
intracoronary glibenclamide concentrations of 2 to 8 ␮mol/L
and 2 to 12 ␮mol/L, respectively. Our findings in humans
with comparable estimated glibenclamide levels are consistent with these data. However, other studies using pacing in
the presence and absence of adrenoceptor agonists have not
supported a role for KATP channels in these processes.14,19
Although the evidence implicating KATP channels in the
regulation of resting CBF is convincing, this is not the case
for exercise-induced coronary metabolic vasodilation. Studies
in conscious chronically instrumented dogs indicate that
glibenclamide does not attenuate the exercise-induced increase in CBF.4 However, peak CBF at each level of exercise
was reduced compared with corresponding measurements
during vehicle infusion.
Bache et al have examined the interplay between KATP
channels and other vasodilator systems including adenosine
and nitric oxide by simultaneously blocking the effects of
these mediators in the canine coronary circulation.6,20,21 They
postulated that preservation of exercise related flow-reserve
after KATP channel inhibition alone might be caused by a
greater dependence on alternative vasodilator pathways. The
collective blockade of KATP channels, adenosine receptors,
and nitric oxide synthesis resulted in minimal exerciseinduced coronary metabolic vasodilation.6 However, data
from the laboratory of Feigl et al using a similar canine model
have been at variance with these findings.16,22 The reason for
these discrepancies may be related to methodological differences such as the use of intracoronary versus intravenous
glibenclamide. Taken together, these studies suggest that KATP
channels are not essential elements of the coronary vascular
response to exercise in the normal porcine or canine heart.
The activity of KATP channels in vascular tissue may be
different in disease states. The role of coronary vascular KATP
channels has been studied in canine hearts with pressureoverload hypertrophy.23 In this model, KATP channel blockade
significantly blunted the exercise-induced increase in CBF,
unlike the situation in normal hearts. A similar situation exists
in the maintenance of basal coronary tone among hypertensive rats with hypertrophied hearts.15 Although our findings
in the coronary circulation of patients with atherosclerosis
differ from the observations in healthy animal hearts, they are
compatible with results of studies performed in diseased
hearts. Furthermore, KATP channels contribute to coronary
vasodilation during reactive hyperemia4 and when coronary
artery pressure decreases.21 Therefore, activation of KATP
channels may be of particular importance in maintaining
myocardial perfusion in patients with coronary stenoses and
ischemia.
Role of Other Vasoactive Pathways in Humans
In the current study, KATP channel inhibition reduced coronary
metabolic vasodilation by a modest degree, implying that
other mechanisms also contribute to metabolic vasodilation.
Previous studies have examined the role of nitric oxide in
metabolic coronary vasodilation, with most of these reports
demonstrating that epicardial flow-mediated dilation is nitric
oxide dependent.24 –26 However, microvascular vasodilation
in response to pacing may not be dependent on nitric
oxide.8,24,25 Data from our laboratory have also emphasized a
role for vasodilator prostanoids in the regulation of metabolic
vasodilation.8
Adenosine has been proposed as an important endogenous
mediator of metabolic coronary vasodilation.27 However,
published studies in humans have not provided convincing
evidence for this theory. Adenosine receptor blockade with
methylxanthines did not alter pacing-induced coronary flowvelocity in patients with nonstenotic coronary arteries, although volumetric flow was not calculated in this study.28 In
another study, coronary venous adenosine levels did not
increase with cardiac pacing in subjects without risk factors
and angiographically smooth coronary arteries, implying that
endogenous adenosine does not contribute to coronary vasodilation in this setting.29 Edlund et al, using coronary sinus
thermodilution, showed a reduction in exercise-induced coronary hyperaemia with intravenous theophylline.30 However,
their conclusion that adenosine contributes to metabolic
vasodilation has been disputed by others.31 Soluble factors
such as bradykinin, endothelin, and endothelium-derived
hyperpolarizing factor may also be involved. It is evident that
multiple elements including chemical and physical factors
play a role; however, further study is required to correlate
their contribution and interactions to this complex process.
Methodological Considerations
We observed a small increase in plasma insulin and C-peptide
levels in keeping with the known insulinotropic action of
sulfonylureas produced by pancreatic KATP channel inhibition.
Insulin is known to possess vasodilator properties, which in
theory may offset the vasoconstrictor effect observed during
glibenclamide infusion. However, it is unlikely that the small
Farouque et al
KATP Channels and Metabolic Coronary Vasodilation
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changes in insulin would have had a significant impact as its
vasoactive effects are delayed in onset and occur at higher
concentrations than the low physiological levels observed
during this study.32
Ethical considerations preclude the study of subjects without coronary pathology, thus subjects enrolled for this study
had atherosclerotic coronary disease. As such they are likely
to have had impairment in endothelium-dependent vasodilatation, as suggested by the lack of epicardial coronary
dilatation with pacing during vehicle infusion. It is possible
that a functional endothelium may have offset the vasoconstrictor response to KATP channel inhibition, and that our
results may not be applicable in healthy patients with normal
coronary arteries.
The magnitude of contribution by KATP channels to metabolic vasodilation may have been underestimated in this
study because of submaximal metabolic vasodilation. Moreover, a higher dose or longer glibenclamide infusion may
have resulted in greater vascular KATP channel inhibition.33
The fact that a slightly greater reduction in basal CBF was
noted in our previous study is consistent with this notion.7
Study subjects were premedicated with low-dose oral aspirin
(300 mg) before catheterization; however, this is unlikely to
have induced changes in CBF. Oral aspirin doses as high as
650 mg do not appear to alter resting CBF or pacing-induced
hyperemia in patients with coronary disease.34 Coronary
vascular effects of prostanoid inhibition are seen with aspirin
doses in the anti-inflammatory dose range.8
The precise mechanisms leading to activation of vascular
KATP channels during increased metabolic demand could not
be determined from this study. Although adenosine has been
proposed as a mediator of metabolic vasodilation that may act
through KATP channels, this may not be the case in the human
circulation.7,28,35 Indeed KATP channels can be activated by
many different stimuli including altered cyclic nucleotide
levels, certain ions, pH levels, and other endogenous vasoactive substances.17 It is conceivable that these stimuli may play
a role in activating KATP channels during increased metabolic
vasodilation.
Clinical Implications
Activation of KATP channels may provide an important compensatory mechanism to maintain myocardial perfusion in the
presence of coronary artery stenoses. In this regard, potassium channel openers have an important role in the management of patients with ischemic heart disease. The antianginal
efficacy of drugs in this class is related to coronary vasodilation produced by the activation of coronary vascular KATP
channels. The potential efficacy of this class of drugs has
been borne out by the results of the randomized IONA study,
which indicate improved cardiovascular outcomes for patients with chronic stable angina treated with the KATP channel
opener, nicorandil.36
In summary, we have demonstrated that KATP channels are
involved in the regulation of resting CBF and metabolic
coronary vasodilation in the human coronary circulation of
patients with atherosclerosis. This was evident by a reduction
in basal CBF and pacing-induced hyperemia after intracoronary infusion of the KATP channel inhibitor, glibenclamide.
909
Our findings suggest that KATP channels are active in the
human coronary circulation and underscore the importance of
ion channels in the maintenance of vascular tone.
Acknowledgments
HMOF was supported by a National Heart Foundation of Australia
Medical Postgraduate Research Scholarship (PM 98 mol/L 0006).
Glibenclamide lyophilisate (HB 419) was generously supplied by
Aventis Pharma Deutschland GmbH, Frankfurt, Germany. We are
grateful to the personnel of the Cardiac Catheterization Laboratories,
Monash Medical Centre for technical assistance.
References
1. Feigl EO. Coronary physiology. Physiol Rev. 1983;63:1–205.
2. Muller JM, Davis MJ, Chilian WM. Integrated regulation of pressure and
flow in the coronary microcirculation. Cardiovasc Res. 1996;32:
668 – 678.
3. Daut J, Maier-Rudolph W, von Beckerath N, Mehrke G, Gunther K,
Goedel-Meinen L. Hypoxic dilation of coronary arteries is mediated by
ATP-sensitive potassium channels. Science. 1990;247:1341–1344.
4. Duncker DJ, Van Zon NS, Altman JD, Pavek TJ, Bache RJ. Role of
K⫹ATP channels in coronary vasodilation during exercise. Circulation.
1993;88:1245–1253.
5. Katsuda Y, Egashira K, Ueno H, Akatsuka Y, Narishige T, Arai Y,
Takayanagi T, Shimokawa H, Takeshita A. Glibenclamide, a selective
inhibitor of ATP-sensitive K⫹ channels, attenuates metabolic coronary
vasodilatation induced by pacing tachycardia in dogs. Circulation. 1995;
92:511–517.
6. Ishibashi Y, Duncker DJ, Zhang J, Bache RJ. ATP-sensitive K⫹
channels, adenosine, and nitric oxide-mediated mechanisms account for
coronary vasodilation during exercise. Circ Res. 1998;82:346 –359.
7. Farouque HMO, Worthley SG, Meredith IT, Skyrme-Jones RA, Zhang
MJ. Effect of ATP-sensitive potassium channel inhibition on resting
coronary vascular responses in humans. Circ Res. 2002;90:231–236.
8. Duffy SJ, Castle SF, Harper RW, Meredith IT. Contribution of vasodilator prostanoids and nitric oxide to resting flow, metabolic vasodilation, and flow-mediated dilation in human coronary circulation. Circulation. 1999;100:1951–1957.
9. Doucette JW, Corl PD, Payne HM, Flynn AE, Goto M, Nassi M, Segal J.
Validation of a Doppler guide wire for intravascular measurement of
coronary artery flow velocity. Circulation. 1992;85:1899 –1911.
10. Standen NB, Quayle JM, Davies NW, Brayden JE, Huang Y, Nelson MT.
Hyperpolarizing vasodilators activate ATP-sensitive K⫹ channels in arterial smooth muscle. Science. 1989;245:177–180.
11. Imamura Y, Tomoike H, Narishige T, Takahashi T, Kasuya H, Takeshita
A. Glibenclamide decreases basal coronary blood flow in anesthetized
dogs. Am J Physiol. 1992;263:H399 –H404.
12. Samaha FF, Heineman FW, Ince C, Fleming J, Balaban RS. ATPsensitive potassium channel is essential to maintain basal coronary
vascular tone in vivo. Am J Physiol. 1992;262:C1220 –C1227.
13. Davis CA, 3rd, Sherman AJ, Yaroshenko Y, Harris KR, Hedjbeli S,
Parker MA, Klocke FJ. Coronary vascular responsiveness to adenosine is
impaired additively by blockade of nitric oxide synthesis and a sulfonylurea. J Am Coll Cardiol. 1998;31:816 – 822.
14. Aversano T, Ouyang P, Silverman H, Ziegelstein RC, Gips S. Effect of
blockade of the ATP-sensitive potassium channel on metabolic coronary
vasodilation in the dog. Pharmacology. 1993;47:360 –368.
15. Numaguchi K, Egashira K, Sakata M, Shimokawa H, Takeshita A. Coronary vascular ATP-sensitive potassium channels are activated to a
greater extent in spontaneously hypertensive rats than in Wistar-Kyoto
rats. J Hypertens. 1996;14:183–189.
16. Tune JD, Richmond KN, Gorman MW, Feigl EO. K(ATP)(⫹) channels,
nitric oxide, and adenosine are not required for local metabolic coronary
vasodilation. Am J Physiol Heart Circ Physiol. 2001;280:H868 –H875.
17. Nelson MT, Quayle JM. Physiological roles and properties of potassium
channels in arterial smooth muscle. Am J Physiol. 1995;268:C799 –C822.
18. Chen Y, Traverse JH, Zhang J, Bache RJ. Selective blockade of mitochondrial K(ATP) channels does not impair myocardial oxygen consumption. Am J Physiol Heart Circ Physiol. 2001;281:H738 –H744.
19. Richmond KN, Tune JD, Gorman MW, Feigl EO. Role of K⫹ATP
channels in local metabolic coronary vasodilation. Am J Physiol. 1999;
277:H2115–H2123.
910
Arterioscler Thromb Vasc Biol.
May 2004
Downloaded from http://atvb.ahajournals.org/ by guest on May 2, 2017
20. Duncker DJ, van Zon NS, Pavek TJ, Herrlinger SK, Bache RJ. Endogenous adenosine mediates coronary vasodilation during exercise after
K(ATP)⫹ channel blockade. J Clin Invest. 1995;95:285–295.
21. Duncker DJ, van Zon NS, Ishibashi Y, Bache RJ. Role of K⫹ ATP
channels and adenosine in the regulation of coronary blood flow during
exercise with normal and restricted coronary blood flow. J Clin Invest.
1996;97:996 –1009.
22. Richmond KN, Tune JD, Gorman MW, Feigl EO. Role of K(ATP)(⫹)
channels and adenosine in the control of coronary blood flow during
exercise. J Appl Physiol. 2000;89:529 –536.
23. Melchert PJ, Duncker DJ, Traverse JH, Bache RJ. Role of K(⫹)(ATP)
channels and adenosine in regulation of coronary blood flow in the
hypertrophied left ventricle. Am J Physiol. 1999;277:H617–H625.
24. Egashira K, Katsuda Y, Mohri M, Kuga T, Tagawa T, Kubota T,
Hirakawa Y, Takeshita A. Role of endothelium-derived nitric oxide in
coronary vasodilatation induced by pacing tachycardia in humans. Circ
Res. 1996;79:331–335.
25. Goodhart DM, Anderson TJ. Role of nitric oxide in coronary arterial
vasomotion and the influence of coronary atherosclerosis and its risks.
Am J Cardiol. 1998;82:1034 –1039.
26. Quyyumi AA, Dakak N, Andrews NP, Gilligan DM, Panza JA, Cannon
RO, 3rd. Contribution of nitric oxide to metabolic coronary vasodilation
in the human heart. Circulation. 1995;92:320 –326.
27. Berne RM. The role of adenosine in the regulation of coronary blood
flow. Circ Res. 1980;47:807– 813.
28. Rossen JD, Oskarsson H, Minor RL, Jr., Talman CL, Winniford MD.
Effect of adenosine antagonism on metabolically mediated coronary
vasodilation in humans. J Am Coll Cardiol. 1994;23:1421–1426.
29. Minamino T, Kitakaze M, Matsumura Y, Nishida K, Kato Y, Hashimura
K, Matsu-Ura Y, Funaya H, Sato H, Kuzuya T, Hori M. Impact of
coronary risk factors on contribution of nitric oxide and adenosine to
metabolic coronary vasodilation in humans. J Am Coll Cardiol. 1998;31:
1274 –1279.
30. Edlund A, Conradsson T, Sollevi A. A role for adenosine in coronary
vasoregulation in man. Effects of theophylline and enprofylline. Clin
Physiol. 1995;15:623– 636.
31. Tune JD, Richmond KN, Gorman MW, Olsson RA, Feigl EO. Adenosine
is not responsible for local metabolic control of coronary blood flow in
dogs during exercise. Am J Physiol Heart Circ Physiol. 2000;278:
H74 – 84.
32. Baron AD. Hemodynamic actions of insulin. Am J Physiol. 1994;267:
E187–E202.
33. Meisheri KD, Khan SA, Martin JL. Vascular pharmacology of ATPsensitive K⫹ channels: interactions between glyburide and K⫹ channel
openers. J Vasc Res. 1993;30:2–12.
34. Martin JL, Fisher CA, Untereker WJ, Laskey WK, Hirshfeld JW, Jr.,
Harken AH, Addonizio VP. Effect of high dose aspirin on coronary
hemodynamics during pacing-induced myocardial ischemia. J Am Coll
Cardiol. 1985;5:210 –215.
35. Banitt PF, Smits P, Williams SB, Ganz P, Creager MA. Activation of
ATP-sensitive potassium channels contributes to reactive hyperemia in
humans. Am J Physiol. 1996;271:H1594 –H1598.
36. The IONA Study group. Effect of nicorandil on coronary events in
patients with stable angina: the Impact Of Nicorandil in Angina (IONA)
randomised trial. Lancet. 2002;359:1269 –1275.
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Effect of ATP-Sensitive Potassium Channel Inhibition on Coronary Metabolic
Vasodilation in Humans
H. M. Omar Farouque, Stephen G. Worthley and Ian T. Meredith
Arterioscler Thromb Vasc Biol. 2004;24:905-910; originally published online March 11, 2004;
doi: 10.1161/01.ATV.0000125701.18648.48
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272
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*
Coronary Blood Flow (ml/min)
60
50
Final Version: ATVB/2004/013649
II
40
30
P = 0.03
20
10
0
Rest
Pacing
4
Final Version: ATVB/2004/013649
1
On-Line Figure Legend
I. The time-course of hyperemia after the cessation of pacing is displayed in this figure
from an individual patient. Compared to vehicle infusion ( ), glibenclamide (
)
reduced the hyperemic flow response after pacing. The area under the flow-time curve
(AUC) was calculated over a 120 second time period.
II. The effect of vehicle and glibenclamide infusions on pacing-induced coronary blood
flow. Coronary blood flow during vehicle infusion is indicated by the solid line, and
glibenclamide infusion by the dashed line. Data are mean ± SEM. *P<0.05 (ANOVA).
Final Version: ATVB/2004/013649
I
2
Final Version: ATVB/2004/013649
3
TABLE I. PACING REPRODUCIBILITY
Pacing Run #1
Pacing Run #2
47.0 ± 11.8
45.9 ± 12.8
2.8 ± 0.8
3.8 ± 0.9
Hyperemic volume at 2 minutes (mL)
4478 ± 1272
4377 ± 1347
Rate-pressure product (bpm • mmHg)
15410 ± 1112
15746 ± 1123
Peak CBF (mL/min)
Minimum CVR (mmHg/mL /min)
There were no statistically significant differences in coronary hemodynamic variables
or rate-pressure product between the two pacing runs